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 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 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 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 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.
Weilbaecher
K N
KN
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Motyckova
G
G
Huber
W E
WE
Takemoto
C M
CM
Hemesath
T J
TJ
Xu
Y
Y
Hershey
C L
CL
Dowland
N R
NR
Wells
A G
AG
Fisher
D E
DE
D020816:Amino Acid Motifs; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D051739:Microphthalmia-Associated Transcription Factor; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010022:Osteopetrosis / Q000503:physiopathology; D010766:Phosphorylation; D014157:Transcription Factors / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D007202:Indicators and Reagents; D008164:Luminescent Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; C069203:TFE3 protein, human; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D016173:Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases