Conditional Knockout of PDK1 in Osteoclasts Suppressed Osteoclastogenesis and Ameliorated Prostate Cancer-Induced Osteolysis

Background: The development and maintenance of normal bone tissue is supported by balanced communication between osteoblasts and osteoclasts. The invasion of cancer cells disrupts this balance, leading to osteolysis. As the only bone resorption cells in vivo, osteoclasts play important roles in cancer-induced osteolysis. However, the function of 3-phosphoinositide–dependent protein kinase-1 (PDK1) in osteoclast resorption remains unclear. Methods: In our study, we used a receptor activator of nuclear factor-kappa B (RANK) promoter‐driven Cre‐LoxP system to conditionally delete the PDK1 gene in osteoclasts in mice. We investigated the impact of Osteoclast‐specific knockout of PDK1 on prostate cancer-induced osteolysis. Bone marrow-derived macrophage cells (BMMs) were extracted and induced to differentiate osteoclasts in vitro to examine the function of PDK1 in osteoclasts.Results: In this study, we found that PDK1 conditional knockout (cKO) mice exhibited smaller body sizes when contrasted with the wild-type (WT) mice. Moreover, deletion of PDK1 in osteoclasts ameliorated osteolysis and reduced bone resorption markers in the murine model of prostate cancer-stimulated osteolysis. In vivo, we discovered that osteoclast‐specific knockout of PDK1 suppressed RANKL-stimulated bone resorption function, osteoclastogenesis, and osteoclast-specific gene expression (Ctsk, TRAP, MMP-9, NFATc1). Western blot analyses of RANKL-induced signaling pathways showed that conditional knockout of PDK1 in osteoclasts inhibited the early nuclear factor κB (NF-κB) activation, which consequently suppressed the downstream induction of NFATc1. Conclusion: These findings demonstrated that PDK1 performs an instrumental function in osteoclastogenesis and prostate cancer-induced osteolysis by modulating the PDK1/AKT/NF-κB signaling pathway.