Novel osteoclast signaling mechanisms.
Osteoclasts are cells of monocyte/macrophage origin that degrade bone matrix. Receptor activator of NF-kappaB ligand (RANKL) induces osteoclast differentiation in the presence of macrophage colony-stimulating factor. RANKL activates the tumor necrosis factor receptor-associated factor 6, c-Fos, and calcium signaling pathways, all of which are indispensable for the induction and activation of nuclear factor of activated T cells (NFAT) c1. NFATc1 is the master transcription factor for osteoclast differentiation, which regulates many osteoclast-specific genes. Multiple immunoglobulin-like receptors associated with immunoreceptor tyrosine-based activation motif (ITAM)-harboring adapters, Fc receptor common chi subunit (FcRgamma), and DNAX-activating protein (DAP) 12 mediate costimulatory signals for RANK, which activate calcium signaling through phospholipase Cgamma (PLCgamma). In addition to calcineurin-NFATc1, calcium signaling activates the CaMK-CREB (calcium/calmodulin activated kinase-cyclic AMP-response element binding protein) pathway, which also plays a critical role in osteoclastogenesis. This review summarizes recent advances in the study of signaling mechanisms of osteoclast differentiation.
Shinohara
Masahiro
M
Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University and COE Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8549, Japan. taka.csi@tmd.ac.jp
Takayanagi
Hiroshi
H
D020013:Calcium Signaling / Q000502:physiology*; D006801:Humans; D050778:NFATC Transcription Factors; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism*; D010024:Osteoporosis / Q000209:etiology; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B
D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B