TNFSF11 as a Key Regulator in Osteoarthritis Pathogenesis: Integrated Bioinformatics Analysis and Potential Therapeutic Targets

Fumin Yuan; Xiwei Fan; Indira Prasadam; Antonia Rujia Sun; Xiaoxin Wu; Yanping Wang; Xinzhan Mao

doi:10.53941/rmd.2026.100004

Abstract

Background: Osteoarthritis (OA) is a chronic joint disease marked by inflammation of the synovium, subchondral bone sclerosis, and cartilage deterioration. Although its underlying molecular mechanisms remain incompletely elucidated, tumour necrosis factor superfamily member 11 (TNFSF11) has been closely linked to the pathophysiology of OA. Elucidating the specific role of TNFSF11 may facilitate the development of novel diagnostic strategies and therapeutic interventions for OA. Methods: This study examined TNFSF11’s function in OA using integrated bioinformatics. Transcriptome data of synovial tissues from OA patients and control (CON) subjects were retrieved from the Gene Expression Omnibus (GEO) database. The diagnostic value of TNFSF11 and differentially expressed genes (DEGs) was evaluated. TNFSF11-related genes were identified using weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis, results of which were confirmed by molecular docking. Immune cell infiltration and biological pathways were investigated using CIBERSORTx and functional enrichment analysis. TNFSF11-targeting medications were predicted using DrugBank. The causal associations between TNFSF11 and its target genes and OA were evaluated using two-sample Mendelian randomisation (MR) methodology. The expression of genes in clinical samples was verified using quantitative real-time polymerase chain reaction (qRT-PCR). Results: TNFSF11 was significantly upregulated in OA synovial tissues and demonstrated good diagnostic potential. A total of 372 TNFSF11-related genes were identified, among which 18 directly interacted with TNFSF11—findings that were validated by molecular docking. Functional enrichment was associated with immune response, cell adhesion, and matrix degradation pathways. TNFSF11 expression correlated with immune infiltration, particularly CD4 memory resting T cells, activated NK cells, and M0 macrophages. Four drugs (AMGN-0007, denosumab, lenalidomide, and thiocolchicoside) were predicted to target TNFSF11 with strong binding affinities. MR analysis revealed that CTSK, SPP1, and TBXAS1 were protective factors (all p < 0.05), while FCGR1A, MMP1, MMP9, TNFRSF11A, and TNFSF11 were risk factors for OA (all p < 0.05). qRT-PCR validation confirmed significant upregulation of TNFSF11, TNFRSF11A, FCGR1A, MMP1, and MMP9 in OA samples (all p < 0.05), which was consistent with bioinformatics findings. Conclusions: TNFSF11 plays a critical role in OA pathogenesis by regulating target genes, immune cell infiltration, and inflammatory pathways. These findings offer novel insights into the function of TNFSF11 in OA and identify potential therapeutic targets for OA management.

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