's role in RANKL-induced osteoclast differentiation: insights from a bone marrow macrophage model.

Background: Osteoporosis (OP) is a chronic disease characterized by decreased bone mass, loss of skeletal structural integrity and increased susceptibility to fracture. Available studies have shown that the pyruvate dehydrogenase kinase (PDK) family is associated with osteoclastogenesis and bone loss, but the specific role of in bone pathology has not been systematically investigated.

Methods: A cell OP model was established in receptor activator for nuclear factor-B Ligand (RANKL)-induced bone marrow macrophages (BMMs). Hereafter, the expression levels of and osteoclastogenesis feature genes including nuclear factor of activated T cells 1 (), Cathepsin K (), osteoclast associated Ig-like receptor () in BMMs-derived osteoclasts were examined based on real-time quantitative PCR and western blotting methods. Further, the phosphorylation of ERK, P65 and JAK/STAT and their correlation was was gauged. In particular, changes in the activity of these signaling pathways were observed by silencing experiments of the gene (using small interfering RNA). Finally, the effects of gene silencing on signaling pathway activity, osteoclastogenesis, and related inflammatory and apoptotic indicators were observed by transfection with PDK3-specific siRNA.

Results: Following RANKL exposure, the levels of and osteoclastogenesis feature genes were all elevated, and a positive correlation between and osteoclastogenesis feature genes was seen. Meanwhile, ERK, P65 and JAK/STAT phosphorylation was increased by RANKL, and was confirmed to be positively correlated with the phosphorylation of ERK, P65 and JAK/STAT. Additionally, in RANKL-exposed osteoclasts, knockdown diminished the phosphorylation of ERK, P65 and JAK/STAT, reduced the expressions of osteoclastogenesis feature genes. Importantly, knockdown of also reduced the expression of inflammatory cytokines and resulted in elevated levels of and expression, as well as downregulation of expression.

Conclusion: This study reveals for the first time the role of Pdk3 in RANKL-induced osteoclastogenesis and OP. These findings provide a foundation for future studies on the role of Pdk3 in other bone diseases and provide new ideas for the development of OP therapeutics targeting Pdk3.