Is Smad3 a major player in signal transduction pathways leading to fibrogenesis?

Transforming growth factor (TGF)-beta plays a central role in fibrosis, con tributing both to the influx and activation of inflammatory cells, as well as to activation of fibroblasts to elaborate extracellular matrix. In the p ast few years, new insight has been gained into signal transduction pathway s downstream of the TGF-beta receptor serine-threonine kinases with the ide ntification of a family of evolutionarily conserved Smad proteins. Two rece ptor-activated Smad proteins, Smad2 and Smad3, are phosphorylated by the ac tivated TGF-beta type I receptor kinase, after which they partner with the common mediator, Smad4, and are translocated to the nucleus to where they p articipate in transcriptional complexes to control expression of target gen es, We have shown in wound healing studies of mice null for Smad3, that los s of this key signaling intermediate interferes with the chemotaxis of infl ammatory cells to TGF-beta as well as with their ability to autoinduce TGF- beta. Moreover, studies,vith mouse embryo fibroblasts null for Smad3 show t hat TGF-beta -dependent induction of c-Jun and c-Fos, important in inductio n of collagen as well as in autoinduction of TGF-beta, is mediated by Smad3 . Based on these observations, we hypothesize that loss of Smad3 will confe r resistance to fibrosis and result in reduced inflammatory cell infiltrate s, reduced autoinduction of TGF-beta, important to sustain the process, and reduced elaboration of collagen. Preliminary observations in a model of ra diation-induced fibrosis confirm this hypothesis and suggest that inhibitor s of Smad3 might have clinical application both to improve wound healing an d to reduce fibrosis.