J147 Inhibits Osteoclastogenesis And Bone Loss Via P66shc Mitochondrial Pathway

This study investigates the effects of J147, a curcumin derivative known for its anti-inflammatory, antioxidant, and mitochondrial-protective properties, on osteoclast differentiation and bone loss, and explores its therapeutic potential and underlying mechanisms in osteoporosis. Bone marrow-derived macrophages (BMDMs) were treated with J147 at varying concentrations to evaluate cell viability, osteoclast formation, F-actin ring formation, and bone resorption. Mitochondrial ROS levels, membrane potential, ATP production, and oxygen consumption rate (OCR) were assessed. The role of human SHC-transforming protein 1 (p66Shc) in J147’s mechanism was examined via knockdown and overexpression. In vivo, an ovariectomized (OVX) mouse model was used to investigate J147’s therapeutic effects on osteoporosis and underlying mechanisms. At 30 μM, J147 does not significantly affect BMDMs cell viability; however, higher concentrations markedly reduce viability. J147 decreases osteoclast number, size, F-actin ring formation, and bone resorption activity in a concentration-dependent manner. It downregulates osteoclast differentiation genes and suppresses RANKL-induced mitochondrial ROS generation, membrane depolarization, ATP production, and OCR. p66Shc knockdown produces similar effects, and J147 effectively lowers p66Shc expression even under overexpression conditions. In OVX mice, J147 increases trabecular bone number and density, reduces marrow cavity space and serum CTX-I levels, and histology confirms fewer osteoclasts with enhanced trabecular bone. These findings suggest that J147, by modulating mitochondrial activity and p66Shc signaling, effectively mitigates osteoclast-related bone loss. J147 demonstrates significant therapeutic potential for osteoporosis by inhibiting osteoclast differentiation and bone resorption through suppression of p66Shc-mediated mitochondrial pathway.