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

Ee Cheng Khor, Tamara Abel, Jennifer Tickner, Shek Man Chim, Cathy Wang, Taksum Cheng, Benjamin Ng, Pei Ying Ng, Dian Astari Teguh, Jacob Kenny, Xiaohong Yang, Honghui Chen, Keiichi I. Nakayama, Keiko Nakayama, Nathan Pavlos, Ming H. Zheng, Jiake Xu

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Abstract

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-δ as the major PKC isoform expressed among all PKCs in osteoclasts; including classical PKCs (-α, -β and -γ), novel PKCs (-δ, -ε, -η and -θ) and atypical PKCs (-ι/λ and -ζ). Interestingly, pharmacological inhibition and genetic ablation of PKC-δ impairs osteoclastic bone resorption in vitro. Moreover, disruption of PKC-δ activity protects against LPS-induced osteolysis in mice, with osteoclasts accumulating on the bone surface failing to resorb bone. Treatment with the PKC-δ inhibitor Rottlerin, blocks LPS-induced bone resorption in mice. Consistently, PKC-δ deficient mice exhibit increased trabeculae bone containing residual cartilage matrix, indicative of an osteoclast-rich osteopetrosis phenotype. Cultured ex vivo osteoclasts derived from PKC-δ 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 -α, -γ and -ε, 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-δ is an intrinsic regulator of osteoclast formation and bone resorption and thus is a potential therapeutic target for pathological osteolysis.

Original languageEnglish
Article numbere70815
JournalPloS one
Volume8
Issue number8
DOIs
Publication statusPublished - Aug 8 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Khor, E. C., Abel, T., Tickner, J., Chim, S. M., Wang, C., Cheng, T., Ng, B., Ng, P. Y., Teguh, D. A., Kenny, J., Yang, X., Chen, H., Nakayama, K. I., Nakayama, K., Pavlos, N., Zheng, M. H., & Xu, J. (2013). Loss of Protein Kinase C-δ Protects against LPS-Induced Osteolysis Owing to an Intrinsic Defect in Osteoclastic Bone Resorption. PloS one, 8(8), [e70815]. https://doi.org/10.1371/journal.pone.0070815