Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Absence of Integrin 21 Alters MMP Expression and TNF-Dependent Inflammatory Cartilage Destruction
Peters1, Marvin A., Strietholt1, Simon, Wendholt1, Doreen, Frank1, Svetlana, Korb1, Adelheid, Kollias2, George, Eckes3, Beate
Integrins are 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. a2b1 integrin functions as a major receptor for type I collagen on a number of different cells, including fibroblasts and inflammatory cells. Although a2 integrin deficient mice appear normal apart from mild platelet dysfunction and abnormal angiogenesis, it was shown that a2 integrin contributes to the induction of MMPs in tissue remodeling. Based on the hypothesis that under stress conditions such as chronic inflammation, a2 integrin may be involved in the activation of synovial cells, we investigated the role of a2 integrin in inflammatory arthritis.
To determine the role of a2 in TNF-mediated joint disease, we crossed a2-deficient mice with arthritic human TNFalpha transgenic (hTNFtg) mice. Clinical signs of arthritis and weight as well as the histological degree of synovitis and cartilage destruction in hind paws were investigated using standard clinical evaluation and histomorphometric analysis. In addition, we analyzed levels of cytokines and MMPs using serum and synovial fibroblasts from all genotypes. In addition, we used an established in vitro assay to investigate the role of the a2-subunit in the attachment of mouse synovial fibroblasts to healthy and IL-1 damaged articular cartilage.
We found that loss of a2 integrin in hTNFtg mice resulted in improved clinical signs and symptoms as compared to hTNFtg mice arthritis score. hTNFtg/a2(-/-) mice had less paw swelling (1.87 vs. 2.66), increased grip strength (-1.83 vs. -2.66) and a less pronounced weight loss. Histological analysis of these mice revealed that loss of a2 integrin lead to a decrease in synovial inflammation as compared to hTNFtg mice. To evaluate the role of a2 for MMPs we analyzed serum levels of a2-deficient and wt mice and found no significant difference in MMP3 or MMP9. However in a2(-/-) synovial fibroblasts MMP3 expression was downregulated, compared to wt synovial fibroblasts (127.5 vs. 170.5 ng/ml). This downregulation was similar in synovial fibroblasts from hTNFtg/a2(-/-) mice compared to fibroblasts from hTNFtg animals. In addition, we found a diminished attachment of a2-deficient mouse synovial fibroblasts particularly after induction of proteoglycan loss in IL-1 treated cartilage pieces in vitro.
Our findings suggest that although a2 integrin appears to be dispensable for normal development, the loss of a2 leads to a decrease in inflammation and bone destruction in an animal model of inflammatory arthritis.
To cite this abstract, please use the following information:
Peters, Marvin A., Strietholt, Simon, Wendholt, Doreen, Frank, Svetlana, Korb, Adelheid, Kollias, George, et al; Absence of Integrin 21 Alters MMP Expression and TNF-Dependent Inflammatory Cartilage Destruction [abstract]. Arthritis Rheum 2009;60 Suppl 10 :672