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

Abstract

Objective. To delineate the expression of transforming growth factor ␤-inducible gene h3 (␤IG-H3) in rheumatoid synovitis and to determine the regulatory role of ␤IG-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 ␤IG-H3 within rheumatoid synovium. Synthesis of ␤IG-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 ␤IG-H3 and function-blocking antibodies to integrins.Results. Expression of ␤IG-H3 was up-regulated in RA synovial tissue compared with synovial tissue from patients with osteoarthritis. FLS isolated from RA synovial tissue constitutively produced ␤IG-H3, which was up-regulated by transforming growth factor ␤1, interleukin-1␤, and tumor necrosis factor ␣. Although FLS expressed a variety of integrins, ␤IG-H3 mediated adhesion and migration of FLS through interaction with ␣v␤3 integrin. Cytokines failed to affect the ␤IG-H3-mediated adhesion. However, migration of FLS guided by ␤IG-H3 was enhanced by interferon-␥ and plateletderived growth factor type BB. The YH18 peptide in the fourth fas-1 domain of ␤IG-H3 inhibited adhesion and migration in a dose-dependent manner. Conclusion.The results suggest that ␤IG-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 ␤IG-H3 and ␣v␤3 integrin-interacting motifs as potential therapeutic targets in this disease.

18F-FPRGD2 PET/CT imaging of musculoskeletal disorders

“…This suggests that more integrins ( 18 F-FPRGD 2 uptake) are expressed by structures that show evidence of inflammation (FDG uptake). These observations in vivo are in agreement with our knowledge of the cross talk between integrins and cytokines/inflammatory mediators in vitro in chondrocytes or fibroblast-like synoviocytes [13,26,27,42]. A publication also showed that decrease of synovial inflammation using therapeutic intervention as assessed by a decrease in a composite clinical disease activity index significantly correlated to the decrease observed in 68 Ga-PRGD 2 SUV max [30].…”

“…This may explain why 18 F-Galacto-RGD uptake is higher in bone metastases compared to primary tumors [47]. Lastly, fibroblasts may represent the target of 18 F-FPRGD 2 foci localized within entheses as fibroblasts originated from OA synovial or disc also express integrin a v b 3 [13,25].…”

“…Of interest, the integrin a v b 3 has been shown to be also expressed by cells that form a joint and neighbouring bone. Indeed, synovial fibroblasts of OA and rheumatoid arthritis (RA) origin express the integrin subunits a v and b 3 , as well as the complete integrin a v b 3 [12][13][14]. Although a v is easily identified in normal primary chondrocytes, the expression of b 3 is weak or absent [15][16][17][18][19].…”

Transforming growth factor-β–induced protein (TGFBIp/β ig-h3) activates platelets and promotes thrombogenesis

“…12 In addition, it also exists in blood and accumulates at inflammatory sites such as fibrosis, rheumatoid arthritis, atherosclerosis, diabetic kidney, diabetic angiopathy, and wound healing. [18][19][20][21] Considering that the expression of TGFBIp in several cell types has been known to be highly induced by TGF-␤ and TGF-␤ that is abundantly present in platelets, TGFBIp could possibly be produced in platelets and play an important role in mediating platelet functions. Until now, however, nothing has been reported on the presence of TGFBIp in platelets and its role in platelet functions.…”

The Roles of B Cells and Their Interactions with Fibroblast-Like Synoviocytes in the Pathogenesis of Rheumatoid Arthritis

“…B cells specifically serve as cellular adjuvants for CD4+ T cell activation, while murine regulatory B cells, including those that produce IL-10 (B10 cells) and transforming growth factor (TGF)-β, function as negative regulators of inflammatory immune responses [18,19]. TGF-β is abundantly expressed in synovial tissue from RA patients, which plays a regulatory role in chronic destructive inflammation through modulation of the adhesion and migration of FLSs [20]. In RA animal models, regulatory B cells suppress inflammation by restoring the Th1/Th2 balance [21].…”