Shp2 Fib KO mice were protected from experimental fibrosis induced by overexpression of a constitutively active TGFβ receptor type I. Moreover, fibroblast-specific inactivation of Shp2 also protected from bleomycin-induced skin fibrosis and ameliorated fibrosis in TSK1 mice, thereby confirming the central regulatory function of Shp2 on TGFβ signaling and fibroblast activation in multiple complementary models of SSc. Here, TGFB1 is linked to systemic sclerosis.