Loss of Protein Kinase C-d Protects against LPS-Induced Osteolysis Owing to an Intrinsic Defect in Osteoclastic

Bone remodeling is intrinsically regulated by cell signaling molecules. The Protein Kinase C (PKC) family of serine/threonine kinases is involved in multiple signaling pathways including cell proliferation, differentiation, apoptosis and osteoclast biology. However, the precise involvement of individual PKC isoforms in the regulation of osteoclast formation and bone homeostasis remains unclear. Here, we identify PKC-d as the major PKC isoform expressed among all PKCs in osteoclasts; including classical PKCs (2a, 2b and 2c), novel PKCs (2d, 2e, 2g and 2h) and atypical PKCs (2i/l and 2f). Interestingly, pharmacological inhibition and genetic ablation of PKC-d impairs osteoclastic bone resorption in vitro. Moreover, disruption of PKC-d activity protects against LPS-induced osteolysis in mice, with osteoclasts accumulating on the bone surface failing to resorb bone. Treatment with the PKC-d inhibitor Rottlerin, blocks LPS-induced bone resorption in mice. Consistently, PKC-d deficient mice exhibit increased trabeculae bone containing residual cartilage matrix, indicative of an osteoclast-rich osteopetrosis phenotype. Cultured ex vivo osteoclasts derived from PKC-d null mice exhibit decreased CTX-1 levels and MARKS phosphorylation, with enhanced formation rates. This is accompanied by elevated gene expression levels o