Fibrillin in Marfan syndrome and tight skin mice provides new insights into transforming growth factor-β regulation and systemic sclerosis

Abstract

Important recent understandings of fibrillins and fibrillin-associated microfibril proteins suggest new ways these proteins might contribute to tissue fibrosis seen in systemic sclerosis by regulating latent transforming growth factor-beta. This review discusses mutant-fibrillin mouse models of Marfan syndrome and SSc (Tsk mice), and studies suggesting that alterations in microfibrils might contribute to human SSc. Fibrillin-1 mutations associated with Marfan syndrome have recently been shown to induce genes activated by TGF-beta. The inhibition of TGF-beta in these mouse models largely reverses phenotypic and pathologic disease manifestations. Recent studies suggest that alterations in the fibrillin-1 structure from mutant Tsk fibrillin cause hypodermal fibrosis and associated changes in dermal gene expression, suggesting stimulation of cytokine-mediating signals. Genetic mutations in fibrillin-1, in a higher frequency in SSc patient populations, and autoantibodies to fibrillin provide potential links to human SSc. Fibrillin is placed centrally not only as the primary structural component of microfibrils, but also a key regulator of cytokines in the TGF-beta superfamily. Fibrillin may thus communicate alterations in matrix to fibroblast gene expression. These observations complement emerging understandings of the effects of Tsk fibrillin, and genetic and autoimmune studies of human fibrillin on dermal fibrosis.