Regulation of Cytokine Signal Transduction and Osteoclastogenesis

This review focuses on the signal transduction of cytokine receptors and of osteoclastogenesis. Cytokines regulate cell growth, differentiation, and transformation in immune, hematopoietic, and nervous system. Many of cytokine receptors exert their functions through JAK kinases and STAT transcription factors. The suppressor of cytokine signaling (SOCS) 1 and SOCS3 proteins are induced after stimulations with several cytokines, and bind to the kinase domain of JAK kinases, thereby inhibiting kinase activity. Hence, these proteins function in a classical negative feedback loop of cytokine signaling. Bone resorbing osteoclast originates from monocyte-macrophage lineage cells. Two cytokines, macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kB ligand (RANKL) are indispensable in the osteoclast differentiation process. RANKL expressed by osteoblasts activates TRAF adaptor proteins, c-Fos, and eventually induction of nuclear factor of activated T cells (NFAT) c1, the master transcription factor of osteoclastogenesis. Cholesterol depletion suppresses the osteoclastogenesis, and the resoponse of signaling molecules to the stimulation of RANKL is disordered. With the notice that RANKL stimulates the expression of caveolin-1, which is the scaffold protein of caveolae, signaling from lipid raft seems essential for the proper differentiation signals