Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma.
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.
Takagawa
Shinsuke
S
Section of Rheumatology, University of Illinois at Chicago, 60607, USA.
Lakos
Gabriella
G
Mori
Yasuji
Y
Yamamoto
Toshiyuki
T
Nishioka
Kiyoshi
K
Varga
John
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003872:Dermatitis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D010766:Phosphorylation; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D000906:Antibodies; D004268:DNA-Binding Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D001761:Bleomycin