THE MOLECULAR TRIAD SYSTEM INVOLVING RANK/RANKL/OPG AS THERAPEUTIC TARGETS FOR METABOLIC BONE DISEASES
Metabolic bone diseases are disorders of bone strength, usually caused by abnormalities of minerals (such as calcium or phosphorus), vitamin D, bone mass and/or structure. The most common metabolic bone disease is osteoporosis. It is a progressive bone disease that is characterized by a decrease in bone mass and density which can lead to an increased risk of fracture. This review was aimed at summarizing a plenty of literatures related to the impact of RANK/RANKL/OPG system on bone metabolic diseases and therapeutic agents targeting it. Data were collected from several legitimate data bases and services such as Pubmed, Pub med central, Medline, Hinari, Scopus, and other data base sources like Crossref, and Google scholar with the help of key words (RANK/RANKL/OPG system, metabolic bone diseases etc.). Important data on the topic of interest were filtered properly. The role of RANK/RANKL/OPG system is well characterized within bone, where RANKL-RANK signaling mediates osteoclastogenesis, osteoclast activation and bone resorption via paracrine signaling between osteoblast and osteoclast cells. OPG produced by osteoblast and stromal cells in bone acts as a natural RANKL antagonist (decoy receptor) that intereferes with RANKL-RANK binding and hence prevents osteoclast differentiation and activation. This system and its interaction with various cytokines and calciotropic hormones in the regulation of osteoclastogenesis has led to a new era for further understanding of the pathophysiology of several disorders of bone metabolism including osteoporosis, primary bone tumors and rheumatoid arthritis. The system has also resulted in the recognition of several rare genetic disorders of bone mineral metabolism such as paget's disease, familial expansile osteolysis and osteopetrosis. Since this cytokine system plays a major role in the pathogenesis of many disorders, several therapeutic agents targeting this system are being developed. Among them, denosumab, a monoclonal antibody against RANKL, is clinically approved for the treatment of osteoporosis and cancer-related bone diseases.
Key words: RANK/RANKL/OPG system, metabolic bone diseases, potential therapeutic approaches
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