Phospholipase Cγ1 (PLCγ1) Controls Osteoclast Numbers via Colony-stimulating Factor 1 (CSF-1)-dependent Diacylglycerol/β-Catenin/CyclinD1 Pathway
Phospholipases C gamma (PLC gamma) 1 and 2 are a class of highly homologous enzymes modulating a variety of cellular pathways through production of inositol 1,4,5-trisphosphate and diacylglycerol (DAG). Our previous studies demonstrated the importance of PLC gamma 2 in osteoclast (OC) differentiation by modulating inositol 1,4,5-trisphosphate-mediated calcium oscillations and the up-regulation of the transcription factor NFATc1. Surprisingly, despite being expressed throughout osteoclastogenesis, PLC gamma 1 did not compensate for PLC gamma 2 deficiency. Because both isoforms are activated during osteoclastogenesis, it is plausible that PLC gamma 1 modulates OC development independently of PLC gamma 2. Here, we utilized PLC gamma 1-specific shRNAs to delete PLC gamma 1 in OC precursors derived from wild type (WT) mice. Differently from PLC gamma 2, we found that PLC gamma 1 shRNA significantly suppresses OC differentiation by limiting colony-stimulating factor 1 (CSF-1)-dependent proliferation and beta-catenin/cyclinD1 levels. Confirming the specificity toward CSF-1 signaling, PLC gamma 1 is recruited to the CSF-1 receptor following exposure to the cytokine. To understand how PLC gamma 1 controls cell proliferation, we turned to its downstream effector, DAG. By utilizing cells lacking the DAG kinase zeta, which have increased DAG levels, we demonstrate that DAG modulates CSF-1-dependent proliferation and beta-catenin/cyclinD1 levels in OC precursors. Most importantly, the proliferation and osteoclastogenesis defects observed in the absence of PLC gamma 1 are normalized in PLC gamma 1/DAG kinase zeta double null cells. Taken together, our study shows that PLC gamma 1 controls OC numbers via a CSF-1-dependent DAG/beta-catenin/cyclinD1 pathway.
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