Development of a new strategy for the prevention of ocular tissue fibrosis by targeting integrin-Smad craootalks

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The expression of extracellular matrix components and fibrotic cytokines in fibroblasts, which were from either osteopontin (OPN) or tenascin C (TNC), both of which are ligands of a9 integrin, knock-out and wild-type mice, were examined. Lacking OPN or TNC decreased the expression of type I collagen, TGF-b1, and alpha-smooth muscle actin. However OPN signaling is directly involved in phosphorylation of Smad3 and p38, the lack of TNC did not affect Smad3 expression levels or phosphorylation. The effects of TNC knock-out on wound healing models, which were scar healing after corneal incision and corneal angiogenesis, were examined. The lack of TNC inhibited both scarring and angiogenesis. The effects of OPN knock-out on another wound healing models associated with angiogenesis, which were angiogenesis and scar tissue formation after laser irradiation on choroid and retina, were examined. The effects of dose of OPN neutralizing antibody were also examined before intraperitoneal administration of a9 integrin neutralizing antibody .Lacking OPN or blocking its signaling induced by systemic administration of an OPN neutralizing antibody suppressed the expression of inflammatory cytokines, choroidal neovascularization and scar tissue formation. Controlling OPN or TNC signaling would be a new treatment strategy for ocular scarring or diseases associated with angiogenesis.