Role of Smad Anchor for Receptor Activation (SARA) in skin fibrosis

Fibrosis is the hallmark of scleroderma (SSc), yet outcomes of former approaches targeting signals mediating fibrogenesis have rather been elusive. Targeting a precursor of myofibroblasts that accumulate and produce extracellular matrixes in healing wounds and fibrosing tissues is a novel concept. However, there are little myofibroblasts in healthy skin, and debates remain as to where those myofibroblasts come from, and how those progenitor cells are activated. Recent studies suggest that vascular pericytes that reside on the outer surface of small vessels and rather dormant in healthy conditions can be activated in early stage of fibrogenesis, become myofibroblasts and proliferate in the interstitium. However, contribution of pericytes in skin fibrosis is largely unknown. We previously reported that Smad Anchor for Receptor Activation (SARA) has a critical role for maintenance of cell phenotype and that loss of SARA results in transdifferntiation toward mesenchymal phenotype. SARA is highly expressed in normal skin. Analyses of the biopsy samples from our SSc cohort and an animal models for SSc revealed that SARA levels are downregulated in fibrotic skin. Data by us and other gene expression profile studies on database also show that SARA levels are low in skin, kidney and liver. We have generated a mouse that expresses SARA under the control of a promoter of choice using the Cre-lox technology. When SARA is expressed specifically in pericytes, fibrosis in skin, as well as in kidney and liver was significantly less severe and proliferation/infiltration of pericytes was greatly reduced. Interestingly, lung fibrosis was not protected by SARA overexpression, likely due to dominant role of alveolar epithelial cells not pericytes in lung fibrosis. Further, in a fly model of heart tube fibrosis, SARA overexpression protects and SARA knockdown suppresses the fibrosis. These data strongly suggest that SARA is an anti-fibrotic molecule and does so by preventing