RANK Signaling in Osteoclasts

Receptor activator of NF-κB ligand (RANKL), also known as OPGL, TRANCE, ODF and TNFSF11, is a member of the TNF family. RANKL and its receptor, RANK (TNFRSF11A) are key regulators of bone remodeling and are essential for the development and activation of osteoclasts. RANKL induces the differentiation of osteoclast precursor cells and stimulates the resorption and survival of mature osteoclasts. Bone remodeling results from the coordinate action of bone resorption by osteoclasts and the formation of new bone by osteoblasts. TRAF adaptor proteins play an important role in initial events of the signal transduction pathways induced by RANK. TRAF2, TRAF5 and TRAF6 bind through a conserved domain to RANK. Among the TRAF proteins, TRAF6 is especially critical for RANK signaling in osteoclasts. TRAF proteins act by activating downstream, Raf/MEK/ERK, MEKK/MKK7/JNK and IKK/NF-κB signaling pathways. These pathways activate various transcriptions factors such as Elk-1, MITF and NFAT2 which increase the expression of osteogenic genes, leading to osteoclast differentiation.TRAF6 plays an important role in osteoclast survival and resorption. Src and the TAB2-TAK1 complex are mediators of TRAF6 signaling. Among the many molecules downstream of Src, PYK2 and c-Cbl are implicated in osteoclast adhesion signaling and bone resorption function. While the association of the actin-binding protein gelsolin with PI3K is important in actin filament formation in osteoclasts, Src activates the PI3K/AKT pathway for osteoclast survival.Increased osteoclast activity is seen in many osteopenic disorders including postmenopausal osteoporosis, Paget's disease, lytic bone metastases and rheumatoid arthritis, leading to increased bone resorption and crippling bone damage. Inhibition of RANKL function via the natural decoy receptor OPG prevents bone loss in postmenopausal osteoporosis and cancer metastases, and is useful to treat osteoporosis and bone loss and pain associated with bone metastases.