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From the Section of Rheumatology,* University of Illinois at Chicago, Chicago, Illinois; the Department of Otolaryngology, Oregon Health Sciences University, Portland, Oregon; the Departments of Orthopedic Surgery and Biochemistry, Rush Medical College, Chicago Illinois; and the Department of Surgery, Loyola University Medical Center, Maywood, Illinois
Transforming growth factor-ß (TGF-ß) is a potent stimulus of connective tissue accumulation, and is implicated in the pathogenesis of scleroderma and other fibrotic disorders. Smad3 functions as a key intracellular signal transducer for profibrotic TGF-ß responses in normal skin fibroblasts. The potential role of Smad3 in the pathogenesis of scleroderma was investigated in Smad3-null (Smad3–/–) mice using a model of skin fibrosis induced by subcutaneous injections of bleomycin. At early time points, bleomycin-induced macrophage infiltration in the dermis and local TGF-ß production were similar in Smad3–/– and wild-type mice. In contrast, at day 28, lesional skin from Smad3–/– mice showed attenuated fibrosis, lower synthesis and accumulation of collagen, and reduced collagen gene transcription in situ, compared to wild-type mice. Connective tissue growth factor and 
-smooth muscle actin expression in lesional skin were also significantly attenuated. Electron microscopy revealed an absence of small diameter collagen fibrils in the dermis from bleomycin-treated Smad3–/– mice. Compared to fibroblasts derived from wild-type mice, Smad3–/– fibroblasts showed reduced in vitro proliferative and profibrotic responses elicited by TGF-ß. Together, these results indicate that ablation of Smad3 is associated with markedly altered fibroblast regulation in vivo and in vitro, and confers partial protection from bleomycin-induced scleroderma in mice. Reduced fibrosis is due to deregulated fibroblast function, as the inflammatory response induced by bleomycin was similar in wild-type and Smad3–/– mice.
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