ArticleBMC medicine2025
MTHFD2 promotes osteoclastogenesis and bone loss in rheumatoid arthritis by enhancing CKMT1-mediated oxidative phosphorylation.
Article in BMC medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Bone organoids and mitochondrial reprogramming.Journal of orthopaedic translation · 2026Review
- Mitochondrial Dysfunction: From Molecular Mechanisms to Modern Approaches for Basic and Clinical Research.Biomedicines · 2026Review
- Natural flavonoid dihydroquercetin blocks Trim14-JAK1-STAT3 signaling and relieves pain-depression comorbidity in rheumatoid arthritis.Translational psychiatry · 2026Article
- Targeting NFATc1-regulated MTHFD2 one-carbon metabolism to suppress sustained T-cell-mediated inflammation in rheumatoid arthritis.Signal transduction and targeted therapy · 2026Article
- MTHFD2: a promising metabolic checkpoint for diseases.Journal of translational medicine · 2026Review
- Integrative analysis of transcriptome and single-cell sequencing combined with experimental validation identifies biomarkers associated with T cell and senescence in sepsis.Scientific reports · 2026Article
- Exploring the prognostic value of T cell exhaustion and mitochondrial dysfunction related genes in breast cancer through bioinformatics analysis and RT-qPCR validation.Clinical and experimental medicine · 2025Article
- Pyroptosis-responsive microspheres modulate the inflammatory microenvironment to retard osteoporosis in female mice.Nature communications · 2025Article
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10 authors.
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Abstract
backgroundRheumatoid 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.
methodsThe 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.
resultsElevated 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 potential without affecting mitochondrial biogenesis. Mechanistically, inhibition of MTHFD2 downregulated the expression of mitochondrial creatine kinase 1 (CKMT1), which in turn affected phosphocreatine energy shuttle and OXPHOS during osteoclastogenesis. Further, a therapeutic strategy to knock down MTHFD2 in knee joint in vivo ameliorated bone loss in CIA mice.
conclusionsOur findings demonstrate that MTHFD2 is upregulated in RA with relation to joint destruction. MTHFD2 promotes osteoclast differentiation and arthritic bone erosion by enhancing mitochondrial energy metabolism through CKMT1. Thus, targeting MTHFD2 may provide a potential new therapeutic strategy for tackling osteoclastogenesis and bone loss in RA.
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