Up‐regulated transforming growth factor β–inducible gene h3 in rheumatoid arthritis mediates adhesion and migration of synoviocytes through αvβ3 integrin: Regulation by cytokines

• Published in: Arthritis and rheumatism 2006-09, Vol.54 (9), p.2734-2744
• Main Authors: Nam, Eon Jeong, Sa, Keum Hee, You, Dong Wan, Cho, Jang Hee, Seo, Jae Seok, Han, Seung Woo, Park, Jae Yong, Kim, Sung Il, Kyung, Hee Soo, Kim, In San, Kang, Young Mo
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Diseases of the osteoarticular system; Inflammatory joint diseases; Medical sciences
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.22076

Objective To delineate the expression of transforming growth factor β–inducible gene h3 (βIG‐H3) in rheumatoid synovitis and to determine the regulatory role of βIG‐H3 in the adhesion and migration of fibroblast‐like synoviocytes (FLS). Methods Synovial tissue was obtained from patients with rheumatoid arthritis (RA) during joint replacement surgery, and FLS were isolated using enzymatic treatment. Immunohistochemical staining was performed to show the expression of βIG‐H3 within rheumatoid synovium. Synthesis of βIG‐H3 from FLS was determined by semiquantitative reverse transcription–polymerase chain reaction, Western blot analysis, and enzyme‐linked immunosorbent assay. Cell adhesion and migration assays were performed using the YH18 peptide in the fourth fas‐1 domain of βIG‐H3 and function‐blocking antibodies to integrins. Results Expression of βIG‐H3 was up‐regulated in RA synovial tissue compared with synovial tissue from patients with osteoarthritis. FLS isolated from RA synovial tissue constitutively produced βIG‐H3, which was up‐regulated by transforming growth factor β1, interleukin‐1β, and tumor necrosis factor α. Although FLS expressed a variety of integrins, βIG‐H3 mediated adhesion and migration of FLS through interaction with αvβ3 integrin. Cytokines failed to affect the βIG‐H3–mediated adhesion. However, migration of FLS guided by βIG‐H3 was enhanced by interferon‐γ and platelet‐derived growth factor type BB. The YH18 peptide in the fourth fas‐1 domain of βIG‐H3 inhibited adhesion and migration in a dose‐dependent manner. Conclusion The results suggest that βIG‐H3, which is abundantly expressed in RA synovial tissue, plays a regulatory role in chronic destructive inflammation through the modulation of the adhesion and migration of FLS. This finding indicates the relevance of βIG‐H3 and αvβ3 integrin–interacting motifs as potential therapeutic targets in this disease.