Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitfmi/mi mice

被引:120
作者
Weilbaecher, KN
Motyckova, G
Huber, WE
Takemoto, CM
Hemesath, TJ
Xu, Y
Hershey, CL
Dowland, NR
Wells, AG
Fisher, DE [1 ]
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Cambridge, MA 02138 USA
[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Cambridge, MA 02138 USA
[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[4] Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO 63110 USA
[5] Johns Hopkins Univ, Div Pediat Hematol, Baltimore, MD 21205 USA
[6] Decode Genet, IS-110 Reykjavik, Iceland
关键词
D O I
10.1016/S1097-2765(01)00360-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Osteoclasts are multinucleated hematopoietic cells essential for bone resorption. Macrophage colony-stimulating factor (M-CSF) is critical for osteoclast development and function, although its nuclear targets in osteoclasts are largely unknown. Miff and TFE3 are two closely related helix-loop-helix (HLH) transcription factors previously implicated in osteoclast development and function. We demonstrate that cultured Mitf(mi/mi) osteoclasts are immature, mononuclear, express low levels of TRAP, and fail to mature upon M-CSF stimulation. In addition, M-CSF induces phosphorylation of Miff and TFE3 via a conserved MAPK consensus site, thereby triggering their recruitment of the coactivator p300. Furthermore, an unphosphorylatable mutant at the MAPK consensus serine is specifically deficient in formation of multinucleated osteoclasts, mimicking the defect in Mitf(mi/mi) mice. These results identify a signaling pathway that appears to coordinate cytokine signaling with the expression of genes vital to osteoclast development.
引用
收藏
页码:749 / 758
页数:10
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