Molecular mechanisms underlying osteoclast formation and activation

Osteoporosis is one of the leading causes of morbidity in the elderly and is characterized by a progressive loss of total bone mass and bone density. Bone loss in osteoporosis is due to the persistent excess of osteoclastic bone resorption over osteoblastic bone formation. Receptor activator of NFkappaB ligand (RANKL) critically regulates both osteoclast differentiation and activation. TRAFs appear to be central coupling molecules in the signal transduction pathways that regulate osteoclastogenesis, cathepsin K is the major mediator of osteoclastic bone resorption, and sex steroids and aging also affect osteoclastogenesis and osteoclast activity. However, bone homeostasis depends upon the intimate coupling of bone formation and bone resorption, wherein both osteoclasts and osteoblasts exert vital stimulatory and inhibitory effects upon each other via molecules such as RANKL, TGFbeta, PDGF, BMP2, and Mim-1. This review will highlight some of the major features of the complex circuit of cytokines, growth factors, and hormones that underlies the formation and function of osteoclasts and the dynamic equilibrium that marks the interaction between osteoclasts and osteoblasts.