| First Author | Khor EC | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 8 | Pages | e70815 |
| PubMed ID | 23951014 | Mgi Jnum | J:205893 |
| Mgi Id | MGI:5546578 | Doi | 10.1371/journal.pone.0070815 |
| Citation | Khor EC, et al. (2013) Loss of protein kinase C-delta protects against LPS-induced osteolysis owing to an intrinsic defect in osteoclastic bone resorption. PLoS One 8(8):e70815 |
| abstractText | 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-delta as the major PKC isoform expressed among all PKCs in osteoclasts; including classical PKCs (-alpha, -beta and -gamma), novel PKCs (-delta, -epsilon, -eta and -theta) and atypical PKCs (-iota/lambda and -zeta). Interestingly, pharmacological inhibition and genetic ablation of PKC-delta impairs osteoclastic bone resorption in vitro. Moreover, disruption of PKC-delta activity protects against LPS-induced osteolysis in mice, with osteoclasts accumulating on the bone surface failing to resorb bone. Treatment with the PKC-delta inhibitor Rottlerin, blocks LPS-induced bone resorption in mice. Consistently, PKC-delta deficient mice exhibit increased trabeculae bone containing residual cartilage matrix, indicative of an osteoclast-rich osteopetrosis phenotype. Cultured ex vivo osteoclasts derived from PKC-delta null mice exhibit decreased CTX-1 levels and MARKS phosphorylation, with enhanced formation rates. This is accompanied by elevated gene expression levels of cathepsin K and PKC -alpha, -gamma and -epsilon, as well as altered signaling of pERK and pcSrc416/527 upon RANKL-induction, possibly to compensate for the defects in bone resorption. Collectively, our data indicate that PKC-delta is an intrinsic regulator of osteoclast formation and bone resorption and thus is a potential therapeutic target for pathological osteolysis. |
