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

Osteoclasts are multinucleated hematopoietic cells essential for bone resor ption. Macrophage colony-stimulating factor (M-CSF) is critical for osteocl ast development and function, although its nuclear targets in osteoclasts a re 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 imm ature, mononuclear, express low levels of TRAP, and fail to mature upon M-C SF 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 M APK consensus serine is specifically deficient in formation of multinucleat ed osteoclasts, mimicking the defect in Mitf(mi/mi) mice. These results ide ntify a signaling pathway that appears to coordinate cytokine signaling wit h the expression of genes vital to osteoclast development.