Impact on vitronectin and secreted protein acidic and rich in cysteine dynamics by estradiol to address rheumatoid arthritis pathogenesis.

Rheumatoid arthritis (RA) is an autoimmune disease caused by intricate signal transductions, where chronic inflammation is manifested in the joints and has a higher prevalence observed in females. To address RA pathogenesis, Estradiol (E2), a prominent form of estrogen, has been used in this study, identifying differentially expressed proteins in RA-Fibroblast-like synoviocytes by SWATH-MS, as well as exploring its mechanistic pathways. In-silico pathway enrichment analysis depicted the major involvement of the proteins in extracellular matrix organization, with Vitronectin (VTN) and Secreted protein acidic and rich in cysteine (SPARC) proteins as prominent protein targets. E2 was found to reduce VTN and SPARC expression and its downstream, angiogenesis, and cell proliferation factors, validated by qRT-PCR, Western blotting, and Scratch assay. VTN and SPARC interaction was also hindered by E2, demonstrated by molecular docking, followed by Immunofluorescence, and co-immunoprecipitation assay. E2 effected the VTN-SPARC dynamics, marking a significant reduction in RA symptoms, validated using the ovariectomized collagen-induced arthritis rat model. Our findings suggested that E2 diminished RA pathogenesis by altering the VTN and SPARC dynamics and their downstream signal transductions.