Loss of protein kinase C-δ protects against LPS-induced osteolysis owing to an intrinsic defect in osteoclastic bone resorption.
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.
Centre for Orthopaedic Research, School of Surgery, University of Western Australia, Nedlands, Western Australia, Australia.
Ee Cheng
EC
Khor
Tamara
T
Abel
Jennifer
J
Tickner
Shek Man
SM
Chim
Cathy
C
Wang
Taksum
T
Cheng
Benjamin
B
Ng
Pei Ying
PY
Ng
Dian Astari
DA
Teguh
Jacob
J
Kenny
Xiaohong
X
Yang
Honghui
H
Chen
Keiichi I
KI
Nakayama
Keiko
K
Nakayama
Nathan
N
Pavlos
Ming H
MH
Zheng
Jiake
J
Xu
D000098:Acetophenones / Q000627:therapeutic use; D000818:Animals; D001578:Benzopyrans / Q000627:therapeutic use; D001862:Bone Resorption / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000473:pathology; D056657:Cathepsin K / Q000235:genetics; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D010014:Osteolysis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction
D000098:Acetophenones; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C085746:rottlerin; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta; D056657:Cathepsin K