Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Loss of Integrin alpha2beta1 Suppresses Joint Inflammation and Cartilage Destruction in Mouse Models of Rheumatoid Arthritis.
Peters4, Marvin A., Wendholt6, Doreen, Strietholt6, Simon, Frank6, Svetlana, Korb5, Adelheid, Joosten2, Leo A. B., Van Den Berg8, Wim B.
Department of Dermatology, University of Cologne
University Hospital Münster, Münster Germany
Department of General Internal Medicine, Radboud University Nijmegen Medical Centre
Department of Internal Medicine and Rheumatology, Justus-Liebig-University Giessen, Kerckhoff Clinic, Bad Nauheim, Germany
Department of Internal Medicine and Rheumatology, Justus-Liebig-University Giessen, Kerckhoff Clinic; Institute of Experimental Musculoskeletal Medicine, University of Muenster, Bad Nauheim, Germany
Department of Internal Medicine D, University of Muenster
Institute of Experimental Musculoskeletal Medicine, University of Muenster, Muenster, Germany
Institute of Immunology, Biomedical Sciences Research Center
Radboud Univ Nijmegen Med Cntr, Nijmegen, The Netherlands
Univ.Giessen/Kerckhoff-Clinic, Bad Nauheim, Germany
Integrins are the main receptors for cell-matrix interactions, and integrin signaling is critical for a variety of cellular functions such as adhesion, cell spreading and inflammatory responses. Alpha2beta1 integrin acts as major receptor for type I collagen on a number of different cells, including inflammatory cells and fibroblasts. Although alpha2-deficient mice appear normal apart from mild platelet dysfunction, it was shown that alpha2 contributes to the induction and activation of MMPs in tissue remodeling. Based on the hypothesis that under stress conditions such as chronic inflammation alpha2beta1 integrin may be involved in the activation of synovial cells, we investigated its role in inflammatory arthritis.
The role of alpha2 was examined in two different murine models of arthritis, (i) alpha2-deficiency during antigen-induced arthritis (AIA), and (ii) alpha2-deficient mice crossed with arthritic human TNFalpha transgenic (hTNFtg) mice. Clinical signs of arthritis, weight and histological scores of synovitis and cartilage destruction were investigated using standard clinical evaluation and histomorphometric analysis. In addition, we analyzed MMP expression in tissue sections, serum and fibroblast-like synociocytes (FLS) from all genotypes and analyzed changes in proliferation and ERK phosphorylation. The role of the alpha2 subunit in the attachment of FLS to healthy and IL-1 damaged articular cartilage was analyzed using an established in vitro assay.
At day 5 after AIA induction, alpha2(-/-) mice showed a decrease of joint inflammation (-57%) and proteoglycan loss (-54%) compared to wildtype mice. In addition, MMP3 levels were significantly lower in tissue sections of alpha2(-/-) mice. In hTNFtg mice, the loss of alpha2 integrin resulted in improved clinical signs and symptoms. hTNFtg/alpha2(-/-) mice had less paw swelling (1.80 vs. 2.38), increased grip strength (-1.71 vs. -2.42) and a less pronounced weight loss compared with hTNFtg mice. The histological analysis revealed that alpha2(-/-) mice had a decreased cartilage erosion (-48,5%) and significantly reduced attachment of FLS to cartilage (-55,5%). MMP-3 expression was reduced in the serum and in FLS of alpha2(-/-) mice. Additionally, the proliferation of alpha2(-/-) FLS was decreased in vitro and we demonstrated that this is mediated through ERK signaling pathways. Futhermore, attachment of alpha2-deficient FLS was reduced, particularly after induction of proteoglycan loss in IL-1 treated articular cartilage in vitro.
The results support the hypothesis that alpha2 deficiency is an important factor in inflammatory cartilage destruction by interfering with fibroblast attachment and proliferation as well as by modulating MMP expression.
To cite this abstract, please use the following information:
Peters, Marvin A., Wendholt, Doreen, Strietholt, Simon, Frank, Svetlana, Korb, Adelheid, Joosten, Leo A. B., et al; Loss of Integrin alpha2beta1 Suppresses Joint Inflammation and Cartilage Destruction in Mouse Models of Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1719