Role of osteopontin in amplification and perpetuation of rheumatoid synovitis
Guangwu Xu, … , Jian Hong, Jingwu Z. Zhang
Guangwu Xu, … , Jian Hong, Jingwu Z. Zhang
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):1060-1067. https://doi.org/10.1172/JCI23273.
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Role of osteopontin in amplification and perpetuation of rheumatoid synovitis

Abstract

Osteopontin (OPN) is an extracellular matrix protein of pleiotropic properties and has been recently recognized as a potential inflammatory cytokine. In this study, we demonstrate, for the first time to our knowledge, that overexpression of OPN in synovial T cells is associated with local inflammatory milieu and that OPN acts as an important mediator in amplification and perpetuation of rheumatoid synovitis. The study revealed that mRNA expression of OPN was highly elevated in CD4+ synovial T cells derived from patients with RA, which correlated with increased OPN concentrations in synovial fluid (SF). The pattern of OPN overexpression was confined to rheumatoid synovium and correlated with coexpression of selected OPN receptors in synovial T cells, including integrins αv and β1 and CD44. RA-derived SF stimulated the expression of OPN in T cells, which was attributable to IL-10 present in SF and abrogated by anti–IL-10 antibody. Among the more than 300 autoimmune and inflammatory response genes examined, OPN selectively induced the expression of proinflammatory cytokines and chemokines known to promote migration and recruitment of inflammatory cells. Furthermore, it was evident that OPN activated transcription factor NF-κB in mononuclear cells. The study has important implications for understanding the role of OPN in rheumatoid synovitis and other inflammatory conditions.

Authors

Guangwu Xu, Hong Nie, Ningli Li, Wenxin Zheng, Dongqing Zhang, Guozhang Feng, Liqing Ni, Rong Xu, Jian Hong, Jingwu Z. Zhang

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Figure 7

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The induction of OPN expression by cytokines and the blocking effect of ...
The induction of OPN expression by cytokines and the blocking effect of anti-IL-10 antibody. (A) PBMCs selected from RA patients (n = 10, as described in the Figure 6 legend) were cultured in the presence and absence of the indicated cytokines at a final concentration of 25 ng/ml for 48 hours. T cells were purified by magnetic bead separation and were subject to real-time PCR analysis of OPN expression. The purity of the isolated T cell preparations was greater than 97%. (B) The same PBMC preparations were cultured in the presence and absence (Medium [control]) of recombinant IL-10 used at the indicated concentrations to determine the dose-response pattern and kinetics of OPN expression in T cells. The resulting cells were harvested at the indicated time points and T cells were purified prior to real-time PCR analysis for OPN expression. (C) In parallel experiments, the same PBMCs (10 untreated samples) were cultured in the presence and absence (Medium [control]) of SF at a dilution of 1:5. A purified mouse anti-human IL-10 antibody or a mouse control antibody of matched isotype (anti-lysozyme antibody), respectively, was added at a final concentration of 5 μg/ml. T cells were subsequently isolated and analyzed for OPN expression by real-time PCR. The purity of T cells was greater than 97%. Dash indicates absence of antibody. (D) CD45RA+ and CD45RO+CD45RA– T cell preparations were purified (n = 10; cell purity >97%) using magnetic beads coupled with specific antibodies and analyzed, together with PBMC preparations, for the expression of OPN by real-time PCR. Relative expression of OPN gene was calculated as described in the Figure 1 legend. In all cases, asterisks indicate statistically significant differences between the groups (P < 0.05).