The loss of α2β1 integrin suppresses joint inflammation and cartilage destruction in mouse models of rheumatoid arthritis

Objective Integrin a2 beta 1 functions as a major receptor for type I collagen on different cell types, including fibroblasts and inflammatory cells. Although in vitro data suggest a role for a2 beta 1 integrin in regulating both cell attachment and expression of matrix-degrading enzymes such as matrix metalloproteinases (MMPs), mice that lack the a2 integrin subunit (Itga2-/- mice) develop normally and are fertile. We undertook this study to investigate the effect of Itga2 deficiency in 2 different mouse models of destructive arthritis: the antigen-induced arthritis (AIA) mouse model and the human tumor necrosis factor a (TNFa)transgenic mouse model. Methods AIA was induced in the knee joints of Itga2-/- mice and wild-type controls. Human TNFtransgenic mice were crossed with Itga2-/- mice and were assessed clinically and histopathologically for signs of arthritis, inflammation, bone erosion, and cartilage damage. MMP expression, proliferation, fibroblast attachment, and ERK activation were determined. Results Under arthritic conditions, Itga2 deficiency led to decreased severity of joint pathology. Specifically, Itga2-/- mice showed less severe clinical symptoms and dramatically reduced pannus formation and cartilage erosion. Mice lacking a2 beta 1 integrin exhibited reduced MMP-3 expression, both in their sera and in fibroblast-like synoviocytes (FLS), due to impaired ERK activation. Further, both the proliferation and attachment of FLS to cartilage were partially dependent on a2 beta 1 integrin in vitro and in vivo. Conclusion Our findings suggest that a2 beta 1 integrin contributes significantly to inflammatory cartilage destruction by promoting fibroblast proliferation and attachment and MMP expression.