osteoprotegerin and Bone-Diseases

Bone remodels via resorption and formation, two phenomena that continuously occur in bone turnover. The RANKL/RANK/OPG pathway is one of the several mechanisms that affect bone turnover. The RANKL/OPG ratio has a substantial role in bone resorption. An imbalance between formation and resorption is related to an increased RANKL/OPG balance. OPG, a member of this system, can bind to RANKL and suppress RANK-RANKL interaction, and subsequently, inhibit further osteoclastogenesis. The serum levels of RANKL and OPG in the bone microenvironment are vital for osteoclasts formation. The RANK/RANKL/OPG system plays a role in the pathogenesis of bone disorders. This system can be considered a new treatment target for bone disorders. Soy isoflavones affect the RANK/RANKL/OPG system through numerous mechanisms. Soy isoflavones decrease RANKL levels and increase OPG levels. Therefore, isoflavones improve bone metabolism and decrease bone resorption. Soy isoflavones decrease serum markers of bone resorption and improve bone metabolism. However, while the available data are promising, the results of several studies reported no change in RANKL and OPG levels with isoflavones supplementation. In this regard, current evidence is insufficient for conclusive approval of the efficacy of isoflavones on RANKL/RANK/OPG and further research, including animal and human studies, are needed to confirm the effect of soy isoflavones on the RANKL/RANK/OPG pathway. This study was a review of available evidence to determine the role of isoflavones in bone hemostasis and the RANK/RANKL/OPG pathway. The identification of the effects of isoflavones on the RANKL/RANK/OPG pathway directs future studies and leads to the development of effective treatment strategies for bone disorders.

Topics: Animals; Bone Density; Bone Diseases; Bone Resorption; Humans; Isoflavones; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Bone is one of the dynamic tissues in the human body that undergoes continuous remodelling through subsequent actions of bone cells, osteoclasts, and osteoblasts. Several signal transduction pathways are involved in the transition of mesenchymal stem cells into osteoblasts. These primarily include Runx2, ATF4, Wnt signaling and sympathetic signalling. The differentiation of osteoclasts is controlled by M-CSF, RANKL, and costimulatory signalling. It is well known that bone remodelling is regulated through receptor activator of nuclear factor-kappa B ligand followed by binding to RANK, which eventually induces the differentiation of osteoclasts. The resorbing osteoclasts secrete TRAP, cathepsin K, MMP-9 and gelatinase to digest the proteinaceous matrix of type I collagen and form a saucer-shaped lacuna along with resorption tunnels in the trabecular bone. Osteoblasts secrete a soluble decoy receptor, osteoprotegerin that prevents the binding of RANK/RANKL and thus moderating osteoclastogenesis. Moreover, bone homeostasis is also regulated by several growth factors like, cytokines, calciotropic hormones, parathyroid hormone and sex steroids. The current review presents a correlation of the probable molecular targets underlying the regulation of bone mass and the role of essential metabolic elements in bone remodelling. Targeting these signaling pathways may help to design newer therapies for treating bone diseases.

Topics: Bone Diseases; Bone Remodeling; Bone Resorption; Cell Differentiation; Humans; Osteoblasts; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD) and is strongly associated with cardiovascular mortality and morbidity. Accumulating evidence over the past decade has challenged the hypothesis of close interaction between bone and VC what raises the possibility of a common underlying pathophysiological mechanism. Lately, bone regulatory proteins such as: osteoprotegerin (OPG) and Receptor Activator for Nuclear Factor κB Ligand (RANKL) has attracted attention of researchers as a possible key mediators of bone-vascular calcification imbalance. The literature search was carried out using the MEDLINE/PubMed database and a combination of keywords and MeSH terms, and only papers published since January 2005 to July 2016 were selected. The search resulted in 562 potential articles. After selection according to the eligibility criteria, 107 studies fulfilled were included (102 full texts and 5 was case reports). OPG and RANKL plays essential role in the regulation of bone metabolism and may be regarded as a possible link between VC, bone and mineral metabolism in CKD patients. Further studies are required to determine the diagnostic significance of these proteins in evaluation of progression and severity of VC process in CKD patients. Finally, the efficacy and safety, especially in regard to VC, of anti-RANKL therapy in CKD patients requires well-designed prospective, randomized trials.

Topics: Animals; Bone Diseases; Humans; Osteoprotegerin; RANK Ligand; Renal Insufficiency, Chronic; Vascular Diseases

There is a well recognized link between the bone and the immune system and in recent years there has been a major effort to elucidate the multiple functions of the molecules expressed in both bone and immune cells. Several molecules that were initially identified and studied in the immune system have been shown to have essential functions also in the bone. An interdisciplinary field embracing immune and bone biology has been brought together and called "osteoimmunology". The co-regulation of the skeletal and immune systems strikingly exemplifies the extreme complexity of such an interaction. Their interdependency must be considered in designing therapeutic approaches for either of the two systems. In other words, it is necessary to think of the osteoimmune system as a complex physiological unit. Denosumab was originally introduced to specifically target bone resorption, but it is now under evaluation for its effect on the long term immune response. Similarly, our current and still growing knowledge of the intimate link between the immune system and bone will be beneficial for the safety of drugs targeting either of these integrated systems. Given the large number of molecules exerting functions on both the skeletal and immune systems, osteoimmunological understanding is becoming increasingly important. Both bone and immune systems are frequently disrupted in cancer; and they may be crucial in regulating tumor growth and progression. Some therapies - such as bisphosphonates and receptor activator of NF-κB ligand (RANKL) targeted drugs - that aim at reducing pathologic osteolysis in cancer may interact with the immune system, thus providing potential favorable effects on survival.

Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bone and Bones; Bone Density Conservation Agents; Bone Diseases; Bone Neoplasms; Bone Remodeling; Bone Resorption; Clodronic Acid; Denosumab; Diphosphonates; Humans; Ibandronic Acid; Imidazoles; Immune System; Osteoclasts; Osteoprotegerin; Pamidronate; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction; Treatment Outcome; Zoledronic Acid

The receptor activator of nuclear factor‑κB ligand (RANKL)/RANK/osteoprotegerin (OPG) system was identified in the late 1990s, ending the search for the specific factors expressed by osteoblasts and stromal cells in order to regulate osteoclastogenesis. The identification of the RANKL/RANK/OPG system was a breakthrough in bone biology; however, the system not only works as a dominant mediator in osteoclast activation, formation and survival, but also functions in other tissues, including the mammary glands, brain and lymph nodes. Evidence has indicated that the existence of the RANKL/RANK/OPG system in these tissues suggests that it may have specific functions beyond those in bone. Disorders of the RANKL/RANK/OPG system are associated with certain human diseases, including postmenopausal osteoporosis, rheumatoid arthritis (RA), bone tumors and certain bone metastatic tumors. Genetic studies have indicated that the RANKL/RANK/OPG system may be a key regulator in the formation of lymph nodes and in the autoimmune disease RA, which further suggests that the immune system may interact with the RANKL/RANK/OPG system. The present review aimed to provide an overview of the role of the RANKL/RANK/OPG system in osteoclastogenesis, bone disease and tissues beyond bone.

Topics: Animals; Bone and Bones; Bone Diseases; Bone Resorption; Humans; Immune System; Organ Specificity; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

RANK and its ligand RANKL are key molecules in bone metabolism and are critically involved in pathologic bone disorders. Deregulation of the RANK/RANKL system is for example a main reason for the development of postmenopausal osteoporosis, which affects millions of women worldwide. Another essential function of RANK and RANKL is the development of a functional lactating mammary gland during pregnancy. Sex hormones, in particular progesterone, induce RANKL expression resulting in proliferation of mammary epithelial cells. Moreover, RANK and RANKL have been shown to regulate mammary epithelial stem cells. RANK and RANKL were also identified as critical mechanism in the development of hormone-induced breast cancer and metastatic spread to bone. In this review, we will focus on the various RANK/RANKL functions ranging from bone physiology, immune regulation, and initiation of breast cancer.

Topics: Animals; Autoimmune Diseases; Bone and Bones; Bone Diseases; Bone Neoplasms; Breast Neoplasms; Cell Transformation, Neoplastic; Female; Humans; Mice; NF-kappa B; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

To review the research progress of the osteogenic effect of strontium (Sr) and its application in the orthopaedics.. The recent literature concerning the osteogenic effect of Sr and its application in orthopaedics at home and abroad was extensively reviewed, and the research and development were summarized.. Both in vivo and in vitro studies showed that Sr could enhance bone formation and inhibit bone resorption. Clinically, Sr was applied for treatment of osteoporosis, composite biomaterials in tissue engineering, and treatment of bone tumors and bone metastases.. Sr is one important combined element of alternative materials in bone tissue engineering, and can strengthen the mechanical and biological properties of the bone replacement material, so it has some development potential in bone tissue engineering.

Topics: Bone and Bones; Bone Density; Bone Diseases; Bone Substitutes; Humans; Osteogenesis; Osteoporosis; Osteoprotegerin; RANK Ligand; Signal Transduction; Strontium; Tissue Engineering

Osteoimmunology is defined as the research area focusing on the crosstalk between the immune system and the muskoskeletal system. After nearly a decade of research, we are now beginning to understand the basic principles of this crosstalk. It seems that almost all immune cells are capable of communicating with osteoblasts, osteoclasts, and their respective progenitors - and vice versa. Diseases that fall into the category of osteoimmunology including osteoporosis, rheumatoid arthritis, and periodontal disease are of particular significance considering their implications in quality of life, their increased incidence in the population, and socioeconomic issues. To better understand the underlying pathogenesis, the main pathways of the crosstalk between the immune system and the muskoskeletal system need to be uncovered. Our current understanding has already provided the scientific basis for the development of targeted therapies. However, the challenge of future studies is to further decipher this crosstalk at cellular and molecular levels.

Topics: Arthritis, Rheumatoid; Bone and Bones; Bone Diseases; Cell Communication; Hematopoietic Stem Cells; Humans; Immunity, Cellular; Osteoblasts; Osteoclasts; Osteoporosis; Osteoprotegerin; Periodontitis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; T-Lymphocytes

Osteoprotegerin (OPG) is a secreted glycoprotein central to bone turnover via its role as a decoy receptor for the receptor activator of nuclear factor kappaB ligand (RANKL) and has traditionally been linked to a number of bone-related diseases. However, there is additional evidence that OPG can promote cell survival by inhibiting TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. As a result, a number of in vitro, in vivo and clinical studies have been performed assessing the role of OPG in tumourigenesis. Similar studies have been performed regarding vascular pathologies, resulting from observations of expression and regulation of OPG in the vasculature. This review aims to provide an update on this area and assess the potential protective or detrimental role of OPG in both vascular pathologies and tumourigenesis.

Topics: Animals; Apoptosis; Bone and Bones; Bone Diseases; Cell Survival; Humans; Immune System; Neoplasms; Osteoprotegerin; RANK Ligand; TNF-Related Apoptosis-Inducing Ligand; Vascular Diseases

Recent studies have suggested that the dys-regulated progressive immune responses in some inflammatory conditions can lead to significantly increased osteoclasts (OC) frequency and activity associated with active bone destruction; termed inflammation-induced bone loss. Among the inflammatory infiltrates, monocytes/macrophages (Mo/MQ), T and B cells, have been well studied and documented as central players in osteoimmunological interactions (osteoimmunology: is an interdisciplinary field linking the immune and skeletal systems). We and others investigated the role(s) of dendritic cells (DC) during inflammation-induced osteoclastogenesis and bone loss. In addition to their innate effector functions, DC are potent professional antigen-presenting cells (APC) involved in triggering and orchestrating adaptive immunity, thereby implicated as potential osteo-immune players. Herein, bone remodeling and DC's biology including their development and functions are reviewed along with the contribution of DC at the crossroad of the osteo-immune interface during the process of inflammation-induced osteoclastogenesis. Furthermore, we provide a summary of recent progress, and discuss a proposed alternative mechanism underlying inflammation-induced bone loss. Understanding the cellular and molecular mechanisms regulating DC's roles in inflammation-induced osteoclastogenesis and bone loss might benefit future treatment approaches, especially if targeting DC can be translated into therapeutic strategies to ameliorate both tissue inflammation and bone destruction during disease progression associated with inflammatory bone diseases.

Topics: Adaptive Immunity; Animals; Bone Diseases; Bone Remodeling; Cytokines; Dendritic Cells; Humans; Immune System Phenomena; Inflammation; Osteoclasts; Osteoprotegerin; RANK Ligand; Signal Transduction; Toll-Like Receptors

Experimental and clinical trials in the field of bone biology helped to clarify the role of receptors, which belong to the tumor necrosis factor family, such as osteoprotegerin and receptor activator of nuclear factor kappaB (RANK), in the regulation of bone remodeling. The ligand of the receptor activator of nuclear factor kappaB (RANKL) is a stimulator of bone resorption, while osteoprotegerin is the soluble "decoy" receptor to RANKL, protecting thereby bone from resorption. Pathological states of bone remodeling (like osteoporosis) are associated with imbalance in the activity of osteoprotegerin and the receptor activator of nuclear factor kappaB. Recent studies, however, also indicate that the osteoprotegerin/RANKL/RANK system has important roles in the regulation of the immune and vascular system as well. In this review we summarize the function and regulation of osteoprotegerin, its role in pathological states--primarily in cardiovascular diseases--and its relevance as a marker of cardiovascular risk. Finally, we present our prospective trial performed among the chronic dialyzed patients, where we examined the association between the cardiovascular mortality, osteoprotegerin levels and the arterial stiffness.

Topics: Aged; Analysis of Variance; Animals; Biomarkers; Blood Flow Velocity; Bone Diseases; Bone Remodeling; Calcinosis; Cardiovascular Diseases; Carotid Arteries; Female; Femoral Artery; Heart Rate; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Osteoprotegerin; Prospective Studies; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Renal Dialysis; Risk Assessment; Risk Factors; Time Factors; Vascular Diseases; Vascular Resistance; Vasodilation

Bone-related diseases, such as osteoporosis and rheumatoid arthritis, affect hundreds of millions of people worldwide and pose a tremendous burden to health care. By deepening our understanding of the molecular mechanisms of bone metabolism and bone turnover, it became possible over the past years to devise new and promising strategies for treating such diseases. In particular, three tumor necrosis factor (TNF) family molecules, the receptor activator of NF-kappaB (RANK), its ligand RANKL, and the decoy receptor of RANKL, osteoprotegerin (OPG), have attracted the attention of scientists and pharmaceutical companies alike. Genetic experiments revolving around these molecules established their pivotal role as central regulators of osteoclast development and osteoclast function. RANK-RANKL signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also fine-tunes bone homeostasis both in normal physiology and disease. In addition, RANKL and RANK have essential roles in lymph node formation, establishment of the thymic microenvironment, and development of a lactating mammary gland during pregnancy. Consequently, novel drugs specifically targeting RANK, RANKL, and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various ailments associated with bone loss, such as arthritis, periodontal disease, cancer metastases, and osteoporosis.

Topics: Adaptor Proteins, Signal Transducing; Animals; B-Lymphocytes; Bone Diseases; Bone Remodeling; Dendritic Cells; Hematopoiesis, Extramedullary; Humans; MAP Kinase Signaling System; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Osteoclastic bone resorption is a critical component of skeletal complications of malignancy including fracture, bone pain, hypercalcemia, and spinal cord compression. Three proteins, RANKL, RANK, and OPG have been recently identified as key determinants of osteoclastogenesis and the regulation of bone resorption. Both RANKL and OPG can be aberrantly regulated in the cancer setting and function as important gatekeepers of tumor-induced osteolytic bone disease. RANKL-induced osteoclastogenesis not only mediates osteolytic bone disease, but also contributes to the pathogenesis of osteoblastic bone disease resulting from tumors. In addition, an important role was recently described for bone marrow derived RANKL to mediate the bone-specific tropism of RANK-expressing tumor cells. This manuscript will review how RANKL contributes to skeletal complications of cancer and the development of targeted, mechanism-based drugs that inhibit RANKL.

Topics: Bone Diseases; Bone Neoplasms; Bone Resorption; Drug Delivery Systems; Humans; Models, Biological; Multiple Myeloma; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

Osteoclasts and osteoblasts dictate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Bone remodeling is a spatially coordinated lifelong process whereby old bone is removed by osteoclasts and replaced by bone-forming osteoblasts. The refilling of resorption cavities is incomplete in many pathological states, which leads to a net loss of bone mass with each remodeling cycle. Postmenopausal osteoporosis and other conditions are associated with an increased rate of bone remodeling, which leads to accelerated bone loss and increased risk of fracture. Bone resorption is dependent on a cytokine known as RANKL (receptor activator of nuclear factor kappaB ligand), a TNF family member that is essential for osteoclast formation, activity, and survival in normal and pathological states of bone remodeling. The catabolic effects of RANKL are prevented by osteoprotegerin (OPG), a TNF receptor family member that binds RANKL and thereby prevents activation of its single cognate receptor called RANK. Osteoclast activity is likely to depend, at least in part, on the relative balance of RANKL and OPG. Studies in numerous animal models of bone disease show that RANKL inhibition leads to marked suppression of bone resorption and increases in cortical and cancellous bone volume, density, and strength. RANKL inhibitors also prevent focal bone loss that occurs in animal models of rheumatoid arthritis and bone metastasis. Clinical trials are exploring the effects of denosumab, a fully human anti-RANKL antibody, on bone loss in patients with osteoporosis, bone metastasis, myeloma, and rheumatoid arthritis.

Topics: Animals; Bone Diseases; Bone Remodeling; Humans; Osteoprotegerin; RANK Ligand

For many bone and joint diseases in humans, including postmenopausal osteoporosis, rheumatoid arthritis, and ankylosing spondylitis, an immune-mediated etiology has either been proven or is considered as a co-factor in pathogenesis. The identification of the receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG)-interplay and the in-depth characterization of the signaling pathways induced upon RANK activation, including molecules such as TNF receptor-associated factor 6 (TRAF6), nuclear factor-kappaB (NF-kappaB), and signal transducer and activator of T cells (STAT)-3, now promise to give the opportunity to target osteoclastogenesis specifically. Additionally, many byways influencing osteoclastogenesis have been elucidated, thus giving rise to additional therapeutic approaches. These are based mainly upon the effects of diverse cytokines on osteoclast differentiation with interleukin (IL)-17 and interferone (IFN)-gamma being most prominent at the moment. The same applies for the recently established signaling pathways in osteoblastogenesis, which have attracted much attention in the recent years. In this respect, much attention has been attributed towards bone morphogenetic proteins (BMPs) and the Wnt signaling cascade. In this review, an overview on the key molecules, which (could) serve as promising targets for novel therapeutic interventions with the aim of enhancing osteoblast formation or suppressing osteoclast development, is given. Further on, antibody-based therapeutical schemes as well as methodologically novel, albeit predominantly theoretical at the moment, strategies in the fight against immune-mediated osteopathologies are discussed.

Topics: Animals; Bone and Bones; Bone Diseases; Cytokines; Humans; Joint Diseases; NF-kappa B; Osteoblasts; Osteoclasts; Osteoprotegerin; RANK Ligand; Signal Transduction; TNF Receptor-Associated Factor 6; Wnt Proteins

Molecular mechanisms of osteoclast formation and activation have been clarified since the discovery of osteoprotegerin (OPG). When receptor activator of NF-kappaB ligands (RANKL) and macrophage colony stimulating factors (M-CSF) bind their receptors RANK and c-fms, respectively, osteoclast precursor cells differentiate into osteoclasts. OPG interferes with the interactions between RANK and RANKL, and inhibits osteoclast formation and function. There is no doubt that RANK, RANKL and OPG are key molecules in osteoclast differentiation and activation in physiological and pathological conditions. This review summarizes mutations of RANK, OPG, RANKL genes found in humans.

Topics: Bone Diseases; Humans; Mutation; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Receptor activator of nuclear factor-kB (RANK), its ligand (RANKL) and its decoy receptor osteoprotegerin (OPG) together play a key role in osteoclastogenesis. Alterations in the RANKL/ OPG ratio are central in the pathogenesis of bone loss, from osteoporosis in all its forms to malignancy-induced bone loss. This fact has led to the search for drugs capable of targeted RANKL inhibition in the management of skeletal disorders associated with bone loss. Promising preclinical data using OPG have paved the way for the development of the new agent denosumab, a high-affinity, high-specificity, fully human monoclonal antibody to RANKL, shown to be able to induce a dose-dependent, rapid, profound and sustained inhibition of bone resorption lasting for months after a single subcutaneous injection in healthy postmenopausal women, men and patients with multiple myeloma or metastatic breast cancer. Data from a phase II study in postmenopausal women with low bone mineral density (BMD) demonstrate that the sustained inhibition of bone resorption induced by three or six monthly subcutaneously administered denosumab was associated with significant increases in BMD for up to two years of treatment. Antifracture efficacy and long-term skeletal and extraskeletal safety of denosumab are being addressed in ongoing phase III trials. The potential of denosumab to prevent bone loss has also been demonstrated in malignancy-induced bone loss. Ongoing studies in rheumatoid arthritis are also promising.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Density; Bone Density Conservation Agents; Bone Diseases; Bone Remodeling; Denosumab; Female; Humans; Injections, Subcutaneous; Male; Neoplasms; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Bone integrity is maintained through a balance between bone formation and bone resorption, and osteoclasts are primary cells involved in bone resorption. Recent studies have revealed an essential role of macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) in the development of osteoclasts, and detailed molecular cascades that induce osteoclast differentiation, activation and apoptosis have been clarified. Osteoclasts are involved in various pathologic conditions, such as osteoporosis, rheumatoid arthritis and tumor-induced bone disease, which are characterized by abnormal bone resorption, and the finding of RANKL has provided us a good therapeutic target for such pathologic conditions.

Topics: Animals; Arthritis, Rheumatoid; Bone Diseases; Bone Resorption; Humans; Neoplasms; Osteoclasts; Osteoporosis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

Receptor activator of nuclear factor-kappaB ligand (RANKL), receptor activator of nuclear factor-kappaB (RANK), and osteoprotegerin (OPG) play a central role in bone remodeling and disorders of mineral metabolism.. A PubMed search was conducted from January 1992 until 2007 for basic, observational, and clinical studies in subjects with disorders related to imbalances in the RANK/RANKL/OPG system.. RANK, RANKL, and OPG are members of the TNF receptor superfamily. The pathways involving them in conjunction with various cytokines and calciotropic hormones play a pivotal role in bone remodeling. Several studies involving mutations in the genes encoding RANK and OPG concluded in the discovery of a number of inherited skeletal disorders. In addition, basic and clinical studies established a consistent relationship between the RANK/RANKL/OPG pathway and skeletal lesions related to disorders of mineral metabolism. These studies were a stepping stone in further defining the role of the RANK/RANKL/OPG pathway in osteoporosis, rheumatoid arthritis, bone loss associated with malignancy-related skeletal diseases, and its relationship to vascular calcifications. Subsequently, the further understanding of this pathway led to the development of new therapeutic modalities including the human monoclonal antibody to RANKL and recombinant OPG as a target for treatment of postmenopausal osteoporosis and multiple myeloma.. The RANK/RANKL/OPG system mediates the effects of calciotropic hormones and, consequently, alterations in their ratio are key in the development of several clinical conditions. New agents with the potential to block effects of RANKL have emerged for treatment of postmenopausal osteoporosis and malignancy-related skeletal disease.

Topics: Animals; Biomarkers, Tumor; Bone Diseases; Bone Remodeling; Humans; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Tumor Necrosis Factor

Focal bone loss around inflamed joints in patients with autoimmune disease, such as rheumatoid arthritis, remains a serious clinical problem. The recent elucidation of the RANK/RANK-ligand/OPG pathway and its role as the final effector of osteoclastogenesis and bone resorption has brought a tremendous understanding of the pathophysiology of inflammatory bone loss, and has heightened expectation of a novel intervention. Here, we review the etiology of inflammatory bone loss, the RANK/RANK-ligand/OPG pathway, and the clinical development of anti-RANK-ligand therapy.

Topics: Arthritis; Bone Diseases; Bone Resorption; Carrier Proteins; Glycoproteins; Humans; Inflammation; Membrane Glycoproteins; Models, Biological; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Hundreds of millions of people worldwide are affected by bone-related diseases, such as osteoporosis and rheumatoid arthritis. Understanding the molecular mechanisms of bone metabolism is crucial for developing novel drugs for treating such diseases. In particular, genetic experiments showing that the receptor activator of NF-kappaB (RANK), its ligand RANKL, and the decoy receptor OPG are essential, central regulators of osteoclast development and osteoclast function were significant turning points in our understanding of bone diseases. RANKL-RANK signaling activates a variety of downstream signaling pathways required for osteoclast development. Moreover, molecular cross-talk between RANKL-RANK and other ligand-receptor systems fine-tunes bone homeostasis in normal physiology and disease. Designing novel drugs that target RANKL-RANK and their signaling pathways in osteoclasts could potentially revolutionize the treatment of many diseases associated with bone loss such as arthritis, tooth loss, cancer metastases or osteoporosis.

Topics: Adaptor Proteins, Signal Transducing; Animals; Bone Diseases; Bone Resorption; Carrier Proteins; Glycoproteins; Humans; MAP Kinase Signaling System; Membrane Glycoproteins; Models, Biological; NF-kappa B; NFATC Transcription Factors; Osteoclasts; Osteoprotegerin; Phosphatidylinositols; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptor Cross-Talk; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Signal Transduction; src-Family Kinases

Patients with end-stage renal disease (ESRD) develop various kinds of abnormalities in bone and mineral metabolism, widely known as renal osteodystrophy (ROD). Although the pathogenesis of ESRD may be similar in many patients, the response of the bone varies widely, ranging from high to low turnover. ROD is classified into several types, depending on the status of bone turnover, by histomorphometric analysis using bone biopsy samples [1,2]. In the mild type, bone metabolism is closest to that of persons with normal renal function. In osteitis fibrosa, bone turnover is abnormally activated. This is a condition of high-turnover bone. A portion of the calcified bone loses its lamellar structure and appears as woven bone. In the cortical bone also, bone resorption by osteoclasts is active, and a general picture of bone marrow tissue infiltration and the formation of cancellous bone can be observed. In osteomalacia, the bone surface is covered with uncalcified osteoid. This condition is induced by aluminum accumulation or vitamin D deficiency. The mixed type possesses characteristics of both osteitis fibrosa and osteomalacia. The bone turnover is so markedly accelerated that calcification of the osteoid cannot keep pace. In the adynamic bone type, bone resorption and bone formation are both lowered. While bone turnover is decreased, there is little osteoid. The existence of these various types probably accounts for the diversity in degree of renal impairment, serum parathyroid hormone (PTH) level, and serum vitamin D level in patients with ROD. However, all patients share a common factor, i.e., the presence of a uremic condition.

Topics: Aluminum; Bone and Bones; Bone Diseases; Bone Resorption; Chronic Kidney Disease-Mineral and Bone Disorder; Glycoproteins; Humans; Indican; Osteitis Fibrosa Cystica; Osteoprotegerin; Parathyroid Hormone; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Toxins, Biological; Uremia; Vitamin D

Multiple myeloma is characterized by accumulation of monoclonal plasma cells in the bone marrow and progression of lytic bone lesions. Myeloma cells enhance bone resorption by triggering a coordinated increase in RANK ligand and decrease in osteoprotegerin in the bone marrow. Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta are secreted by myeloma cells, and play a major role in the enhancement of bone resorption by myeloma cells. Furthermore, the growth and survival of myeloma cells are enhanced by contact with osteoclasts, suggesting the presence of a vicious cycle between bone destruction and myeloma cell expansion. In addition, myeloma cells secrete soluble Wnt inhibitors, dickkopf (Dkk)-1 and secreted Frizzled-related protein (sFRP)-2, to suppress bone formation. Thus, myeloma cells closely interact with bone cells in the bone marrow microenvironment to enhance bone resorption and concomitantly suppress bone formation, which causes the formation of destructive bone lesions and a rapid loss of bone. Disruption of the pathognomonically skewed cellular interactions in myeloma bone marrow microenvironment may ameliorate bone destruction along with myeloma expansion.

Topics: Bone Diseases; Bone Resorption; Carrier Proteins; Cell Differentiation; Chemokine CCL3; Chemokine CCL4; Chemokines, CC; Glycoproteins; Humans; Macrophage Inflammatory Proteins; Membrane Glycoproteins; Multiple Myeloma; Osteoblasts; Osteoclasts; Osteogenesis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Wnt Proteins

A new understanding of the regulation of bone resorption developed with the discovery of receptor activator of nuclear factor-kappaB, receptor activator of nuclear factor-kappaB ligand, and osteoprotegerin in 1997-1998. The RANK signaling system is abnormally regulated in multiple myeloma, and this favors increased osteoclast function, which early in the disease is compensated by increased osteoblast function. Later in the disease osteoblast activity decreases, resulting in osteolytic lesions. We review the factors implicated in osteoclast and osteoblast function. Among these are receptor activator of nuclear factor-kappaB, receptor activator of nuclear factor-kappaB ligand, osteoprotegerin, hepatocyte growth factor, macrophage inflammatory protein-1alpha, bone morphogenetic proteins, and the Wnt system. Bisphosphonates are the only drugs used in routine clinical management; however, the complex regulation system of bone homeostasis offers a number of of possible targets for therapy, which are discussed.

Topics: Bone and Bones; Bone Diseases; Cytokines; Diphosphonates; Humans; Multiple Myeloma; NF-kappa B; Osteoblasts; Osteoclasts; Osteoprotegerin; Receptor Activator of Nuclear Factor-kappa B

This review focuses on the impact of a recent breakthrough in bone cell biology for understanding the pathophysiology of bone/vascular abnormalities associated with uraemia.. Osteoprotegerin is a humoral osteoclastogenesis/osteoclast activation inhibitory factor, which belongs to the TNF-alpha receptor superfamily. Serum osteoprotegerin levels are elevated along with the deterioration of the glomerular filtration rate. The circulating osteoprotegerin molecules were likely to preserve the activity of osteoclastogenesis inhibition, and the levels in many dialysis patients were high enough to inhibit osteoclastogenesis. The higher serum osteoprotegerin levels were related to the development of vascular calcification.. Osteoprotegerin is a potential uraemic toxin that increases the skeletal resistance to PTH. However, the roles of increased circulating osteoprotegerin on bone and/or vascular abnormalities in uraemia remain to be clarified.

Topics: Bone and Bones; Bone Density; Bone Diseases; Glycoproteins; Humans; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Renal Insufficiency; Uremia; Vascular Diseases

Bone resorption by osteoclasts is coupled with bone formation by osteoblasts, and this balanced process continuously remodels and adapts the skeleton. The receptor activator of nuclear factor kappaB ligand (RANKL) has been identified as an essential cytokine for the formation and activation of osteoclasts. The effects of RANKL are physiologically counterbalanced by the decoy receptor osteoprotegerin (OPG). Estrogen deficiency, glucocorticoid exposure, T-cell activation (eg, rheumatoid arthritis), and skeletal malignancies (eg, myeloma, metastases) enhance the ratio of RANKL to OPG and, thus, promote osteoclastogenesis, accelerate bone resorption, and induce bone loss. Moreover, alterations of the OPG/RANKL/RANK system have been implicated in vascular diseases. RANKL blockade (using OPG or RANK fusion proteins or RANKL antibodies) has prevented bone loss caused by osteoporosis, chronic inflammatory disorders, and malignant tumors in animal models and may emerge as a therapy in humans based on studies in postmenopausal osteoporosis, myeloma bone disease, and osteolytic metastases. This review summarizes the clinical implications of the OPG/RANKL/RANK system for bone and vascular diseases.

Topics: Animals; Antibodies, Monoclonal; Bone Diseases; Bone Remodeling; Bone Resorption; Carrier Proteins; Glycoproteins; Humans; Ligands; Membrane Glycoproteins; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Recombinant Proteins; Vascular Diseases

The past decade has seen an explosion in the field of bone biology. The area of bone biology over this period of time has been marked by a number of key discoveries that have opened up entirely new areas for investigation. The recent identification of the receptor activator of nuclear factor kappaB ligand (RANKL), its cognate receptor RANK, and its decoy receptor osteoprotegerin (OPG) has led to a new molecular perspective on osteoclast biology and bone homeostasis. Specifically, the interaction between RANKL and RANK has been shown to be required for osteoclast differentiation. The third protagonist, OPG, acts as a soluble receptor antagonist for RANKL that prevents it from binding to and activating RANK. Any dysregulation of their respective expression leads to pathological conditions such as bone tumor-associated osteolysis, immune disease, or cardiovascular pathology. In this context, the OPG/RANK/RANKL triad opens novel therapeutic areas in diseases characterized by excessive bone resorption. The present article is an update and extension of an earlier review published by Kwan Tat et al. [Kwan Tat S, Padrines M, Theoleyre S, Heymann D, Fortun Y. IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology. Cytokine Growth Factor Rev 2004;15:49-60].

Topics: Animals; Blood Vessels; Bone and Bones; Bone Diseases; Bone Remodeling; Carrier Proteins; Cell Differentiation; Glycoproteins; Humans; Immune System; Membrane Glycoproteins; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; TNF Receptor-Associated Factor 6

Osteoclasts are the only cells capable of resorbing mineralised bone, dentine and cartilage. Osteoclasts act in close concert with bone forming osteoblasts to model the skeleton during embryogenesis and to remodel it during later life. A number of inherited human conditions are known that are primarily caused by a defect in osteoclasts. Most of these are rare monogenic disorders, but others, such as the more common Paget's disease, are complex diseases, where genetic and environmental factors combine to result in the abnormal osteoclast phenotype. Where the genetic defect gives rise to ineffective osteoclasts, such as in osteopetrosis and pycnodysostosis, the result is the presence of too much bone. However, the phenotype in many osteoclast diseases is a combination of osteosclerosis with osteolytic lesions. In such conditions, the primary defect is hyperactivity of osteoclasts, compensated by a secondary increase in osteoblast activity. Rapid progress has been made in recent years in the identification of the causative genes and in the understanding of the biological role of the proteins encoded. This review discusses the known osteoclast diseases with particular emphasis on the genetic causes and the resulting osteoclast phenotype. These human diseases highlight the critical importance of specific proteins or signalling pathways in osteoclasts.

Topics: Animals; Bone and Bones; Bone Diseases; Bone Resorption; Cell Differentiation; Glycoproteins; Humans; Osteitis Deformans; Osteoclasts; Osteolysis; Osteopetrosis; Osteoprotegerin; Osteosclerosis; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Topics: Bone Diseases; Bone Resorption; Carrier Proteins; Chemokine CCL4; Cytokines; Diphosphonates; Glycoproteins; Humans; Macrophage Inflammatory Proteins; Membrane Glycoproteins; Multiple Myeloma; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Topics: Animals; Arthritis, Rheumatoid; Bone Demineralization, Pathologic; Bone Diseases; Bone Remodeling; Bone Resorption; Carrier Proteins; Glycoproteins; Humans; Membrane Glycoproteins; Mice; NF-kappa B; Osteoclasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Vaccines

Advances in genomics and proteomics have revolutionised the drug discovery process and target validation. Identification of novel therapeutic targets for chronic skeletal diseases is an extremely challenging process based on the difficulty of obtaining high-quality human diseased versus normal tissue samples. The quality of tissue and genomic information obtained from the sample is critical to identifying disease-related genes. Using a genomics-based approach, novel genes or genes with similar homology to existing genes can be identified from cDNA libraries generated from normal versus diseased tissue. High-quality cDNA libraries are prepared from uncontaminated homogeneous cell populations harvested from tissue sections of interest. Localised gene expression analysis and confirmation are obtained through in situ hybridisation or immunohistochemical studies. Cells overexpressing the recombinant protein are subsequently designed for primary cell-based high-throughput assays that are capable of screening large compound banks for potential hits. Afterwards, secondary functional assays are used to test promising compounds. The same overexpressing cells are used in the secondary assay to test protein activity and functionality as well as screen for small-molecule agonists or antagonists. Once a hit is generated, a structure-activity relationship of the compound is optimised for better oral bioavailability and pharmacokinetics allowing the compound to progress into development. Parallel efforts from proteomics, as well as genetics/transgenics, bioinformatics and combinatorial chemistry, and improvements in high-throughput automation technologies, allow the drug discovery process to meet the demands of the medicinal market. This review discusses and illustrates how different approaches are incorporated into the discovery and validation of novel targets and, consequently, the development of potentially therapeutic agents in the areas of osteoporosis and osteoarthritis. While current treatments exist in the form of hormone replacement therapy, antiresorptive and anabolic agents for osteoporosis, there are no disease-modifying therapies for the treatment of the most common human joint disease, osteoarthritis. A massive market potential for improved options with better safety and efficacy still remains. Therefore, the application of genomics and proteomics for both diseases should provide much needed novel therapeutic approaches to treating these major world health

Topics: Animals; Bone Diseases; Carrier Proteins; Caspases; Cathepsin K; Cathepsins; Cysteine Proteinase Inhibitors; DNA-Binding Proteins; Drug Design; Drug Evaluation, Preclinical; Early Growth Response Protein 1; Genomics; Glycoproteins; Humans; Immediate-Early Proteins; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Transgenic; Molecular Structure; Osteoarthritis; Osteoporosis; Osteoprotegerin; Proteomics; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; src-Family Kinases; Transcription Factors; Two-Hybrid System Techniques

The discovery of receptor activator for nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) as the fundamental factors in controlling osteoclast formation and activation has led to a greater understanding of bone biology over the past few years. Here we discuss the role of these molecules in immunology and skeletal remodelling and assess their involvement in diseases of bones and joints, including rheumatoid arthritis, Paget's disease, post-menopausal osteoporosis and malignant bone diseases. OPG has been identified as a potential anabolic agent for treating conditions in which there is net bone loss and is currently in Phase I clinical trials. This review examines the current evidence indicating that OPG increases bone mass, and discusses other possible beneficial effects of OPG, such as inhibition of tumour growth and relief from bone cancer pain. OPG can be measured in human serum, and numerous studies have suggested that increased or decreased serum concentrations of this molecule can indicate the existence of remodelling disorders. Here we discuss how abnormal serum OPG concentrations could potentially be used to indicate imbalances of bone resorption and formation. The possible applications of serum OPG concentration as a marker for non-skeletal disease conditions are also considered.

Topics: Biomarkers; Bone Diseases; Carrier Proteins; Glycoproteins; Humans; Joint Diseases; Membrane Glycoproteins; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Receptor activator of nuclear factor (NF-kappaB) ligand (RANKL), its cellular receptor, receptor activator of NF-kappaB (RANK), and the decoy receptor osteoprotegerin (OPG) constitute a novel cytokine system. RANKL produced by osteoblastic lineage cells and activated T lymphocytes is the essential factor for osteoclast formation, fusion, activation, and survival, thus resulting in bone resorption and bone loss. RANKL activates its specific receptor, RANK located on osteoclasts and dendritic cells, and its signaling cascade involves stimulation of the c-jun, NF-kappaB, and serine/threonine kinase PKB/Akt pathways. The effects of RANKL are counteracted by OPG which acts as a soluble neutralizing receptor. RANKL and OPG are regulated by various hormones (glucocorticoids, vitamin D, estrogen), cytokines (tumor necrosis factor alpha, interleukins 1, 4, 6, 11, and 17), and various mesenchymal transcription factors (such as cbfa-1, peroxisome proliferator-activated receptor gamma, and Indian hedgehog). Transgenic and knock-out mice with excessive or defective production of RANKL, RANK, and OPG display the extremes of skeletal phenotypes, osteoporosis and osteopetrosis. Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of postmenopausal osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, benign and malignant bone tumors, bone metastases, and hypercalcemia of malignancy, while administration of OPG has been demonstrated to prevent or mitigate these disorders in animal models. RANKL and OPG are also important regulators of vascular biology and calcification and of the development of a lactating mammary gland during pregnancy, indicating a crucial role for this system in extraskeletal calcium handling. The discovery and characterization of RANKL, RANK, and OPG and subsequent studies have changed the concepts of bone and calcium metabolism, have led to a detailed understanding of the pathogenesis of metabolic bone diseases, and may form the basis of innovative therapeutic strategies.

Topics: Animals; Apoptosis; Bone and Bones; Bone Diseases; Carrier Proteins; Cell Differentiation; Glycoproteins; Humans; Membrane Glycoproteins; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

The current review summarizes the roles of the ligand, receptor activator of nuclear factor-kappaB ligand (RANKL), its receptor, receptor activator of nuclear factor-kappaB (RANK), and its decoy receptor, osteoprotegerin (OPG), on osteoclast biology and bone resorption. Furthermore, it highlights the impact of these compounds on the pathogenesis of malignant bone diseases, including tumor metastasis, humoral hypercalcemia of malignancy, and multiple myeloma. Finally, the authors discuss the therapeutic potential of OPG in the management of malignancies involving the skeleton.. After its discovery and cloning, the biologic effects of RANKL, RANK, and OPG have been characterized by in vitro experiments and in vivo studies. The generation of knock-out mice and transgenic mice has produced animal models with absent or excessive production of these cytokine components that display opposite abnormal skeletal phenotypes (osteoporosis or osteopetrosis). The potential effect of RANKL and OPG has been assessed by evaluating these compounds in various animal models of metabolic and malignant bone disease and by administering OPG to humans.. Abnormal bone resorption due to local or systemic stimulation of osteoclast differentiation and activation is a hallmark of various benign and malignant bone diseases. RANKL, RANK, and OPG form an essential cytokine system that is capable of regulating all aspects of osteoclast functions, including proliferation, differentiation, fusion, activation, and apoptosis. The balance of bone resorption depends on the local RANKL-to-OPG ratio, which is enhanced in bone metastases and humoral hypercalcemia of malignancy. The exogenous administration of OPG to tumor-bearing animals corrects the increased RANKL-to-OPG ratio, and reverses the skeletal complications of malignancies.. Abnormalities of the RANKL/OPG system have been implicated in the pathogenesis of various primary and secondary bone malignancies. The systemic administration of OPG appears to be a potent novel therapeutic agent for treatment of these disorders.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Bone Diseases; Bone Neoplasms; Carrier Proteins; Glycoproteins; Humans; Membrane Glycoproteins; Neoplasm Metastasis; Osteoprotegerin; Prognosis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

As people with Cystic Fibrosis (CF) live longer, extra-pulmonary complications such as CF-related bone disease (CFBD) are becoming increasingly important. The etiology of CFBD is poorly understood but is likely multifactorial. Bones undergo continuous remodeling via pathways including RANK (receptor activator of NF-κB)/sRANKL (soluble ligand)/OPG (osteoprotegerin). We sought to examine the association between sRANKL (stimulant of osteoclastogenesis) and OPG levels (inhibitor of osteoclast formation) and CFBD to investigate their potential utility as biomarkers of bone turnover in people with CF.. We evaluated sRANKL and OPG in plasma from people with CF and healthy controls (HC) and compared levels in those with CF to bone mineral density results. We used univariable and multivariable analysis to account for factors that may impact sRANKL and OPG.. We found a higher median [IQR] sRANKL 10,896pg/mL [5,781-24,243] CF; 2,406pg.mL [659.50-5,042] HC; p= 0.0009), lower OPG 56.68pg/mL [36.28-124.70] CF; 583.20pg/mL [421.30-675.10] HC; p < 0.0001), and higher RANKL/OPG in people with CF no BD than in HC (p < 0.0001). Furthermore, we found a higher RANKL/OPG ratio 407.50pg/mL [214.40-602.60] CFBD; 177.70pg/mL [131.50-239.70] CF no BD; p = 0.007) in people with CFBD versus CF without bone disease. This difference persisted after adjusting for variables thought to impact bone health.. The current screening recommendations of imaging for CFBD may miss important markers of bone turnover such as the RANKL/OPG ratio. These findings support the investigation of therapies that modulate the RANK/RANKL/OPG pathway as potential therapeutic targets for bone disease in CF.

Topics: Biomarkers; Bone Density; Bone Diseases; Bone Remodeling; Cystic Fibrosis; Humans; Osteoprotegerin

The aim of this study is to evaluate the relationship between OPG and the degree of glycaemic control in a population of elderly subjects.. Data presented included 172 elderly subjects, of whom 107 were hospitalized for a hip fracture and 65 were non fractured outpatients. All participants received a multidimensional geriatric evaluation and underwent blood sampling. HbA1c, OPG, CTX and OC were measured and DXA scans were performed. Carotid intima-media thickness (IMT) was measured in all outpatients. Diabetic patients had more comorbidities, higher mean values of lumbar spine and femoral neck BMD and T-score, lower circulating levels of OC and CTX, and higher circulating levels of OPG compared to non-diabetic subjects. OPG was directly correlated with HbA1c. This association was most evident in non-fractured elderly subjects. Moreover, diabetic patients with IMT>1.5 mm had greater mean values of OPG than non-diabetic subjects with high IMT and than elderly subjects with IMT < 1.5 mm, with and without T2DM.. Diabetic patients have reduced circulating levels of OC and CTX, and elevated serum levels of OPG, suggesting a state of low bone turnover. Reduced bone turnover causes an increase of BMD and could lead to a poor bone quality. OPG and HbA1c were directly correlated and OPG mean values were higher in diabetic patients with poor glucose control. Diabetic osteopathy could be considered a late complication of T2DM, directly related with the degree of glucose control and the duration of the disease.

Topics: Age Factors; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Bone Density; Bone Diseases; Collagen Type I; Diabetes Mellitus, Type 2; Female; Frail Elderly; Glycated Hemoglobin; Health Status; Humans; Male; Osteocalcin; Osteoprotegerin; Peptides; Prevalence; Risk Factors; Rome

Background Sclerostin and osteoprotegerin (OPG) are new markers of chronic kidney disease (CKD) mediated mineral bone disease (CKD-MBD) which were extensively evaluated in adult population. We aimed to evaluate the associations between serum levels of sclerostin/OPG and parameters of bone turnover and compare the serum levels of sclerostin/OPG in different stages of CKD in children. Methods 70 children with CKD stage 1-5, aged 2-21 years were examined. Serum levels of alkaline phosphatase (ALP), creatinine, total calcium, phosphorus , intact parathyroid hormone (iPTH) and vitamin D were measured. Serum sclerostin and OPG levels were measured in children with different levels of CKD stage and their association with bone turnover parameters were noted. Results We did not observe any significant correlation between serum levels of sclerostin and OPG and stages of CKD. A negative relationship was present between serum sclerostin and 25-OH vitamin D levels. Osteoprotegerin was positively and significantly correlated with ALP but serum sclerostin was negatively correlated with ALP. Conclusion Our study, which includes only children and adolescents with a growing skeleton under uremic conditions and excluding diabetes and atherosclerosis interference, is very valuable. We couldn't find any significant relationship between either sclerostin or OPG levels among different stages of CKD. Also our study demonstared a strong negative relationship between ALP and sclerostin levels and a strong positive relationship between ALP and OPG levels, reminding the importance of ALP levels to predict the bone-mineral status of the children with CKD.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Age of Onset; Biomarkers; Bone Diseases; Child; Child, Preschool; Female; Glomerular Filtration Rate; Humans; Male; Minerals; Osteoprotegerin; Prognosis; Renal Insufficiency, Chronic; Turkey; Young Adult

Chronic kidney disease (CKD) is an irreversible loss of kidney function, and it represents a major global public health burden due to both its prevalence and its continuously increasing incidence. Mineral bone disorders (MBDs) constitute a hallmark of CKD, and alongside cardiovascular complications, they underlie a poor prognosis for these patients. Thus, our study focused on novel CKD biomarker patterns and their impact on the clinical staging of the disease. As a first testing approach, the relative expression levels of 105 proteins were assessed by the Proteome Profiler Cytokine Array Kit for pooled CKD stage 2-4 serum samples to establish an overall view regarding the proteins involved in CKD pathogenesis. Among the molecules that displayed significant dysregulation in the CKD stages, we further explored the involvement of Dickkopf-related protein 1 (Dkk-1), a recognised inhibitor of the Wnt signalling pathway, and its crosstalk with 1,25OH

Topics: Aged; Algorithms; Biomarkers; Bone Density; Bone Diseases; Calcitriol; Cross-Sectional Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-6; Male; Middle Aged; Osteocalcin; Osteopontin; Osteoprotegerin; Phenotype; Prognosis; Proteome; Renal Insufficiency, Chronic; Tumor Necrosis Factor-alpha; Wnt Signaling Pathway

An etiological treatment is currently lacking for Langerhans Cell Histiocytosis (LCH). Receptor activator of nuclear factor κB ligand (RANKL) appears to play a central role in the lesional immunological process inducing compensatory osteoprotegerin (OPG) activation. In a preliminary study we aimed to evaluate for the first time the use of denosumab, a RANKL inhibitor, as a targeted treatment strategy in LCH in order to support and enhance endogenous OPG action in order to control or alter the lesional immunological process.. Two adult female patients with painful osteolytic bone lesions and concomitant pulmonary involvement received bimonthly denosumab 120mg in a total of 4 doses.. Both patients reported an immediate pain relief within the first two weeks following the 1st dose of denosumab. One month following the last dose an almost full remission of the initial osteolytic and lung lesions was observed, although an apparent new bone lesion was detected in one patient that was treated with a single intralesional steroid injection. No adverse events were recorded throughout the treatment period. Both patients have no active disease 6months following the last denosumab dose.. Denosumab could be considered an effective treatment option in adults with multisystem LCH also exerting a significant analgesic effect in bone lesions, warranting further investigation.

Topics: Adult; Bone Density Conservation Agents; Bone Diseases; Denosumab; Female; Histiocytosis, Langerhans-Cell; Humans; Lung Diseases; Magnetic Resonance Imaging; Osteoprotegerin; Pain; Positron-Emission Tomography; RANK Ligand; Treatment Outcome

A major complication of multiple myeloma (MM) is the development of osteolytic lesions, fractures and bone pain. To identify genetic variants influencing the development of MM bone disease (MBD), we analyzed MM patients of European ancestry (totaling 3774), which had been radiologically surveyed for MBD. Each patient had been genotyped for ~6 00 000 single-nucleotide polymorphisms with genotypes for six million common variants imputed using 1000 Genomes Project and UK10K as reference. We identified a locus at 8q24.12 for MBD (rs4407910, OPG/TNFRSF11B, odds ratio=1.38, P=4.09 × 10(-9)) and a promising association at 19q13.43 (rs74676832, odds ratio=1.97, P=9.33 × 10(-7)). Our findings demonstrate that germline variation influences MBD and highlights the importance of RANK/RANKL/OPG pathway in MBD development. These findings will contribute to the development of future strategies for prevention of MBD in the early precancerous phases of MM.

Topics: Aged; Biomarkers, Tumor; Bone Diseases; Female; Genotype; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Osteoprotegerin; Polymorphism, Single Nucleotide; Prognosis; Risk Factors

HIV-infected patients appear to have a significantly greater risk of non-AIDS comorbidities such as osteoporosis and atherosclerosis. Subjects with osteoporosis are at a higher risk of developing cardiovascular disease than those with normal bone mass, therefore a possible relation between these two conditions can be hypothesized. In the setting of HIV infection, several factors might contribute to bone disease and endothelial dysfunction. The aim of our study was to evaluate the relationship between bone and cardiovascular disease and to investigate the role of traditional factors, T-cell phenotype and osteoprotegerin in HIV positive subjects on effective antiretroviral therapy. We included 94 HIV positive subjects on antiretroviral therapy with virological suppression and 41 healthy subjects matched for age and gender as a control group. Carotid-Intima Media Thickness (c-IMT) and bone mineral density (BMD) were performed by ultrasound and DEXA, respectively. CD4+/CD8+ T-cell activation, senescence and osteoprotegerin plasma levels were measured by flow-cytometry and ELISA, respectively. Among HIV positive patients, 56.4% had osteopenia/osteoporosis and 45.7% had pathological c-IMT (>0.9 mm). Subjects with pathological c-IMT and BMD exhibited higher CD4+ and CD8+ activated, CD8+ senescent and osteoprotegerin than subjects with normal c-IMT and BMD. HIV positive subjects with osteopenia/osteoporosis had higher c-IMT than subjects with normal BMD, and linear regression analysis showed a negative correlation between BMD and c-IMT. Several factors are implicated in the pathogenesis of non-AIDS comorbidities in HIV positive patients. Osteoprotegerin together with inflammation and immunosenescence in HIV positive patients could affect bone and vascular system and could be considered as a possible common link between these two diseases.

Topics: Anti-HIV Agents; Biomarkers; Bone Diseases; Cardiovascular Diseases; Carotid Intima-Media Thickness; Comorbidity; Female; HIV Infections; Humans; Immunosenescence; Male; Middle Aged; Osteoprotegerin; Phenotype; T-Lymphocytes

Icariin (ICA) is an active compound extracted from Epimedium brevicornum Maxim. Previous reports have shown that icariin has a clinically significant therapeutic effect on rheumatoid arthritis. However, little is known about the mechanism by which icariin inhibits cartilage and bone degradation.. New Zealand rabbits were immunized with antigen-induced arthritis (AIA) and treated with icariin. Joint tissues from rabbits were studied by histological analysis, transmission electron microscopy (TEM), and micro-CT. The expression levels of receptor activator of nuclear factor-B ligand (RANKL) and osteoprotegerin (OPG) in joint tissues were determined using immunohistochemistry and real-time PCR analysis.. Histological analysis and TEM sections of cartilage in the ICA treated group showed a low level of chondrocyte destruction. Micro-CT analysis showed that the bone mineral density value and bone structural level in ICA treated rabbits were significantly higher compared with those in the AIA group. Immunohistochemistry and real-time PCR analysis showed that icariin treatment reduced RANKL expression and enhanced OPG expression levels, as compared to the AIA group.. These data indicate that ICA suppresses articular bone loss and prevents joint destruction. This study also determined that ICA regulated articular bone loss in part by regulating RANKL and OPG expression.

Topics: Animals; Arthritis, Experimental; Bone Diseases; Cartilage; Flavonoids; Microscopy, Electron, Transmission; Models, Theoretical; Osteoprotegerin; Rabbits; RANK Ligand

Bone fragility and loss are a significant cause of morbidity in patients with cystic fibrosis (CF), and the lack of effective therapeutic options means that treatment is more often palliative rather than curative. A deeper understanding of the pathogenesis of CF-related bone disease (CFBD) is necessary to develop new therapies. Defective CF transmembrane conductance regulator (CFTR) protein and chronic inflammation in bone are important components of the CFBD development. The receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) drive the regulation of bone turnover. To investigate their roles in CFBD, we evaluated the involvement of defective CFTR in their production level in CF primary human osteoblasts with and without inflammatory stimulation, in the presence or not of pharmacological correctors of the CFTR. No major difference in cell ultrastructure was noted between cultured CF and non-CF osteoblasts, but a delayed bone matrix mineralization was observed in CF osteoblasts. Strikingly, resting CF osteoblasts exhibited strong production of RANKL protein, which was highly localized at the cell membrane and was enhanced in TNF (TNF-α) or IL-17-stimulated conditions. Under TNF stimulation, a defective response in OPG production was observed in CF osteoblasts in contrast to the elevated OPG production of non-CF osteoblasts, leading to an elevated RANKL-to-OPG protein ratio in CF osteoblasts. Pharmacological inhibition of CFTR chloride channel conductance in non-CF osteoblasts replicated both the decreased OPG production and the enhanced RANKL-to-OPG ratio. Interestingly, using CFTR correctors such as C18, we significantly reduced the production of RANKL by CF osteoblasts, in both resting and TNF-stimulated conditions. In conclusion, the overexpression of RANKL and high membranous RANKL localization in osteoblasts are related to defective CFTR, and may worsen bone resorption, leading to bone loss in patients with CF. Targeting osteoblasts with CFTR correctors may represent an effective strategy to treat CFBD. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Topics: Adolescent; Adult; Bone Diseases; Cell Membrane; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Susceptibility; Humans; Interleukin-17; Osteoblasts; Osteoprotegerin; RANK Ligand; Tumor Necrosis Factor-alpha; Young Adult

Osteocyte apoptosis due to microdamage and/or oxidative stress is related to increased local bone turnover and resorption observed in various bone diseases. Previous data on osteoblasts and osteoclasts have linked reactive oxygen species and antioxidants to bone remodelling. This study performs a comprehensive analysis on the effect of antioxidants such as glutathione (GSH), N-acetylcysteine and lipoic acid (LA) on starvation-induced osteocyte apoptosis and on cytokines involved in bone remodelling such as the receptor activator kB ligand (RANKL), osteoprotegerin (OPG) and sclerostin. For this study, apoptosis was induced by serum starvation in a murine osteocyte-like cell line MLO-Y4; this condition mimics in part osteocyte apoptosis due to microdamage. The results show that starvation-induced apoptosis and expression of RANKL, OPG and sclerostin are redox regulated processes. All antioxidants are able to inhibit the apoptosis due to starvation. They down-regulate the expression and the release of RANKL, the expression of sclerostin and RANKL/OPG ratio, whereas they only in part up-regulate OPG expression. Antioxidants mediate their effect on starvation-induced apoptosis by JNK signalling and on cytokine expression by both JNK and ERK1/2 activities. This study shows the possible involvement of biological antioxidants such as GSH and LA on redox regulated mechanisms related to apoptosis and expression of cytokines involved in bone remodelling. Moreover, it suggests that both JNK and ERK1/2 may be useful biological targets for drugs affecting bone diseases associated with increased oxidative stress.

Topics: Acetylcysteine; Adaptor Proteins, Signal Transducing; Animals; Antioxidants; Apoptosis; Bone Diseases; Bone Remodeling; Cell Line; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Glutathione; Glycoproteins; Hydrogen Peroxide; Intercellular Signaling Peptides and Proteins; MAP Kinase Kinase 4; Mice; Necrosis; Osteocytes; Osteoprotegerin; Oxidation-Reduction; Phosphorylation; RANK Ligand; Thioctic Acid

Bone disease is one of the hallmarks of multiple myeloma (MM). The role of osteoprotegerin (OPG) in the RANK/RANKL/OPG signaling system is well defined in the myeloma bone disease. Polymorphisms of the TNFRSF11B gene encoding OPG have been studied in various bone diseases. However, relationship between the levels of OPG and development of bone lesions regardless of RANKL is yet unknown. In this study, the effects of OPG gene polymorphism on the development of bone lesions in MM were investigated.. C950T and C1181G polymorphisms of the OPG gene were studied in 52 MM patients (36 with bone lesions and 16 without bone lesions) and in another 20 control subjects using DNA sequencing.. 1181 G and 950 T alleles were overrepresented in MM patients having bone lesions. 950 TT/1181 GG haplotype frequency and TT/GG combined haplotype were also higher in MM patients having bone lesions compared to MM patients without bone lesions or to control.. This is the first study searching for the relationship between OPG gene variants C950T (promoter), C1181G (exon 1), and myeloma bone disease. It was concluded that the presence of polymorphic 1181 G/950 T alleles and 950 TT/1181 GG genotypes may play a role in the development of bone disease.

Topics: Aged; Bone Diseases; Female; Gene Frequency; Genotype; Humans; Male; Middle Aged; Multiple Myeloma; Osteoprotegerin; Polymorphism, Single Nucleotide

Low bone mass and increased fracture risk are recognized complications of cystic fibrosis (CF). CF-related bone disease (CFBD) is characterized by uncoupled bone turnover--impaired osteoblastic bone formation and enhanced osteoclastic bone resorption. Intestinal malabsorption, vitamin D deficiency and inflammatory cytokines contribute to CFBD. However, epidemiological investigations and animal models also support a direct causal link between inactivation of skeletal cystic fibrosis transmembrane regulator (CFTR), the gene that when mutated causes CF, and CFBD. The objective of this study was to examine the direct actions of CFTR on bone. Expression analyses revealed that CFTR mRNA and protein were expressed in murine osteoblasts, but not in osteoclasts. Functional studies were then performed to investigate the direct actions of CFTR on osteoblasts using a CFTR knockout (Cftr-/-) mouse model. In the murine calvarial organ culture assay, Cftr-/- calvariae displayed significantly less bone formation and osteoblast numbers than calvariae harvested from wildtype (Cftr+/+) littermates. CFTR inactivation also reduced alkaline phosphatase expression in cultured murine calvarial osteoblasts. Although CFTR was not expressed in murine osteoclasts, significantly more osteoclasts formed in Cftr-/- compared to Cftr+/+ bone marrow cultures. Indirect regulation of osteoclastogenesis by the osteoblast through RANK/RANKL/OPG signaling was next examined. Although no difference in receptor activator of NF-κB ligand (Rankl) mRNA was detected, significantly less osteoprotegerin (Opg) was expressed in Cftr-/- compared to Cftr+/+ osteoblasts. Together, the Rankl:Opg ratio was significantly higher in Cftr-/- murine calvarial osteoblasts contributing to a higher osteoclastogenesis potential. The combined findings of reduced osteoblast differentiation and lower Opg expression suggested a possible defect in canonical Wnt signaling. In fact, Wnt3a and PTH-stimulated canonical Wnt signaling was defective in Cftr-/- murine calvarial osteoblasts. These results support that genetic inactivation of CFTR in osteoblasts contributes to low bone mass and that targeting osteoblasts may represent an effective strategy to treat CFBD.

Topics: Animals; Bone Diseases; Bone Resorption; Cell Differentiation; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Female; Fractures, Bone; Gene Expression; Mice; Mice, Knockout; Osteoblasts; Osteoclasts; Osteogenesis; Osteoprotegerin; Parathyroid Hormone; Wnt Signaling Pathway

The role of osteoprotegerin (OPG) as a marker of cardiovascular disease (CVD) in Type 2 diabetes (T2DM) is not well established. Moreover, the relationship between OPG, osteoporosis, and vertebral fractures in T2DM remains to be elucidated.. To determine the role of serum OPG in the prediction of CVD and bone disease in T2DM males.. Cross-sectional study with 68 males, 43 with T2DM and 25 subjects without diabetes. We measured: serum OPG by inmunoassay, the presence of CVD (coronary heart disease, cerebrovascular and peripheral artery disease), surrogate markers of CVD [intima- media thickness (IMT) and aortic calcification] and bone disease (bone mineral density and prevalent vertebral fractures).. OPG serum levels (in pmol/l) were significantly higher in T2DM males with abnormal IMT (5.12 ± 1.59 vs 3.76 ± 1.98), carotid plaque (5.46 ± 1.67 vs 4.20 ± 1.81), aortic calcification (5.91 ± 1.39 vs 4.07 ± 1.76), hypertension (5.11 ± 1.86 vs 3.81 ± 1.47), and peripheral artery disease (6.24 ± 1.64 vs 4.21 ± 1.63, p < 0.05 for all comparisons). In the logistic regression analysis (after adjustment for age and main cardiovascular risk factors), serum OPG (per 1 pmol/l increase in OPG) was associated with increased risk of abnormal IMT [odds ratio (OR) 1.84, confidence interval (CI) 1.21-2.79, p = 0.004), carotid plaque (OR 1.71, CI 1.13-2.58, p = 0.012), aortic calcification (OR 2.21, CI 1.27-3.84, p = 0.05) and peripheral artery disease (OR 4.02, CI 1.65-9.8 p = 0.002). However, OPG were not related to bone mass or vertebral fractures.. Our results suggest that in T2DM males OPG serum concentrations constitute a marker of CVD, but not a marker of bone disease.

Topics: Absorptiometry, Photon; Biomarkers; Blood Pressure Determination; Bone Density; Bone Diseases; Cardiovascular Diseases; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Osteoprotegerin; Prognosis; Risk Factors

Extra-skeletal calcification and disordered phosphate metabolism are hallmarks of chronic kidney disease-mineral bone disorder (CKD-MBD). Osteoprotegerin (OPG) and fibroblast growth factor 23 (FGF-23) are increased in chronic kidney disease (CKD) and have been associated with arterial and cardiac dysfunction and reduced survival. Troponin T (cTnT) is released from cardiac myocytes under conditions of stress and is predictive of mortality across a range of renal functions. However, the utility of this biomarker was formerly limited by the lower limit of assay detection. The introduction of a high-sensitivity assay has enabled more detailed study of myocyte stress below the previous limit of detection. We studied the association of mediators of CKD-MBD with arterial stiffness and also of these mediators and arterial stiffness with myocardial damage in patients with CKD stages 3-4.. OPG and FGF-23 were measured in 200 CKD stages 3-4 patients. cTnT was measured using a high-sensitivity assay. Aortic stiffness was assessed using aortic pulse wave velocity (APWV).. Mean age was 69 ± 11 years, mean systolic and diastolic blood pressure was 151 ± 22/81 ± 11 mmHg and renal function was 33 ± 11 mL/min/1.73 m(2). OPG, FGF-23, high-sensitivity troponin T (hs-cTnT) and APWV all correlated with renal function. After multivariate analysis, OPG and age remained independently associated with aortic stiffness. OPG and FGF-23 were independently associated with hs-cTnT in addition to other non-traditional risk factors (Model R(2) = 0.596).. We have shown that changes in bone mediators and phosphate metabolism induced by CKD are independently associated with vascular and cardiomyocyte dysfunction. Our findings suggest that cardiac dysfunction may be specifically associated with such abnormalities in addition to recognized increases in vascular stiffness.

Topics: Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Biomarkers; Bone Density; Bone Diseases; Cardiomyopathies; Cardiovascular Diseases; Cohort Studies; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Prognosis; Regression Analysis; Risk Assessment; Severity of Illness Index; Sex Factors; Survival Rate; Troponin T; Vascular Resistance

Osteoprotegerin (OPG), the soluble decoy receptor of RANKL is released by bone marrow osteoblasts and plays an important role in physiological osteoblastogenesis and pathological bone disease. In earlier studies, we have shown that generated stromal cell lines from the aorta-gonad-mesonephros (AGM)-region serving as good supporters of murine and human hematopoietic progenitor cell (HPC) expansion highly express OPG detected by microarray analysis. Here, we investigated the role of OPG to HPC expansion in vitro. Addition of OPG leads to an enhanced expansion of HPC in liquid culture. In addition, progenitor cell function, measured by colony and cobblestone formation, was increased. The observed effects were partially antagonized by addition of RANKL. In conclusion, these findings suggest an important role of OPG maintaining progenitor cell function in the osteoblastic niche.

Topics: Antigens, CD34; Bone Diseases; Cell Growth Processes; Cells, Cultured; Gene Expression Regulation, Developmental; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Microarray Analysis; Osteoblasts; Osteogenesis; Osteoprotegerin; RANK Ligand

The RANK-RANKL-OPG system is an essential signaling pathway involved in bone cell-cell communication, with ample evidence that modification of the RANK-RANKL-OPG signaling pathway has major effects on bone remodeling. The first focus of this paper is to demonstrate that a theoretical model of bone cell-cell interactions is capable of qualitatively reproducing changes in bone associated with RANK-RANKL-OPG signaling. To do this we consider either biological experiments or bone diseases related to receptor and/or ligand deficiencies, including RANKL over-expression, ablation of OPG production and/or RANK receptor modifications. The second focus is to investigate a wide range of possible therapeutic strategies for re-establishing bone homeostasis for various pathologies of the RANK-RANKL-OPG pathway. These simulations indicate that bone diseases associated with the RANK-RANKL-OPG pathway are very effective in triggering bone resorption compared to bone formation. These results align with Hofbauer's "convergence hypothesis", which states that catabolic bone diseases most effectively act through the RANK-RANKL-OPG system. Additionally, we demonstrate that severity of catabolic bone diseases strongly depends on how many components of this pathway are affected. Using optimization algorithms and the theoretical model, we identify a variety of successful "virtual therapies" for different disease states using both single and dual therapies.

Topics: Animals; Bone and Bones; Bone Diseases; Bone Remodeling; Cell Count; Mice; Models, Biological; Organ Size; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

This study was purposed to investigate the relationship between the levels of soluble receptor activator of nuclear factor kappa B ligand (sRANKL) and osteoprotegerin (OPG) in serum of the patients with multiple myeloma (MM) and multiple myeloma bone disease (MBD). The serum levels of sRANKL, OPG, tartrate-resistant acid phosphatase-5b (TRAP-5b) and C-terminal telopeptide of collagen I (CTP-I) which both are indexes for metabolism of osteoclast (OC) in newly diagnosed MM patients (n=42, experimental group) and healthy persons (n=25, control group) were detected by enzyme-linked immunosorbent assay. The roentgenography was used to determine bone damage in MM patients at the same time. According to these results acquired, the correlation of sRANKL/OPG ratio with levels of TRAP-5b/CTP-I, the incidence and degree of bone destruction were analyzed. The results indicated that the level of sRANKL (median value 9.33 microg/L) increased and level of OPG (median value 4.93 microg/L) decreased and the sRANKL/OPG ratio (2.65) increased significantly in experimental group. Compared with control group, the differences in all the corresponding indicators were statistically significant (p<0.05). The sRANKL/OPG ratio was closely related to levels of TRAP-5b (r=0.512, p<0.05) and CTP-I (r=0.481, p<0.05) in MM patients. After all patients in experimental groups were divided into group with bone destruction (n=29) and without bone destruction (n=13), the sRANKL/OPG ratio in the group with bone destruction was 5.13 and much higher than that in group without bone destruction (1.12) (p<0.05). A close correlation between the sRANKL/OPG ratio and degree of bone destruction (r=0.445, p<0.05) was acquired when all MM patients were divided into three groups according to degree of bone destruction, but no difference between the ratio and clinical classification and International Staging System (ISS) in MM patients was found. It is concluded that the sRANKL/OPG ratio in serum of MM patients is significantly elevated, which may be closely related to increase metabolism of OC along with the incidence and degree of bone destruction. In short, the sRANKL/OPG ratio can be used as a reference index for the diagnosis of MBD.

Topics: Adult; Aged; Bone Diseases; Case-Control Studies; Female; Humans; Male; Middle Aged; Multiple Myeloma; Osteoprotegerin; RANK Ligand

Tooth eruption is a complex and tightly regulated process that involves cells of the tooth organ and the surrounding alveolus. Recent researches have shown that tooth eruption depends on the presence of osteoclasts to create an eruption pathway through the alveolar bone. The most important physiologic role likely being at the eruptive site, in the formation of osteoclasts through signaling via the RANKL/OPG pathway. Calcitonin is an endogenous inhibitor of osteoclast development and function and thus of bone resorption. Specific calcitonin receptors are expressed on osteoclasts and their activation leads to the inhibition of osteoclast development and functions. Recent concepts about inhibiting osteoclastogenesis of calcitonin is that RANKL-induced osteoclastogenesis were blocked by the endogenous decoy receptor osteoprotegerin and were also strongly reduced by calcitonin, we hypothesize that calcitonin may has anti-eruption properties. For the clinical point of view, we can inject calcitonin in the oral mucosa of the affected tooth to inhibit bone resorption, then to facilitate root forming which may useful to premature eruption of tooth and short root anomaly disease (SRA) caused by every reasons such as hypoplasia of teeth root (HTR), Singleton-Mertern syndrome (SMS), infection and iatrogenic factors, etc.

Topics: Bone Diseases; Bone Resorption; Calcitonin; Gene Expression Regulation; Humans; Models, Biological; Models, Theoretical; Mouth Mucosa; Mutation; Osteoclasts; Osteoprotegerin; RANK Ligand; Signal Transduction; Syndrome; Tooth Eruption

Studying consanguineous families with Ghosal hematodiaphyseal dysplasia syndrome (GHDD), a disorder of increased bone density, we identified mutations in TBXAS1, which encodes thromboxane synthase (TXAS). TXAS, an enzyme of the arachidonic acid cascade, produces thromboxane A(2) (TXA(2)). Platelets from subjects with GHDD showed a specific deficit in arachidonic acid-produced aggregation. We also found that TXAS and TXA(2) modulated expression of TNFSF11 and TNFRSF11B (encoding RANKL and osteoprotegerin (OPG), respectively) in primary cultured osteoblasts.

Topics: Amino Acid Substitution; Bone Density; Bone Diseases; Bone Remodeling; Catalytic Domain; Cells, Cultured; Consanguinity; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Humans; Models, Biological; Osteoprotegerin; Point Mutation; RANK Ligand; Syndrome; Thromboxane A2; Thromboxane-A Synthase

Whilst not strictly a neuropathic injury, cancer-induced bone pain (CIBP) is a unique state with features of neuropathy and inflammation. Recent work has demonstrated that osteoclasts damage peripheral nerves (peptidergic C fibres and SNS) within trabeculated bone leading to deafferentation. In addition, glia cell activation and neuronal hyperexcitability within the dorsal horn, are all similar to a neuropathy. Gabapentin and carbamazepine (both anti-convulsants that modulate neuropathy) are effective at attenuating dorsal horn neuronal excitability and normalizing pain-like behaviours in a rat model of CIBP. However alterations in neuroreceptors in the dorsal horn do not mimic neuropathy, rather only dynorphin is upregulated, glia cells are active and hypertrophic and c-fos expression is increased post-noxious behavioural stimulus. CIBP perhaps illustrates best the complexity of cancer pains. Rarely are they purely neuropathic, inflammatory, ischaemic or visceral but rather a combination. Management is multimodal with radiotherapy, analgesics (opioids, NSAIDs), bisphosphonates, radioisotopes and tumouricidal therapies. The difficulty with opioids relates to efficacy on spontaneous pain at rest and movement-related pain. Potential adjuvants to standard analgesic therapies for CIBP are being explored in clinical trials and include inhibitors of glutamate release.

Topics: Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Bone Density Conservation Agents; Bone Diseases; Bone Neoplasms; Diphosphonates; Drug Administration Routes; Endothelin-1; Humans; Lidocaine; N-Methylaspartate; Osteoprotegerin; Pain; Receptors, Vitronectin

Decoy receptor 3 (DcR3), a soluble receptor for FasL, LIGHT, and TL1A, induces osteoclast formation from monocyte, macrophage, and bone stromal marrow cells. However, the function of DcR3 on bone formation remains largely unknown. To understand the function of DcR3 in bone formation in vivo, transgenic mice overexpressing DcR3 were generated. Bone mineral density (BMD) and bone mineral content (BMC) of total body were significantly lower in DcR3 transgenic mice as compared with wild-type controls. The difference in BMD and BMC between DcR3 transgenic and control mice was confirmed by histomorphometric analysis, which showed a 35.7% decrease in trabecular bone volume in DcR3 transgenic mice in comparison with wild-type controls. The number of osteoclasts increased in DcR3 transgenic mice. In addition, local administration of DcR3 (30 microg/ml, 10 microl, once/day) into the metaphysis of the tibia via the implantation of a needle cannula significantly decreased the BMD, BMC, and bone volume of secondary spongiosa in tibia. Local injection of DcR3 also increased osteoclast numbers around trabecular bone in tibia. Furthermore, coadminstration of soluble tumor necrosis factor receptor inhibitor/Fc chimera (TNFRSF1A) but not osteoprotegerin inhibited the action of DcR3. In addition, in an assay of osteoclast activity on substrate plates, DcR3 significantly increased the resorption activity of mature osteoclasts. Treatment with higher concentrations of DcR3 slightly increased nodule formation and alkaline phosphatase activity of primary cultured osteoblasts. These results indicate that DcR3 may play an important role in osteoporosis or other bone diseases.

Topics: Animals; Bone Density; Bone Diseases; Cell Count; Etanercept; Gene Expression; Immunoglobulin G; Mice; Mice, Transgenic; Osteoclasts; Osteoprotegerin; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Member 6b; Receptors, Tumor Necrosis Factor, Type I; Tibia

To assess the effect of osteoprotegerin (OPG) on joint swelling, synovial inflammation and cartilage destruction, periarticular and axial bone volume, and bone turnover in rat antigen-induced arthritis (AIA).. Rats were treated with OPG (3 mg/kg/day) at regular intervals from day 1 to day 20 of AIA. Disease activity was evaluated by measurement of joint swelling as well as, joint inflammation and destruction by histology. Bone volume and cellular turnover parameters of secondary spongiosa of the right tibia head and the third lumbar vertebra were evaluated by histomorphometry. Periarticular bone volume of the primary spongiosa at the right tibia head was measured by linear scanning. The findings were compared with those of PBS-treated AIA and healthy animals.. OPG treatment did not reduce joint swelling or histological signs of inflammation. Cartilage destruction was reduced. However, this effect did not reach statistical significance . In the secondary spongiosa OPG treatment reduced the loss of periarticular bone volume. However, the latter did not reach the level of healthy controls. OPG treatment significantly reduced parameters of bone formation and bone resorption. In the primary spongiosa, OPG-treatment led to a higher amount of mineralized tissue and a greater number of trabeculae compared to PBS-treated animals with AIA or healthy controls. In the axial skeleton, OPG treatment reduced bone formation and bone resorption parameters compared to healthy animals. This treatment had no influence on bone volume.. In periarticular bone of AIA rats, OPG treatment reduced the loss of bone volume and decreased the bone turnover, thus preventing periarticular bone destruction. OPG treatment had no influence on inflammatory process or on cartilage destruction.

Topics: Animals; Antigens; Arthritis, Experimental; Bone and Bones; Bone Diseases; Disease Models, Animal; Female; Inflammation; Knee Joint; Osteoprotegerin; Rats; Rats, Inbred Lew; Time Factors

Osteoclasts (OCs) are large multinucleated cells derived from progenitor cells of the monocyte-macrophage lineage. Signal transduction via the macrophage-colony-stimulating factor (M-CSF) receptor, c-fms, is essential for OC formation. Since we have previously demonstrated inhibition of c-fms by imatinib, we examined the effect of imatinib on OC formation and activity. OC formation was not affected by concentrations of 1.0 microM imatinib and lower, but was reduced by 75% at 3.0 microM imatinib. In contrast, both the area of resorption and the number of resorption lacunae were reduced by 80% at 0.3 microM imatinib, and no resorption was observed at concentrations above 3.0 microM. A dose-dependent decrease in receptor activator of nuclear factor kappaB (RANK) expression was observed in OCs when cultured in the presence of imatinib, providing a mechanism for the decrease in OC function. In vivo analysis of the effect of imatinib on OC activity in adult mice following 8 weeks of imatinib treatment also demonstrated a decrease in OC activity. These results suggest that imatinib may have therapeutic value as an antiosteolytic agent in diseases such as osteoporosis, metastatic bone disease, and multiple myeloma.

Topics: Animals; Benzamides; Bone Diseases; Bone Resorption; Dose-Response Relationship, Drug; Glycoproteins; Humans; Imatinib Mesylate; Mice; Mice, Inbred BALB C; Monocytes; Osteoclasts; Osteoprotegerin; Piperazines; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Topics: Animals; Bone Diseases; Bone Resorption; Carrier Proteins; Disease Models, Animal; Female; Glycoproteins; Humans; Membrane Glycoproteins; Osteoclasts; Osteoporosis, Postmenopausal; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Multiple myeloma (MM) is often associated with an increased osteoclast (OC) activity. Using an in vitro osteoclastogenesis model consisting of MM unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs), we showed that T cells support OC formation and survival. Differently, in T cell-depleted MM PBMC cultures, exogenous macrophage-colony stimulating factor (M-CSF) and receptor activated of nuclear factor-kappaB ligand (RANKL) were necessary for osteoclastogenesis. We found RANKL, OPG, and TRAIL overexpression by fresh MM T cells. Despite high osteoprotegerin (OPG) levels, the persistence of osteoclastogenesis can be related to the formation of the OPG/TRAIL complex. Our results highlight that MM T cells support OC formation and survival, possibly involving OPG/TRAIL interaction.

Topics: Apoptosis Regulatory Proteins; Bone Diseases; Cells, Cultured; Female; Glycoproteins; Humans; Male; Membrane Glycoproteins; Models, Biological; Multiple Myeloma; Osteoclasts; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

To investigate whether the bone-preserving effects of a RANKL antagonist or a tumor necrosis factor (TNF) antagonist could be further improved by the addition of a bone anabolic agent in inflammatory arthritis.. Lewis rats with either adjuvant-induced arthritis (AIA) or collagen-induced arthritis (CIA) were treated for 10 days with PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI), interleukin-1 receptor antagonist (IL-1Ra), osteoprotegerin (OPG), parathyroid hormone (PTH), or combinations of these agents starting on day 4 after disease onset. Treatment effects were assessed clinically, radiologically, and histologically, and by morphometry for the extent of paw swelling, bone erosive changes, and synovial inflammation.. Paw swelling and synovial inflammation were significantly inhibited by PEG sTNFRI in AIA and CIA, and by IL-1Ra in CIA. OPG and PTH had no significant effect on these parameters. Analysis of bone erosion revealed a significant bone-sparing effect of monotherapy with PEG sTNFRI or OPG in both models, whereas IL-1Ra was only effective in CIA. PTH treatment alone did not show a bone-protective effect in either model. With the combination of PEG sTNFRI and PTH, erosion scores (-74% in AIA and -61% in CIA versus controls) were significantly lower than those elicited by PEG sTNFRI alone (-41% and -29%, respectively, versus controls). Similar results were also obtained with the combination of OPG and PTH (-88% in AIA and -73% in CIA, compared with -70% and -55%, respectively, with OPG monotherapy). Coadministration of IL-1Ra and PTH had no synergistic bone-sparing effect. Morphometric analysis revealed that the addition of PTH to PEG sTNFRI or OPG resulted in higher bone volume and higher osteoblast numbers in both AIA and CIA.. The bone-protective effects resulting from RANKL or TNF antagonism can be further improved by the addition of a bone anabolic agent.

Topics: Animals; Arthritis; Bone Development; Bone Diseases; Bone Resorption; Carrier Proteins; Cell Count; Disease Models, Animal; Drug Synergism; Female; Glycoproteins; Male; Membrane Glycoproteins; Osteoblasts; Osteoprotegerin; Parathyroid Hormone; Polyethylene Glycols; RANK Ligand; Rats; Rats, Inbred Lew; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha

It has recently been discovered that the receptor activator of nuclear kappaB-ligand (RANKL) plays a key role in the activation, differentiation and proliferation ofosteoblasts. The effects of RANKL are counteracted by the decoy receptor osteoprotegerin (OPG), which protects against bone resorption by preventing RANKL from coupling to its receptor RANK. An increase in the balance between RANKL and OPG leads to increased bone resorption (both locally and generalised), e.g. in patients with postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, multiple myeloma, other malignancies with skeletal metastases, or rheumatoid arthritis. The development of new anti-osteoporotic drugs, based on the restoration of the imbalance between RANKL and OPG, may be a breakthrough in optimising the treatment of patients with bone diseases. However, the results of studies on fracture reduction, the safety profile, the costs of the new drugs and their comparison with bisphosphonates, currently the gold standard in osteoporosis treatment, must be awaited.

Topics: Bone Diseases; Bone Resorption; Carrier Proteins; Glycoproteins; Humans; Membrane Glycoproteins; Organophosphonates; Osteoblasts; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.

Topics: Adult; Aged; Biomarkers; Bone Diseases; Bone Remodeling; Bone Resorption; Carrier Proteins; Case-Control Studies; Diphosphonates; Female; Follow-Up Studies; Glycoproteins; Hematopoietic Stem Cell Transplantation; Humans; Male; Membrane Glycoproteins; Middle Aged; Multiple Myeloma; Osteogenesis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Time Factors; Transplantation, Autologous

The development of multiple myeloma (MM) bone disease is mediated by increased number and activity of osteoclasts (OCs). Using an in vitro osteoclastogenesis model consisting of unstimulated and unfractionated peripheral blood mononuclear cells (PBMCs) from patients with MM, we showed that T cells support the formation of OCs with longer survival. Different from T-cell-depleted MM PBMC cultures, exogenous macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-kappaB ligand (RANKL) were necessary for the formation of OCs; however, they did not exhibit longer survival. We found up-regulated production of RANKL, osteoprotegerin (OPG), and TNF-related apoptosis-inducing ligand (TRAIL) by fresh MM T cells. Despite high OPG levels, the persistence of osteoclastogenesis can be related to the formation of the OPG/TRAIL complex demonstrated by immunoprecipitation experiments and the addition of anti-TRAIL antibody which decreases OC formation. OCs overexpressed TRAIL decoy receptor DcR2 in the presence of MM T cells and death receptor DR4 in T-cell-depleted cultures. In addition, increased Bcl-2/Bax (B-cell lymphoma-2/Bcl2-associated protein X) ratio, following Bcl-2 up-regulation, was detected in OCs generated in the presence of T cells. Our results highlight that MM T cells support OC formation and survival, possibly involving OPG/TRAIL interaction and unbalanced OC expression of TRAIL death and decoy receptors.

Topics: Aged; Aged, 80 and over; Apoptosis Regulatory Proteins; Bone Diseases; Case-Control Studies; Cell Survival; Cells, Cultured; Cytokines; Female; Glycoproteins; Humans; Male; Membrane Glycoproteins; Middle Aged; Multiple Myeloma; Osteoclasts; Osteoprotegerin; Protein Binding; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; T-Lymphocytes; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

Periodontitis is a complex, multifactorial process affected by bacterial plaque-components and host defense mechanisms. Inflammation of the periodontitium may lead the destruction of the underlying ligament and alveolar bone. Receptor activator of NF-kappaB ligand (RANKL), a novel TNF receptor-related protein is an important factor for osteoclast differentiation and activation. Given osteolysis by osteoclast has been demonstrated in periodontitis, we hypothesized that RANKL expression may be associated with bone destruction in periodontitis. We used semi-quantitative RT-PCR to compare the gene expression of RANKL and osteoprogerin (OPG), a decoy receptor of RANKL, between moderate and advanced periodontitis, and healthy subjects. The level of RANKL mRNA was highest in advanced periodontitis. In contrast, the level of OPG mRNA in both advanced and moderate periodontitis was lower than that in the healthy group. It appears that the ratio of RANKL to OPG mRNA in periodontitis has increased. To determine the localization of RANKL gene transcripts in gingival tissue at the cellular level, in situ hybridization was performed using digoxigenin-labeled specific riboprobes. RANKL mRNA was expressed in inflammatory cells, mainly lymphocyte and macrophages. In addition, proliferating epithelium in the vicinity of inflammatory cells expressed high levels of RANKL mRNA. In short, our data suggest that up regulation of RANKL mRNA in both inflammatory cells and epithelium may be associated with the activation of osteoclastic bone destruction in periodontitis.

Topics: Adult; Aged; Bone Diseases; Carrier Proteins; Gingiva; Glycoproteins; Humans; In Situ Hybridization; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; Periodontitis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transcription, Genetic

Cytokines are supposed to play an essential role in the regulation of the bone metabolic unit. However, information on cytokine production of primary human osteoblasts from patients with metabolic bone disease is scarce, and few attempts have been made to correlate such data to histomorphometric parameters of individual patients. We investigated 11 patients with metabolic bone disease referred to our outpatient department for bone biopsy and analyzed interleukin (IL)-1, IL-6, and TNF-alpha protein release and gene expression in primary osteoblast cultures. Compared with four controls, five patients showed normal cytokine protein release, whereas six patients showed much higher levels of interleukin-6 (26-fold) and TNF-alpha (84-fold). All three cytokines were strongly correlated concerning gene expression and/or protein levels (r = 0.72-0.96). Histomorphometric analysis of the bone samples showed that eroded surface (ES/BS) as a parameter of bone resorption was significantly associated with TNF-a. In addition, RANKL gene expression was positively associated with ES/BS and osteoclast surface (Oc.S/BS). Finally, the formation parameters osteoid volume and osteoid surface were negatively associated with TNF-alpha. In conclusion, in an in vitro-ex vivo model of bone cells obtained from a group of 11 patients with different forms of metabolic bone disease, cytokine release in conditioned medium was significantly associated with bone resorption and bone formation, as quantified by histomorphometry. TNF-alpha seemed to be the more important cytokine; its effect on bone resorption could be mediated by RANKL.

Topics: Adult; Aged; Base Sequence; Bone Diseases; Bone Remodeling; Carrier Proteins; Cytokines; DNA Primers; Female; Gene Expression; Glycoproteins; Humans; In Vitro Techniques; Male; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Interaction between receptor activator of nuclear factor kappaB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRP), and beta2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We generated a prognostic index based on these factors that divided our patients into 3 risk groups. The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively. Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.

Topics: Adult; Aged; Aged, 80 and over; beta 2-Microglobulin; Biomarkers; Bone Diseases; Bone Remodeling; C-Reactive Protein; Carrier Proteins; Cell Survival; Female; Glycoproteins; Humans; Male; Membrane Glycoproteins; Middle Aged; Multiple Myeloma; Multivariate Analysis; Osteoprotegerin; Prognosis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Severity of Illness Index; Solubility; Survival Analysis

Rheumatoid arthritis is characterized by progressive synovial inflammation and joint destruction. While matrix metalloproteinases (MMPs) are implicated in the erosion of unmineralized cartilage, bone destruction involves osteoclasts, the specialized cells that resorb calcified bone matrix. RANK ligand (RANKL) expressed by stromal cells and T cells, and its cognate receptor, RANK, were identified as a critical ligand-receptor pair for osteoclast differentiation and survival. A decoy receptor for RANKL, osteoprotegerin, (OPG) impinges on this system and regulates osteoclast numbers and activity. RANKL is also expressed in collagen-induced arthritis (CIA) in which focal collections of osteoclasts are prominent at sites of bone destruction. To determine the role of RANK signaling events in the effector phase of CIA, we investigated effects of Fc-osteoprotegerin fusion protein (Fc-OPG) in CIA. After induction of CIA in Dark Agouti rats, test animals were treated with or without Fc-OPG (3 mg/kg/day) subcutaneously for 5 days, beginning at the onset of disease. Paraffin-embedded joints were then analyzed histologically and the adjacent bone assessed by histomorphometry. Osteoclasts were identified using TRAP staining and expression of the mRNA for OPG and RANKL was identified by in situ hybridization. The results indicated that short-term Fc-OPG effectively prevented joint destruction, even though it had no impact on the inflammatory aspects of CIA. In arthritic joints, Fc-OPG depleted osteoclast numbers by over 75% and diminished bone erosion scores by over 60%. Although cartilage loss was also reduced by Fc-OPG, the effects on cartilage were less striking than those on bone. In arthritic joints OPG mRNA was highly expressed and co-localized with RANK ligand, and treatment with Fc-OPG did not affect the expression of endogenous RANKL or OPG mRNA. These data demonstrate that short term Fc-OPG treatment has powerful anti-erosive effects, principally on bone, even though synovitis is not affected. These findings indicate the potential utility of disrupting RANK signaling to preserve skeletal integrity in inflammatory arthritis.

Topics: Animals; Arthritis, Experimental; Bone Diseases; Carrier Proteins; Collagen; Glycoproteins; Membrane Glycoproteins; Osteoclasts; Osteoprotegerin; RANK Ligand; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Time Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha

Topics: Animals; Bone Diseases; Clinical Trials as Topic; Cytokines; Genetic Therapy; Glycoproteins; Humans; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Topics: Apoptosis; Bone and Bones; Bone Diseases; Cytokines; Glycoproteins; Humans; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Space Flight; Weightlessness