title: AG490 inhibits NFATc1 expression and STAT3 activation during RANKL induced osteoclastogenesis.
abstract: Commonly, JAK/STAT relays cytokine signals for cell activation and proliferation, and recent studies have shown that the elevated expression of JAK/STAT is associated with the immune rejection of allografts and the inflammatory processes of autoimmune disease. However, the role which JAK2/STAT3 signaling plays in the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis is unknown. In this study, we investigated the effects of AG490, specific JAK2 inhibitor, on osteoclast differentiation in vitro. AG490 significantly inhibited osteoclastogenesis in murine osteoclast precursor cell line RAW264.7 induced by RANKL. AG490 suppressed cell proliferation and delayed the G1 to S cell cycle transition. Furthermore, AG490 also suppressed the expression of nuclear factor of activated T cells (NFAT) c1 but not c-Fos in RAW264.7. Subsequently, we investigated various intracellular signaling components associated with osteoclastogenesis. AG490 had no effects on RANKL-induced activation of Akt, ERK1/2. Interestingly, AG490 partly inhibited RANKL-induced phosphorylation of Ser(727) in STAT3. Additionally, down-regulation of STAT3 using siRNA resulted in suppression of TRAP, RANK and NFATc1 expression. In conclusion, we demonstrated that AG490 inhibited RANKL-induced osteoclastogenesis by suppressing NFATc1 production and cell proliferation via the STAT3 pathway. These results suggest that inhibition of JAK2 may be useful for the treatment of bone diseases characterized by excessive osteoclastogenesis.
authors.affiliation: Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, PR China.
authors.forename: Chang-hong
authors.initials: CH
authors.lastname: Li
authors.forename: Jin-xia
authors.initials: JX
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Zhong-qiang
authors.initials: ZQ
authors.lastname: Yao
authors.forename: Xiao-li
authors.initials: XL
authors.lastname: Deng
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Xiang-yuan
authors.initials: XY
authors.lastname: Liu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C505689:Tnfsf11 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide