TgA86 mouse model demonstrated potential markers for Bone Formation in Spondyloarthritis through ROS Detoxification, Folate Metabolism, and Inositol Phosphate Metabolism

Background Spondyloarthritis (SpA) represents a collection of inflammatory conditions distinguished by abnormal bone formation within the axial skeleton, ultimately resulting in ankylosis. The precise mechanisms responsible for this pathological bone development remain poorly understood. The TgA86 mouse model, featuring overexpression of a mutant human TNF transgene, accurately recapitulates essential features of human SpA, particularly spinal fusion. While mitochondrial metabolism has gained recognition for its role in SpA pathogenesis, the particular metabolic alterations that promote pathological bone formation have yet to be comprehensively examined. Methods Bulk RNA sequencing data obtained from TgA86 mice at 4 and 10 months (n = 5 per group) along with their corresponding controls (n = 5 per group) underwent analysis through a multi-system approach encompassing differential gene expression analysis, protein-protein interaction assessment, and metabolic flux modeling. Results During disease development, TgA86 mice exhibited an immunological transition characterized by enhanced innate immune activity and reduced adaptive immune signaling. This immune transformation occurred alongside transcriptional modifications indicating suppressed mitochondrial oxidative phosphorylation and widespread activation of carbohydrate, amino acid, lipid and fatty acid metabolic pathways. Furthermore, we detected reduced SOD1 expression (ROS detoxification) and MTHFD1 expression (folate metabolism), combined with elevated INPP1 expression (inositol phosphate metabolism). Immunohistochemical analysis validated these changes within nucleus pulposus and surrounding cartilage tissue. Conclusion The TgA86 mouse model successfully reproduces the immunometabolic disruption characteristic of SpA. The documented transcriptomic pattern, reflecting a shift toward glycolysis, indicates that metabolic restructuring serves as an important factor in disease advancement. Notably, the altered regulation of SOD1, MTHFD1, and INPP1 represents a potential mechanism underlying pathological bone formation. These observations highlight the intricate relationship between immune function, cellular energy production, and bone development in SpA.