title: RANKL downregulates cell surface CXCR6 expression through JAK2/STAT3 signaling pathway during osteoclastogenesis.
abstract: The receptor activator of nuclear factor-κB ligand (RANKL), as a member of the tumor necrosis factor (TNF) family, plays an essential role in osteoclast differentiation and function. Chemokines and their receptors have recently been shown to play critical roles in osteoclastogenesis, however, whether CXCL16-CXCR6 plays role in RANKL-mediated osteoclastogenesis is unknown. In this study, we first reported that RANKL decreased CXCR6 in a dose-dependent manner, which may be through deactivation of Akt and STAT3 signaling induced by CXCL16. Interestingly, RANKL-mediated CXCR6 reduction may be associated to the activation of STAT3 by phosphorylation. When STAT3 activation was blocked by JAK2/STAT3 inhibitor AG490, RANKL failed to shut down CXCR6 expression during osteoclastogenesis. However, CXCL16 alone did not augment RANKL-mediated osteoclast differentiation and did not alter RANKL-receptor RANK mRNA expression. These results demonstrate that reduction of CXCL16-CXCR6 is critical in RANKL-mediated osteoclastogenesis, which is mainly through the activation of JAK2/STAT3 signaling. CXCL16-CXCR6 axis may become a novel target for the therapeutic intervention of bone resorbing diseases such as rheumatoid arthritis and osteoporosis.
authors.affiliation: Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, PR China.
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.forename: Jinxia
authors.initials: J
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Zhongqiang
authors.initials: Z
authors.lastname: Yao
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Huang
authors.forename: Xiangyuan
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000378:metabolism; D015536:Down-Regulation; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism* / Q000494:pharmacology; D054387:Receptors, CXCR / Q000378:metabolism*; D000075744:Receptors, CXCR6; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; C498926:Cxcl16 protein, mouse; C482906:Cxcr6 protein, mouse; D053245:RANK Ligand; D054387:Receptors, CXCR; D000075744:Receptors, CXCR6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2