MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing CKMT1-mediated oxidative phosphorylation

作者：Yujing Li, Minglong Cai, Yi Qin, Xiaojuan Dai, Liyuan Liang, Zhenyu Li, Xi Wen, Huizhi Jin, Chao Yang, Zhu Chen · 发表于：BMC Medicine · 年份：2025 · DOI：10.1186/s12916-025-03945-y · 被引用次数：10 · 研究领域：Bone Metabolism and Diseases、Rheumatoid Arthritis Research and Therapies、Bone health and osteoporosis research

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by disrupted bone homeostasis. This study investigated the effect and underlying mechanisms of one-carbon metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) on osteoclast differentiation and bone loss in RA. METHODS: The expression of MTHFD2 was examined in CD14 + monocytes and murine bone marrow-derived macrophages (BMMs). RNA-sequencing was performed to evaluate the regulatory mechanisms of MTHFD2 on osteoclastogenesis. Extracellular flux assay, JC-1 staining, and transmission electron microscopy were used to detect mitochondrial function and energy metabolism changes during osteoclast formation. Collagen-induced arthritis (CIA) mice were used to evaluate the therapeutic effect of MTHFD2 knockdown on bone loss. Bone volume and osteoclast counts were quantified by μCT and histomorphometry. RESULTS: Elevated MTHFD2 was observed in RA patients and CIA mice with a positive correlation to bone resorption parameters. During osteoclast formation, MTHFD2 was significantly upregulated in both human CD14 + monocytes and murine BMMs. The application of MTHFD2 inhibitor and MTHFD2 knockdown suppressed osteoclastogenesis, while MTHFD2 overexpression promoted osteoclast differentiation in vitro. RNA-sequencing revealed that MTHFD2 inhibition blocked oxidative phosphorylation (OXPHOS) in osteoclasts, leading to decreased adenosine triphosphate (ATP) production and mitochondrial membrane p...