FSCN1 Promotes Rheumatoid Arthritis Progression via Inhibiting TRIM38-Mediated Ubiquitination of IGF2BP1 in Fibroblast-Like Synoviocytes.

OBJECTIVE

Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) synovium acquire a unique aggressive phenotype and produce cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Actin-bundling protein Fascin-1 (FSCN1) is involved in FLS migration and invasion, but its role and mechanism in FLS phenotypic activation remain unclear.

METHODS

FSCN1 expression was analyzed in the synovium from healthy controls (n = 6), patients with RA (n = 6), and patients with osteoarthritis (n = 6) with written informed consent obtained before sample collection, as well as synovium from control (n = 6) and arthritic mice (n = 6). Transcriptome profiling, RNA immunoprecipitation sequencing, and mass spectrometry analysis were performed to determine the underlying mechanism. FLS-specific FSCN1 knockout, FSCN1 intra-articular overexpression mice, and FSCN1 inhibitors were used to characterize the role and therapeutic potential of FSCN1 in experimental arthritis (n = 5-8).

RESULTS

FSCN1 was significantly increased in RA synovium and predominantly localized to PDPN-positive FLS (P < 0.001). FSCN1 overexpression enhanced F-actin remodeling, FLS migration, invasion, proliferation, and inflammatory activation and exacerbated synovitis and cartilage damage in arthritis mouse models (P < 0.0026). Conversely, FLS-specific FSCN1 ablation reduced knee swelling, pain-related behavior, synovial inflammation, and Osteoarthritis Research Society International scores in arthritis mouse models (P < 0.0196). Mechanistically, FSCN1 promoted F-actin fiber formation, spatially sequestered tripartite motif-containing protein 38 (TRIM38), inhibited TRIM38-mediated IGF2BP1 ubiquitination, and sustained PI3K-AKT/NF-κB signaling. The FSCN1 inhibitors imipramine and NP-G2-044 suppressed FLS activation and alleviated arthritis pathology in mice (P < 0.001).

CONCLUSION

Pharmacologic inhibition of FSCN1 restrains synovial inflammation and joint destruction by suppressing the aggressive phenotype change of FLS, representing a promising therapeutic strategy against RA.