Mice overexpressing integrin αv in fibroblasts exhibit dermal thinning of the skin

•Integrins, especially αv integrin (ITGAV), are thought to play central roles in tissue fibrosis and the pathogenesis of scleroderma. So far, skin phenotype of tissue-specific transgenic mice of ITGAV have not been investigated.•To develop scleroderma mice model with apparent skin sclerosis and to investigate the role of ITGAV in the skin fibrosis, we engineered transgenic mice that overexpress ITGAV in the fibroblasts under the control of α2(I) collagen enhancer promoter. However, contrary to our expectation, mice overexpressing ITGAV in fibroblasts exhibit dermal thinning of the skin. This is the first study indicating the complex and paradoxical role of ITGAV in skin fibrosis.

BackgroundIntegrins, especially αv integrin (ITGAV), are thought to play central roles in tissue fibrosis and the pathogenesis of scleroderma. So far, skin phenotype of tissue-specific transgenic mice of ITGAV have not been investigated.ObjectiveTo investigate the role of ITGAV in the skin fibrosis, we engineered transgenic mice that overexpress ITGAV in the fibroblasts under the control of the COL1A2 enhancer promoter.MethodsProtein or RNA expression was evaluated by real-time PCR, immunohistochemistry, immunoblotting and immunoprecipitation.ResultsDermal thickness and Masson's trichrome staining were decreased in ITGAV transgenic (Tg) mice compared with wild-type (WT) mice. Protein and mRNA levels of COL1A2, COL3A1, CTGF and integrin β3 were down-regulated in the skin of Tg mice. In addition, the cell proliferation of cultured dermal fibroblasts obtained from Tg mice skin was decreased compared to those of WT mice.FAK phosphorylation was reduced in fibroblasts cultured from Tg mice skin in comparison to WT mice fibroblasts. Integrin β3 siRNA inhibited FAK phosphorylation levels, while FAK inhibitor reduced the expression of collagens and CTGF in mice dermal fibroblasts.ConclusionsThe down-regulation of collagen or CTGF by decreased integrin β3 and FAK phosphorylation may cause the dermal thinning in Tg mice. Lower CTGF may also result in reduced growth of Tg mice fibroblasts. Our hypothesis is that the balance between α and β chain of integrins positively or negatively control collagen expression and dermal thickness. This study gave a new insight in the treatment of tissue fibrosis and scleroderma by balancing integrin expression.