osteoprotegerin and Osteosclerosis

Paget's disease was first described more than 150 years ago, but the exact cause is still unknown--genes and the environment are both important. This article explores the basic science and clinical aspects of this intriguing condition.

Topics: Adaptor Proteins, Signal Transducing; Alkaline Phosphatase; Bone and Bones; Bone Density Conservation Agents; Diphosphonates; Humans; Orthopedic Procedures; Osteitis Deformans; Osteolysis; Osteoprotegerin; Osteosclerosis; Radiography; Receptor Activator of Nuclear Factor-kappa B; Sequestosome-1 Protein

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: Absorptiometry, Photon; Aged; Antineoplastic Agents; Bone Density; Bone Marrow Examination; Cladribine; Humans; Immunohistochemistry; Injections, Subcutaneous; Leukemia, Hairy Cell; Male; Osteoprotegerin; Osteosclerosis; Positron-Emission Tomography; Treatment Outcome

Osteosclerotic metastases account for 20% of breast cancer metastases with the remainder osteolytic or mixed. In mouse models, osteolytic metastases are dependent on bone resorption for their growth. However, whether the growth of osteosclerotic bone metastases depends on osteoclast or osteoblast actions is uncertain. In this study, we investigate the effects of high and low bone resorption on tumour growth in a mouse model of osteosclerotic metastasis. We implanted human breast cancer, MCF-7, cells into the tibiae of mice. Low and high levels of bone resorption were induced by osteoprotegerin (OPG) treatment or calcium deficient diet respectively. We demonstrate that OPG treatment significantly reduces tumour area compared to vehicle (0.42 +/- 0.06 vs. 1.27 +/- 0.16 mm2, P < 0.01) in association with complete inhibition of osteoclast differentiation. In contrast, low calcium diet increases tumour area compared to normal diet (0.90 +/- 0.30 vs. 0.58 +/- 0.20 mm2, P < 0.05) in association with increased osteoclast numbers (84.44 +/- 5.18 vs. 71.11 +/- 3.56 per mm2 bone lesion area, P < 0.05). Osteoblast surfaces and new woven bone formation were similarly increased within the tumour boundaries in all treatment groups. Tumour growth in this model of osteosclerotic metastasis is dependent on ongoing bone resorption, as has been observed in osteolytic models. Bone resorption, rather than bone formation, apparently mediates this effect as osteoblast surfaces in the tumour mass were unchanged by treatments. Treatment of breast cancer patients through correction of calcium deficiency and/or with anti-resorptive agents such as OPG, may improve patient outcomes in the adjuvant as well as palliative settings.

Topics: Animals; Bone Neoplasms; Bone Resorption; Calcium; Cell Differentiation; Diet; Disease Models, Animal; Female; Humans; Mammary Neoplasms, Experimental; Mice; Mice, Nude; Osteoblasts; Osteoclasts; Osteoprotegerin; Osteosclerosis

Topics: Aged; Hepatitis C; Humans; Male; Osteoblasts; Osteoprotegerin; Osteosclerosis; RANK Ligand

Hepatitis C-associated osteosclerosis (HCAO) is an impressive example of acquired diffuse osteosclerosis in adults, recently described in ten patients infected with hepatitis C virus (HCV). Its hallmark is a painful and generalized increase of bone mass. Bone biopsies show enhanced accretion rate, usually without histological abnormalities. The HCAO pathogenesis is hitherto unknown. HCV might induce a slow bone cell infection and the production of bone growth factors, such as insulin-like growth factors. Recently, receptor activator of nuclear factor-kappaB (RANK), its ligand (RANKL), and soluble decoy receptor osteoprotegerin (OPG) have been identified as a pivotal cytokine system in the bone remodeling control. We describe the 11th case of HCAO. Notably, the patient's bone biopsy showed the presence of a high number of OPG-positive osteoblasts, a slight increase of RANKL-positive stromal cells, and a dramatic reduction of the osteoclasts. Moreover, OPG serum levels were increased. These findings reported here for the first time are consistent with a pathogenetic role of the OPG/RANKL system imbalance in HCAO.

Topics: Absorptiometry, Photon; Aged; Biomarkers; Biopsy; Bone and Bones; Bone Density; Bone Remodeling; Carrier Proteins; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Glycoproteins; Hepacivirus; Hepatitis C Antibodies; Humans; Immunoblotting; Ligands; Male; Membrane Glycoproteins; Osteoblasts; Osteoprotegerin; Osteosclerosis; Radionuclide Imaging; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral

Advanced chronic idiopathic myelofibrosis (IMF) with osteosclerosis and increase and thickening of bone trabeculae is typically contrasted by the absence or sparse presence of osteoclasts. Because osteoclast formation can be inhibited by osteoprotegerin (OPG) we investigated OPG expression in IMF with severe fibrosis and osteosclerosis, which expressed significantly higher (up to 71-fold) OPG mRNA levels when compared with prefibrotic cellular IMF and control cases. The receptor activator of nuclear factor kappaB ligand (RANKL), a positive regulator of osteoclast differentiation and putative antagonist of OPG was overexpressed by up to 34-fold exclusively in advanced IMF. Case-specific calculation of the RANKL/OPG ratio in advanced IMF showed a wide range without significant differences when compared with the prefibrotic IMF and non-neoplastic haematopoiesis. Immunohistochemical detection of OPG protein revealed strong labelling of endothelial cells within proliferating vessels in fibrotic IMF and heterogeneously labelled megakaryocytes, and fibroblasts. Osteosclerosis and impaired osteoclast function in IMF appears to be associated with upregulated endothelial OPG expression but concomitant reduction of the antagonist RANKL could not be demonstrated. We conclude that osteosclerosis in IMF is associated with increased endothelial OPG expression without concomitant RANKL downregulation.

Topics: Adult; Aged; Aged, 80 and over; Bone Marrow Examination; Carrier Proteins; Endothelial Cells; Female; Fibroblasts; Glycoproteins; Humans; Immunohistochemistry; Male; Megakaryocytes; Membrane Glycoproteins; Middle Aged; Osteoclasts; Osteoprotegerin; Osteosclerosis; Primary Myelofibrosis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

We report a new case of hepatitis C-associated osteosclerosis (HCAO). The clinical presentation of the patient was an acquired deep severe bone pain with increased serum bone alkaline phosphatase activity (up to 12 times the upper limit of normal), and generalized bone sclerosis, temporally related to the hepatitis C-virus (HCV) infection. We documented in this patient an increase of circulating osteoprotegerin (OPG), and a concentration of circulating receptor activator for nuclear factor-kB ligand (RANKL) below the lower limit of the reference range. The observed abnormalities of the OPG/RANKL system may contribute to the maintenance of the positive balance of bone remodeling that characterizes patients with HCAO.

Topics: Aged; Alkaline Phosphatase; Bone Density; Carrier Proteins; Female; Femur; Glycoproteins; Hepatitis C; Humans; Membrane Glycoproteins; Osteoprotegerin; Osteosclerosis; Pelvis; Radiography; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

We came across a rare case of acute megakaryocytic leukemia, the clinical course of which was relatively chronic and nonaggressive. This case was complicated with generalized severe osteosclerosis (OS). The medium in which blastic cells from the patient were cultured showed a strong activity to enhance the expression of an osteosclerotic cytokine, osteoprotegerin (OPG), as revealed by real-time quantitative RT-PCR and Western blot analysis. The OPG-inducing activity of the culture medium was neutralized by the anti-interleukin-11 (IL-11) antibody. These results indicate that IL-11 produced by the blasts was a causative factor of the OS observed in this patient.

Topics: Adult; Blast Crisis; Glycoproteins; Humans; Interleukin-11; Leukemia, Megakaryoblastic, Acute; Male; Osteoprotegerin; Osteosclerosis; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Tumor Cells, Cultured; Up-Regulation

The aim of this study is to investigate the mechanism of osteosclerosis in IMF in relation to OPG derangement.. Plasma OPG level was assayed by OPG ELISA in 19 patients with IMF, 15 patients with other myeloproliferative disorders (MPDs), and 12 normal volunteers as controls and correlated with the degree of osteosclerosis. Furthermore, the level of OPG mRNA, in the cultured bone marrow stromal (BMS) cells of patients with IMF and anemia patients used as controls, in the presence or absence of TGF-beta1, was studied by real-time RT-PCR.. The present study showed that blood OPG level was significantly elevated in patients with IMF as compared to patients with other MPDs (p < 0.01) or normal volunteer controls (p < 0.05), and there was no significant difference in the level between patients with MPDs and controls. In addition, there was a positive correlation (r=0.67, p=0.04) between plasma OPG levels and the degree of osteosclerosis. There was no difference in the OPG mRNA in patients with IMF as compared with controls even on TGF-beta1 stimulation.. These results suggest that osteosclerosis in IMF may be related to overproduction of OPG and enhanced level of OPG is not due to the effect of TGF-beta1 on the BMS cells. It could be due to the effect of TGF-beta1 or other growth factors on cells other than BMS cells such as the osteoblasts.

Topics: Bone Marrow Cells; Case-Control Studies; Cells, Cultured; Glycoproteins; Humans; Myeloproliferative Disorders; Osteoprotegerin; Osteosclerosis; Primary Myelofibrosis; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; RNA, Messenger; Stromal Cells; Transforming Growth Factor beta; Transforming Growth Factor beta1

Myelofibrosis and osteosclerosis are prominent features arising in mice overexpressing thrombopoietin (TPO). The pivotal role of transforming growth factor beta 1 (TGF-beta 1) in the pathogenesis of myelofibrosis has been documented, but the mechanisms mediating osteosclerosis remain unclear. Here, we used mice deficient in osteoprotegerin (OPG), a secreted inhibitor of bone resorption, to determine whether osteosclerosis occurs through a deregulation of osteoclastogenesis. Marrow cells from opg-deficient mice (opg(-/-)) or wild-type (WT) littermates were infected with a retrovirus encoding TPO and engrafted into an opg(-/-) or WT background for long-term reconstitution. The 4 combinations of graft/host (WT/WT, opg(-/-)/opg(-/-), opg(-/-)/WT, and WT/opg(-/-)) were studied. Elevation of TPO and TGF-beta 1 levels in plasma was similar in the 4 experimental groups and all the mice developed a similar myeloproliferative syndrome associated with severe myelofibrosis. Osteosclerosis developed in WT hosts engrafted with WT or opg(-/-) hematopoietic cells and was associated with increased OPG levels in plasma and decreased osteoclastogenesis. In contrast, opg(-/-) hosts exhibited an osteoporotic phenotype and a growth of bone trabeculae was rarely seen. These findings suggest that osteosclerosis in mice with TPO overexpression occurs predominantly via an up-regulation of OPG in host stromal cells leading to disruption of osteoclastogenesis.

Topics: Animals; Bone and Bones; Bone Marrow Transplantation; Cells, Cultured; Disease Models, Animal; Gene Expression Regulation; Genetic Vectors; Glycoproteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloproliferative Disorders; Osteoclasts; Osteoporosis; Osteoprotegerin; Osteosclerosis; Primary Myelofibrosis; Radiation Chimera; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins; Retroviridae; Thrombopoietin; Transduction, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1