INCREASED EXPRESSION OF INTEGRIN αvβ5 IN SCLERODERMA FIBROBLASTS.

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Extracellular matrix (ECM) metabolism of fibroblasts is tightly regulated by multiple environmental influences, including adhesion to the ECM and soluble factors (i.e. polypeptide growth factors and inflammatoty cytokines). Cell-ECM interaction is mediated through distinct receptors on the cell surface, mainly belonging to the integrins. Metabolism of collagen, the major structural component of ECM, is partially mediated through its receptors, including integrin α1β1 and α2β1. Integrin α1β1 provides negative feedback on collagen synthesis, whereas integrin α2β1 stimulates the synthesis of matrix metalloproteases. Reduced expression of both integrins in scleroderma fibroblasts correlate with upregulated collagen synthesis and downregulated metalloproteases of these cells. Thus, to date, much of the focus in scleroderma fibroblasts has been on the expression of the collagen receptors. In this study, we focused on another integrin, αvβ5, and its ligand, vitronectin. Vitronectin is a plasma protein that is also found distributed in ECM of various tissues in vivo, including dermal fibers in the skin. Matrix vitronectin binds various kinds of protease inhibitor, including plasnimogen activator inhibitor type-i, and controls their activities. The conformation of vitronectin regualtes its removal from ECM by human skin fibroblasts through integrin αvβ5. Increasing evidence supports the notion that integrin αvβ5 might regulate matrix turnover and remodeling through vitronectin related pericellular proteolysis. In the present study, we compared expression levels of integrin αvβ5 on dermal fibroblasts and the deposition levels of vitronectin in dermal tissue between scleroderma and healthy controls. Immunoblotting and Northern blot analysis showed that β5 subunit is upregulated in scleroderma fibroblasts. Increased expression of integrin αvβ5 on cell surface of scleroderma fibroblasts was also demonstrated by immunoprecipitation In immunohistochemical analysis, expression levels of integrin αvβ5 on dermal fibroblasts as well as vitronectin in dermal tissue was elevated in scleroderma skin sections. These results indicate that vitronectin dependent inhibition of pericellular proteolytic cascade may contribute to excessive extracellular matrix deposition in scleroderma and suggest the possibility that integrin αvβ5 serves to transduce a signal related to activation of lesional fibroblasts. Our data strengthen the concept that an important pathogenetic mechanism in scleroderma may be the abberant expression of ECM receptors.
日本結合組織学会の論文

INCREASED EXPRESSION OF INTEGRIN αvβ5 IN SCLERODERMA FIBROBLASTS.

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