Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Adiponectin Affects Gene Expression of Rheumatoid Arthritis Effector Cells Including Synovial Fibroblasts, Lymphocytes, Endothelial Cells and Chondrocytes
Frommer1, Klaus W., Zimmermann1, Birgit, Schroder1, Dirk, Schaffler2, Andreas, Buchler2, Christa, Brentano3, Fabia, Gay4, Steffen
Justus-Liebig-University of Giessen and Kerckhoff-Clinic. Bad Nauheim, Germany
University Hospital Regensburg, Regensburg, Germany
Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology (ZIHP). Zurich, Switzerland
Ctr Exp Rheum, Univ Hosp Zurich/Zurich Ctr Integr Hum Physiol (ZIHP), Zurich, Switzerland
Justus-Liebig-University of Giessen, Internal Medicine and Rheumatology. Kerckhoff-Klinik, Bad Nauheim, Germany
Justus-Liebig-University of Giessen and Kerckhoff-Clinic. 61231 Bad Nauheim, Germany
Rheumatoid arthritis (RA) is associated with increased production of adipokines. Elevated levels of these cytokine-like mediators are found both in synovial tissue and synovial fluid of RA patients. RA effector cells may be affected by these adipokines. We therefore investigated the effect of the adipokine adiponectin on human synovial fibroblasts (SF), lymphocytes, endothelial cells and chondrocytes. We focused on the expression of proinflammatory and matrix-degrading mediators induced by adiponectin. We also analyzed the signaling pathways of adiponectin in RASF.
Human RASF, lymphocytes, endothelial cells and chondrocytes were stimulated in vitro with adiponectin. Affymetrix microarrays and protein arrays were used to screen for changes in gene expression. Real-time PCR and immunoassays were used to quantify mRNA and protein levels, respectively. Signaling analysis was performed using intracellular chemical inhibitors.
Adiponectin stimulation of RASF induced the expression and secretion of chemokines (protein: e.g. ENA-78, 22.5-fold), proinflammatory cytokines (mRNA: e.g. IL-11, 24.3-fold), other inflammatory molecules (mRNA: e.g. PGE synthase, 3.4-fold), growth factors (mRNA: e.g. fibroblast growth factor 10, 5.0 fold), genes involved in bone metabolism (mRNA: e.g. stanniocalcin-1, 19.8-fold) and matrix remodeling proteins (mRNA: e.g. MMP3 62.5 fold; protein: e.g. pro-MMP1 15.4-fold). Increased chemokine and cytokine secretion (e.g. IL-8, IL-6) was a common response to adiponectin stimulation found in all cell types studied, while chondrocytes additionally secreted increased levels of MMPs. Adiponectin-induced secretion of IL-6, MCP-1 and MMP10 by RASF was decreased using inhibitors against p38 MAPK and PKC but not by inhibitors against PKA and NFkB.
Adiponectin promotes the progression of RA primarily by inducing the secretion of proinflammatory molecules, chemokines and matrix-degrading enzymes in cell types involved in RA pathophysiology. While proinflammatory molecules such as IL-6 and PGES promote inflammation directly, chemokines attract and activate inflammatory cells further increasing inflammation. Additionally, elevated levels of MMPs lead to degradation of extracellular matrix and cartilage. According to our results, adiponectin-induced signaling in RASF is not only mediated by p38 MAPK but also by PKC, whereas PKA and NFkB appear not to be involved. Our data further elucidate the complex molecular mechanisms of RA.
To cite this abstract, please use the following information:
Frommer, Klaus W., Zimmermann, Birgit, Schroder, Dirk, Schaffler, Andreas, Buchler, Christa, Brentano, Fabia, et al; Adiponectin Affects Gene Expression of Rheumatoid Arthritis Effector Cells Including Synovial Fibroblasts, Lymphocytes, Endothelial Cells and Chondrocytes [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1649