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(American Journal of Pathology. 2005;166:1451-1463.)
© 2005 American Society for Investigative Pathology

Constitutive Thrombospondin-1 Overexpression Contributes to Autocrine Transforming Growth Factor-ß Signaling in Cultured Scleroderma Fibroblasts

Yoshihiro Mimura, Hironobu Ihn, Masatoshi Jinnin, Yoshihide Asano, Kenichi Yamane and Kunihiko Tamaki

From the Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan

The extracellular matrix (ECM) glycoprotein thrombospondin-1 (TSP-1) has been reported to activate the latent complex of transforming growth factor-ß (TGF-ß), the major effects of which in mesenchymal cells is stimulation of the synthesis of ECM. Previous reports suggested the involvement of an autocrine TGF-ß loop in the pathogenesis of scleroderma. In this study, we examined whether TSP-1 plays a role in maintaining the autocrine TGF-ß loop in scleroderma. TSP-1 expression was increased in scleroderma patients compared with in healthy controls in vivo and in vitro. TGF-ß blocking antibody or TGF-ß1 antisense oligonucleotide markedly reduced the up-regulated TSP-1 expression in scleroderma fibroblasts but had little effect on normal fibroblasts. The expression of TSP-1 is up-regulated in scleroderma fibroblasts, possibly at the post-transcriptional level just like in normal fibroblasts stimulated with exogenous TGF-ß1. TSP-1 blocking peptide or antisense oligonucleotide had an inhibitory effect on the up-regulated {alpha}2(I) collagen and phosopho-Smad3 levels in scleroderma fibroblasts but had little effects on normal fibroblasts. The transient overexpression of TSP-1 up-regulated {alpha}2(I) collagen and phospho-Smad3 levels in normal fibroblasts but had no major effect on scleroderma fibroblasts. Furthermore, these effects of transiently overexpressed TSP-1, which possibly occurred via the activation of latent TGF-ß1, were abolished by the TGF-ß1 antisense oligonucleotide. These results indicate that the constitutive overexpression of TSP-1 may play an important role in autocrine TGF-ß signaling and accumulation of ECM in scleroderma fibroblasts.




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