Most of the physiological effects of the rennin-angiotensin system (RAS) are mediated by angiotensin II (AgII) type one receptors (AT1R), producing cellular dedifferentiation and proliferation; vasoconstriction; renal tubule sodium (Na+) reabsorption etc. However, the pathophysiologic role of AgII type two receptor (AT2R) has not been clearly defined yet. This review was, therefore, aimed at summarizing a plenty of primary literatures related to the role of AT2R. AT2R is a special G protein coupled receptor that is not coupled with the usual second messengers. The expression level of AT2R is greater in the neonates and fetal ages than in adults though its expression is up-regulated following tissue injury in adults implicating its role in regulating cell differentiation, growth and inflammations. Most of the cellular actions mediated by AT2R are counter regulatory to that of AT1R. AgII produces the cellular effects by acting on AT2R via different signal transduction pathways. The common cellular effects mediated by AT2R are antiproliferative, anti-inflammatory, vasodilation, natriuresis, etc which may be essential for modulating the cardiovascular, renal and brain injuries caused by different etiologies. The principal molecular signal transductions mediated by AT2R involve stimulation of the bradykinin and/or nitric oxide-cGMP pathwy, inactivation of mitogen activated protein kinase pathway by stimulating tyrosine and serine/threonien phosphatses, production of the neuroprotective factors, like BDNF, etc. These signaling pathways may exert cardio-renal and neuroprotective functions. Therefore, the development of drugs that stimulate the AT2R may the potential target to promote the treatment of different disorders related to the cardiovascular, renal and brain dysfunctions.

Introduction: 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 to summarize a plenty of literatures related to the impact of Receptor Activator of Nuclear factor k-B (RANK)/RANK Ligand/Osteoprotegrin (OPG) system on bone metabolic diseases and therapeutic agents targeting this system. Method: 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.). The data collection was carried out from July to October, 2016. Important data on the topic of interest were filtered properly. Review body: 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. Conclusion: 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.