MSMP promotes an aberrant phenotype of fibroblast-like synoviocytes in rheumatoid arthritis by blocking autophagy via the RUNX1/GPR137B axis

Microseminoprotein (MSMP) is a secreted protein that has been identified as a novel ligand for C-C chemokine receptor 2 (CCR2), despite lacking the classical chemokine structure. Emerging evidence suggests that MSMP is implicated in the progression of various cancers and inflammatory diseases. However, its role in rheumatoid arthritis (RA) remains unknown. The study aims to investigate the regulatory mechanism of MSMP in RA. We screened MSMP as a candidate gene from the GEO database. RT-qPCR was used to detect mRNA expression, and protein expression was evaluated by Western blotting. The concentrations of MSMP or inflammatory cytokines were examined by ELISA. Cell migration and invasion were assessed with a Transwell system. EdU incorporation assay was used to determine cell proliferation. Cell apoptosis was measured by Annexin V-FITC using flow cytometry. Dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to analyze promoter activity and transcription factor binding, respectively. In vivo experiments were carried out using a collagen-induced arthritis (CIA) model. MSMP expression was increased in fibroblast-like synoviocytes (FLSs) and synovial tissues (STs) from RA patients. Functional experiments showed that MSMP knockdown inhibited the migration and invasion of RA FLSs. Mechanistically, we identified GPR137B as a downstream target of MSMP. Our results also revealed that the transcription factor RUNX1 controlled GPR137B expression by binding to the promoter region of GPR137B. Furthermore, GPR137B knockdown reduced the migration and invasion of RA FLSs by promoting autophagy, and these effects were partially reversed by treatment with the autophagy inhibitor 3-Methyladenine (3-MA). Intriguingly, intra-articular Ad-shRNA-MSMP administration alleviated the severity of arthritis in mice with CIA. Our results suggest that elevated MSMP levels in FLSs may contribute to rheumatoid synovial aggression and joint destruction by suppressing autophagy via the RUNX1/GPR137B axis. MSMP may be a potential target against RA.