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.
Highlights
Bone remodeling is a tightly coupled process involving boneforming osteoblasts and bone-resorbing osteoclasts [1]
The results show that Protein Kinase C (PKC)-d is most abundantly expressed in osteoclasts among the PKC family of genes (Fig. 1A–B), which includes classical PKCs (2a, 2b and 2c), novel PKCs (2d, 2e, 2g and 2h) and atypical PKCs (2i/l and 2f)
We found that inhibition of PKC-d by Rottlerin (Fig. 2A) or KO of PKC-d in mice (Fig. 2B) resulted in impaired osteoclastic bone resorption
Summary
Bone remodeling is a tightly coupled process involving boneforming osteoblasts and bone-resorbing osteoclasts [1]. An imbalance in bone homeostasis in favor of osteoclast activity can lead to osteolytic diseases including osteoporosis, Paget’s disease, and rheumatoid arthritis [2]. It is commonly observed in systemic or local inflammation in bone, and in cancer cell metastasis to bone that results in hypercalcemia and pathological fractures in affected individuals [2]. RANKL is typically expressed by osteoblasts and binds to its receptor RANK expressed on precursor cells and mature osteoclasts to initiate signals for osteoclastogenesis and bone resorption, respectively [6,7]. Research into the molecular mechanisms underlying osteoclast activity is beneficial in providing new avenues for the prevention and treatment of bone disease
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