Pro-inflammatory regulation of EGFR-Annexin A2 synergy by sodium butyrate: An upstream target to reduce articular inflammation and cartilage destruction in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by persistent articular inflammation and joint damage. Our prior research identified a pro-inflammatory interplay between the epidermal growth factor receptor (EGFR) and Annexin A2 (AnxA2), which is exacerbated by Annexin A1 (AnxA1) downregulation in RA pathogenesis. The present study elucidates the immunomodulatory potential of sodium butyrate, a gut microbiota-derived short-chain fatty acid, in disrupting the EGFR-AnxA2 axis and restoring AnxA1 homeostasis. Employing an integrative in vitro–in vivo paradigm, we establish that sodium butyrate attenuates EGFR and AnxA2 expression in primary human RA synovial fibroblasts, concomitantly upregulating AnxA1 and diminishing TNF-α release. In vivo, using a collagen-induced arthritis (CIA) murine model, histopathological and molecular analysis reveal that sodium butyrate-treated mice exhibit significantly attenuated synovial hyperplasia, reduced pannus formation, and elevated AnxA1 expression, culminating in a disruption of EGFR-AnxA2 crosstalk. Furthermore, X-ray computed tomography substantiates a marked preservation of joint architecture, with diminished osteolytic lesions and joint space narrowing, notably in the tibia and calcaneum. These findings underscore sodium butyrate's potential as regulator of EGFR-AnxA2 complex modulator that reinstates anti-inflammatory homeostasis through AnxA1 induction, attenuating RA-mediated inflammatory cascades and structural deterioration.