Fyn positively regulates the activation of DAP12 and FcR纬-mediated costimulatory signals by RANKL during osteoclastogenesis

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• 作者：H.S. Kim^a ; ¹ ; D.K. Kim^a ; ¹ ; A.R. Kim^a ; S.H. Mun^a ; ^b ; S.K. Lee^b ; J.H. Kim^a ; Y.M. Kim^c ; W.S. Choi^a ; ^{wahnchoi@kku.ac.kr}
• 关键词：Fyn ; Costimulatory signal ; FcR纬 ; DAP12 ; Osteoclast ; Differentiation
• 刊名：Cellular Signalling
• 出版年：2012
• 期刊代码：42_08986568
• 类别：bio
• 出版时间：June, 2012
• 卷：24
• 期：6
• 页码：1306-1314
• 文件大小：1662 K

摘要

Osteoclasts (OCs) are the only bone-resorbing cells and are critically involved in various bone-associated diseases, including osteoporosis and rheumatoid arthritis. Differentiation of OCs from bone marrow macrophage cells (BMMs) is regulated by RANK and the adaptor protein (DAP12/FcR纬)-mediated costimulatory signals. However, it is unknown how RANKL/RANK signal stimulates phosphorylation of DAP12/FcR纬 to initiate the costimulatory signals. As reported here, we found that OC differentiation and acquisition of bone resorption capacity were suppressed in RANKL-stimulated Fyn^{鈭?鈭?/sup> or Fyn-siRNA-transfected BMMs, but could be restored by overexpression of Fyn kinase in Fyn鈭?鈭?/sup> BMMs. However, the RANKL-stimulated proliferation of BMMs was unaffected by the absence of Fyn. In addition, RANKL-stimulated Fyn鈭?鈭?/sup> BMMs no longer exhibited the optimal induction of typical OC markers such as NFATc1, c-Fos, c-Src, TRAF6, and cathepsin K or costimulatory signals such as the activating phosphorylations of Syk, PLC纬2, and Gab2. These were restored by overexpression of Fyn in Fyn鈭?鈭?/sup> BMMs. Immunoprecipitation studies also indicated that the adaptor proteins DAP12/FcR纬 and Syk interacted with RANK during RANKL stimulation in BMMs in a Fyn-dependent manner. Phosphorylation of the DAP12/FcR纬 and the recruitment of Syk by DAP12/FcR纬 were suppressed in Fyn鈭?鈭?/sup> BMMs. This is the first demonstration that Fyn relays the initial RANK/RANKL signal to the ITAM-containing adaptors DAP12/FcR纬 for OC differentiation.}