Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma.

Abstract

Transforming growth factor-beta is responsible for triggering a cascade of events leading to fibrosis in scleroderma. The Smads are intracellular signal transducers recently shown to mediate fibroblast activation and other profibrotic responses elicited by transforming growth factor-betain vitro. To understand better the involvement of Smads in the pathogenesis of fibrosis, we examined Smad expression and activation in situ in a murine model of scleroderma. Bleomycin injections induced striking dermal infiltration with macrophages by 3 d, and progressive fibrosis by 2 wk. Infiltrating macrophages and resident fibroblasts expressed Smad3, the positive mediator for transforming growth factor-beta responses. Importantly, in bleomycin-injected skin, fibroblasts showed predominantly nuclear localization of Smad3 and intense staining for phospho-Smad2/3. Furthermore, phosphorylated Smad2/3 in fibroblasts was detected even after the resolution of inflammation. Expression of Smad7, the endogenous inhibitor of transforming growth factor-beta/Smad signaling, was strongly induced in dermal cells by transforming growth factor-beta, but not by bleomycin injections. Collectively, these results indicate that bleomycin-induced murine scleroderma is associated with rapid and sustained induction of transforming growth factor-beta/Smad signaling in resident dermal fibroblasts. Despite apparent activation of the intracellular transforming growth factor-beta signaling pathway in the lesional dermis, the expression of transforming growth factor-beta-inducible Smad7 was not upregulated. In light of the critical function of Smad7 as an endogenous inhibitor of Smad signaling that restricts the duration and magnitude of transforming growth factor-beta responses, and as a mediator of apoptosis, relative Smad7 deficiency observed in the present studies may account for sustained activation of transforming growth factor-beta/Smad signaling in lesional tissues. These findings raise the possibility that Smads plays an important part in the pathogenesis of fibrosis, and may therefore represent targets for selective anti-fibrotic interventions.

• Authors: Shinsuke Takagawa, Gabriella Lakos, Yasuji Mori, Toshiyuki Yamamoto, Kiyoshi Nishioka, John Varga
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 121 Issue 1 Pg. 41-50 (Jul 2003) ISSN: 0022-202X [Print] United States
• PMID: 12839562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Antibodies
• DNA-Binding Proteins
• Smad2 Protein
• Smad2 protein, mouse
• Smad3 Protein
• Smad3 protein, mouse
• Smad7 Protein
• Smad7 protein, mouse
• Trans-Activators
• Transforming Growth Factor beta
• Bleomycin

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Antibodies (pharmacology)
• Bleomycin (pharmacology)
• Cells, Cultured
• DNA-Binding Proteins (genetics, metabolism)
• Dermatitis (metabolism, pathology, physiopathology)
• Disease Models, Animal
• Female
• Fibroblasts (cytology, metabolism)
• Mice
• Mice, Inbred C3H
• Phosphorylation
• Scleroderma, Systemic (metabolism, pathology, physiopathology)
• Signal Transduction (drug effects, physiology)
• Smad2 Protein
• Smad3 Protein
• Smad7 Protein
• Trans-Activators (genetics, metabolism)
• Transforming Growth Factor beta (immunology, metabolism)