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

Katherine N. Weilbaecher, Gabriela Motyckova, Wade E. Huber, Clifford M Takemoto, Timothy J. Hemesath, Ying Xu, Christine L. Hershey, Nikki R. Dowland, Audrey G. Wells, David E. Fisher

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Abstract

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. Mitf and TFE3 are two closely related helix-loop-helix (HLH) transcription factors previously implicated in osteoclast development and function. We demonstrate that cultured Mitfmi/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 Mitf 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 Mitfmi/mi mice. These results identify a signaling pathway that appears to coordinate cytokine signaling with the expression of genes vital to osteoclast development.

Original languageEnglish (US)
Pages (from-to)749-758
Number of pages10
JournalMolecular Cell
Volume8
Issue number4
DOIs
StatePublished - 2001

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ASJC Scopus subject areas

  • Molecular Biology

Cite this

Weilbaecher, K. N., Motyckova, G., Huber, W. E., Takemoto, C. M., Hemesath, T. J., Xu, Y., Hershey, C. L., Dowland, N. R., Wells, A. G., & Fisher, D. E. (2001). Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitfmi/mi mice. Molecular Cell, 8(4), 749-758. https://doi.org/10.1016/S1097-2765(01)00360-4