osteoprotegerin and Osteogenesis-Imperfecta

Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs), the bone-reabsorbing cells, and osteoblasts (OBs), and the bone-forming cells. This equilibrium is regulated by numerous cytokines, but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/β-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis, respectively. The pro-osteoblastogenic activity of the Wnt/β-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1). RANKL, sclerostin and DKKs-1 are often up-regulated in bone diseases, and they are the target of new monoclonal antibodies.. The authors performed a systematic literature search in PubMed and EMBASE to June 2018, reviewed and selected articles, based on pre-determined selection criteria.. We re-evaluated the role of RANKL, osteoprotegerin, sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases, such as type 1 diabetes mellitus (T1DM), alkaptonuria (AKU), hemophilia A, osteogenesis imperfecta (OI), 21-hydroxylase deficiency (21OH-D) and Prader-Willi syndrome (PWS). To do so, we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways have been investigated, and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed.. The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases. Furthermore, for some of them, bone damage began in childhood but only manifested with age. The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children, although further studies need to be carried out.

Topics: Adrenal Hyperplasia, Congenital; Alkaptonuria; Biomarkers; Bone Remodeling; Bone Resorption; Child; Diabetes Mellitus, Type 1; Hemophilia A; Humans; Intercellular Signaling Peptides and Proteins; Osteogenesis Imperfecta; Osteoprotegerin; Prader-Willi Syndrome; RANK Ligand; Up-Regulation; Wnt Signaling Pathway

Osteoporosis is a systemic skeletal disease characterized by low bone mass and the microarchitectural deterioration of bone tissue. The pathophysiology of osteoporosis is complex, involving a broad spectrum of endogenous and environmental factors. Recently, molecular and genetic approaches are revealing that genetic backgrounds are important for the pathophysiology of osteoporosis. We discuss about recent findings of osteoporosis and osteopenia caused by monogenic mutations in humans and mice.

Topics: Animals; Bone Diseases, Metabolic; Glycoproteins; Humans; LDL-Receptor Related Proteins; Low Density Lipoprotein Receptor-Related Protein-5; Mice; Mice, Mutant Strains; Mice, Transgenic; Osteitis Deformans; Osteogenesis Imperfecta; Osteoporosis; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

In this study, we investigated the bone cell activity in patients with osteogenesis imperfecta (OI) treated and untreated with neridronate. We demonstrated the key role of Dickkopf-1 (DKK1), receptor activator of nuclear factor-κB ligand (RANKL), and tumor necrosis factor alpha (TNF-α) in regulating bone cell of untreated and treated OI subjects. These cytokines could represent new pharmacological targets for OI.. Bisphosphonates are widely used in the treatment of children with osteogenesis imperfecta (OI) with the objective of reducing the risk of fractures. Although bisphosphonates increase bone mineral density in OI subjects, the effects on fracture incidence are conflicting. The aim of this study was to investigate the mechanisms underlying bone cell activity in subjects with mild untreated forms of OI and in a group of subjects with severe OI treated with cycles of intravenous neridronate.. Sclerostin, DKK1, TNF-α, RANKL, osteoprotegerin (OPG), and bone turnover markers were quantified in serum of 18 OI patients (12 females, mean age 8.86 ± 3.90), 8 of which were receiving cyclic intravenous neridronate, and 21 sex- and age-matched controls. The effects on osteoblastogenesis and OPG expression of media conditioned by the serum of OI patients and anti-DKK1 neutralizing antibody were evaluated. Osteoclastogenesis was assessed in cultures from patients and controls.. DKK1 and RANKL levels were significantly increased both in untreated and in treated OI subjects with respect to controls. The serum from patients with high DKK1 levels inhibited both osteoblast differentiation and OPG expression in vitro. High RANKL and low OPG messenger RNA (mRNA) levels were found in lymphomonocytes from patients. High amounts of TNF-α were expressed by monocytes, and an elevated percentage of circulating CD11b-CD51/CD61+ osteoclast precursors was observed in patients.. Our study demonstrated the key role of DKK1, RANKL, and TNF-α in regulating bone cell activity of subjects with OI untreated and treated with bisphosphonates. These cytokines could represent new pharmacological targets for OI patients.

Topics: Adaptor Proteins, Signal Transducing; Bone Morphogenetic Proteins; Bone Remodeling; Child; Diphosphonates; Female; Genetic Markers; Glycoproteins; Humans; Intercellular Signaling Peptides and Proteins; Male; Osteoclasts; Osteogenesis; Osteogenesis Imperfecta; Osteoprotegerin; RANK Ligand; Tumor Necrosis Factor-alpha

Receptor activator of nuclear factor-κB ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, osteoprotegerin-immunoglobulin Fc segment complex (OPG-Fc), in a growing animal model of OI, the col1α2-deficient mouse (oim/oim) and its wild-type controls (+/+).. Treated mice showed runting and radiographic evidence of osteopetrosis with either high- (20 mg/kg twice weekly) or low-dose (1 mg/kg/week) OPG-Fc. Because of this adverse event, OPG-Fc treatment was halted, and the mice were killed or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (tartrate-resistant acid phosphatase 5b, TRACP-5b) until 25 wk of age.. Twelve weeks of OPG-Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative tartrate-resistant acid phosphatase staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared 4-8 wk post-treatment.. Both high- and low-dose OPG-Fc treatment resulted in osteopetrotic changes in infant mice, an outcome that was not seen in studies with the RANKL inhibitor RANK-immunoglobulin Fc segment complex (RANK-Fc) or in studies with older animals. Further investigations of RANKL inhibitors are necessary before their consideration for use in children.

Topics: Acid Phosphatase; Age Factors; Animals; Biomarkers; Bone Remodeling; Collagen Type I; Dentin; Disease Models, Animal; Female; Immunoconjugates; Immunoglobulin Fc Fragments; Isoenzymes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoclasts; Osteogenesis Imperfecta; Osteopetrosis; Osteoprotegerin; Radiography; RANK Ligand; Risk Assessment; Tartrate-Resistant Acid Phosphatase; Time Factors; Tooth Eruption; Weight Gain