The loss of alpha2beta1 integrin suppresses joint inflammation and cartilage destruction in mouse models of rheumatoid arthritis.
SourceArthritis and Rheumatism, 64, 5, (2012), pp. 1359-68
01 mei 2012
Article / Letter to editor
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Arthritis and Rheumatism
SubjectN4i 1: Pathogenesis and modulation of inflammation NCMLS 1: Infection and autoimmunity; NCMLS 1: Infection and autoimmunity N4i 4: Auto-immunity, transplantation and immunotherapy; ONCOL 1: Hereditary cancer and cancer-related syndromes
OBJECTIVE: Integrin alpha2beta1 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 alpha2beta1 integrin in regulating both cell attachment and expression of matrix-degrading enzymes such as matrix metalloproteinases (MMPs), mice that lack the alpha2 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 alpha (TNFalpha)-transgenic mouse model. METHODS: AIA was induced in the knee joints of Itga2(-/-) mice and wild-type controls. Human TNF-transgenic 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 alpha2beta1 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 alpha2beta1 integrin in vitro and in vivo. CONCLUSION: Our findings suggest that alpha2beta1 integrin contributes significantly to inflammatory cartilage destruction by promoting fibroblast proliferation and attachment and MMP expression.
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