Conditional Knockout of PKC-δ in Osteoclasts Favors Bone Mass Accrual in Males Due to Decreased Osteoclast Function.

Protein kinase C delta (PKC-delta) functions as an important regulator in bone metabolism. However, the precise involvement of PKC-delta in the regulation of osteoclasts remains elusive. We generated an osteoclast specific PKC-delta knockout mouse strain to investigate the function of PKC-delta in osteoclast biology. Bone phenotype was investigated using microcomputed tomography. Osteoclast and osteoblast parameters were assessed using bone histomorphometry, and analysis of osteoclast formation and function with osteoclastogensis and hydroxyapatite resorption assays. The molecular mechanisms by which PKC-delta regulated osteoclast function were dissected by Western Blotting, TUNEL assay, transfection and transcriptome sequencing. We found that ablation of PKC-delta in osteoclasts resulted in an increase in trabecular and cortical bone volume in male mice, however, the bone mass phenotype was not observed in female mice. This was accompanied by decreased osteoclast number and surface, and Cathepsin-K protein levelsin vivo, as well as decreased osteoclast formation and resorptionin vitroin a male-specific manner. PKC-delta regulated androgen receptor transcription by binding to its promoter, moreover, PKC-delta conditional knockout did not increase osteoclast apoptosis but increased MAPK signaling and enhanced androgen receptor transcription and expression, finally leding to significant alterations in gene expression and signaling changes related to extracellular matrix proteins specifically in male mice. In conclusion, PKC-delta plays an important role in osteoclast formation and function in a male-specific manner. Our work reveals a previously unknown target for treatment of gender-related bone diseases.