MSDC-0160, a novel clinical-stage mitochondrial pyruvate carrier inhibitor, suppresses osteoclast differentiation and alleviates type 2 diabetes-related bone loss

Objective: Diabetic osteoporosis is a secondary complication of diabetes mellitus, characterized by reduced bone mass, increased bone fragility, and impaired fracture healing. However, the mechanisms underlying diabetic bone loss remain to be fully elucidated. More importantly, there is an urgent need to identify therapeutic agents that not only lower blood glucose levels but also alleviate bone loss. Therefore, this study aims to investigate the mechanisms of diabetes-associated bone loss and to explore potential therapeutic agents. Methods: We established a mouse model of type 2 diabetes (T2D) induced by streptozotocin and a high-fat diet (HFD). Bone mass and osteoclast numbers were assessed using micro-CT and TRAP staining. In vitro, the effects of MSDC-0160 (MSD) on osteoclast differentiation and function were evaluated through TRAP staining and bone resorption assays. To elucidate the molecular mechanisms underlying MSD-mediated inhibition of osteoclastogenesis, qPCR, Western blotting, and immunofluorescence staining were performed. Finally, micro-CT scanning and immunohistochemical staining were conducted to examine the effects of MSD on bone microstructure and the bone microenvironment in T2D mice, as well as to clarify specific mechanism of action. Results: T2D mice exhibited significant bone loss and enhanced osteoclast activation. Moreover, mitochondrial pyruvate carrier (MPC) activity was elevated in osteoclasts of T2D mice. Given the potential for mitigating diabetic bone loss by inhibiting MPC activity, we selected MSD, a novel insulin sensitizer that also serves as an MPC inhibitor. Further detailed investigations revealed that MSD suppresses osteoclast differentiation and function by reducing the energy supply required for osteoclast maturation. This effect results from impaired mitochondrial oxidative phosphorylation (OXPHOS) and reduced mitochondrial biogenesis. In vivo administration of MSD significantly ameliorated bone loss and reduced osteoclast numbers in T2D mice. Conclusion: Our findings indicate that the bone loss in T2D mice is associated with excessive osteoclast activation, where MPC playing a crucial role in osteoclast differentiation and maturation. MSD, a novel insulin sensitizer, mitigates diabetic bone loss by suppressing MPC activity in osteoclasts.