| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
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.
This article has been cited by other articles:
 |
|
 |
|
  A. Vitsky, J. Waire, R. Pawliuk, A. Bond, D. Matthews, E. LaCasse, M. L. Hawes, C. Nelson, S. Richards, P. A. Piepenhagen, et al. Homeostatic Role of Transforming Growth Factor-{beta} in the Oral Cavity and Esophagus of Mice and Its Expression by Mast Cells in These Tissues Am. J. Pathol., June 1, 2009; 174(6): 2137 - 2149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Badea, M. Taylor, A. Rosenberg, and M. Foldvari Pathogenesis and therapeutic approaches for improved topical treatment in localized scleroderma and systemic sclerosis Rheumatology, March 1, 2009; 48(3): 213 - 221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wu, D. S. Melichian, E. Chang, M. Warner-Blankenship, A. K. Ghosh, and J. Varga Rosiglitazone Abrogates Bleomycin-Induced Scleroderma and Blocks Profibrotic Responses Through Peroxisome Proliferator-Activated Receptor-{gamma} Am. J. Pathol., February 1, 2009; 174(2): 519 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bhattacharyya, S.-J. Chen, M. Wu, M. Warner-Blankenship, H. Ning, G. Lakos, Y. Mori, E. Chang, C. Nihijima, K. Takehara, et al. Smad-Independent Transforming Growth Factor-{beta} Regulation of Early Growth Response-1 and Sustained Expression in Fibrosis: Implications for Scleroderma Am. J. Pathol., October 1, 2008; 173(4): 1085 - 1099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yu, G. C. Sharp, and H. Braley-Mullen TGF-{beta} Promotes Thyroid Epithelial Cell Hyperplasia and Fibrosis in IFN-{gamma}-Deficient NOD.H-2h4 Mice J. Immunol., August 1, 2008; 181(3): 2238 - 2245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Black Jr. and P. C. Trackman Transforming Growth Factor-{beta}1 (TGF{beta}1) Stimulates Connective Tissue Growth Factor (CCN2/CTGF) Expression in Human Gingival Fibroblasts through a RhoA-independent, Rac1/Cdc42-dependent Mechanism: STATINS WITH FORSKOLIN BLOCK TGF{beta}1-INDUCED CCN2/CTGF EXPRESSION J. Biol. Chem., April 18, 2008; 283(16): 10835 - 10847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hayashida, M.-H. Wu, A. Pierce, A.-C. Poncelet, J. Varga, and H. W. Schnaper MAP-kinase activity necessary for TGFbeta1-stimulated mesangial cell type I collagen expression requires adhesion-dependent phosphorylation of FAK tyrosine 397 J. Cell Sci., December 1, 2007; 120(23): 4230 - 4240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Pandey, S. M. Umphress, Y. Kang, J. Angdisen, A. Naumova, K. L. Mercer, T. Jacks, and S. B. Jakowlew Modulation of tumor induction and progression of oncogenic K-ras-positive tumors in the presence of TGF- 1 haploinsufficiency Carcinogenesis, December 1, 2007; 28(12): 2589 - 2596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Black Jr., A. H. Palamakumbura, M. Stan, and P. C. Trackman Tissue-specific Mechanisms for CCN2/CTGF Persistence in Fibrotic Gingiva: INTERACTIONS BETWEEN cAMP AND MAPK SIGNALING PATHWAYS, AND PROSTAGLANDIN E2-EP3 RECEPTOR MEDIATED ACTIVATION OF THE c-JUN N-TERMINAL KINASE J. Biol. Chem., May 25, 2007; 282(21): 15416 - 15429. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pannu, S. Nakerakanti, E. Smith, P. t. Dijke, and M. Trojanowska Transforming Growth Factor-beta Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways J. Biol. Chem., April 6, 2007; 282(14): 10405 - 10413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Chen, H. Ning, W. Ishida, S. Sodin-Semrl, S. Takagawa, Y. Mori, and J. Varga The Early-Immediate Gene EGR-1 Is Induced by Transforming Growth Factor-beta and Mediates Stimulation of Collagen Gene Expression J. Biol. Chem., July 28, 2006; 281(30): 21183 - 21197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Shi-Wen, F. Rodriguez-Pascual, S. Lamas, A. Holmes, S. Howat, J. D. Pearson, M. R. Dashwood, R. M. du Bois, C. P. Denton, C. M. Black, et al. Constitutive ALK5-Independent c-Jun N-Terminal Kinase Activation Contributes to Endothelin-1 Overexpression in Pulmonary Fibrosis: Evidence of an Autocrine Endothelin Loop Operating through the Endothelin A and B Receptors. Mol. Cell. Biol., July 1, 2006; 26(14): 5518 - 5527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. R. Arany, K. C. Flanders, T. Kobayashi, C. K. Kuo, C. Stuelten, K. V. Desai, R. Tuan, S. I. Rennard, and A. B. Roberts Smad3 deficiency alters key structural elements of the extracellular matrix and mechanotransduction of wound closure PNAS, June 13, 2006; 103(24): 9250 - 9255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Qi, X. Chen, T. S. Polhill, S. Sumual, S. Twigg, R. E. Gilbert, and C. A. Pollock TGF-beta1 induces IL-8 and MCP-1 through a connective tissue growth factor-independent pathway Am J Physiol Renal Physiol, March 1, 2006; 290(3): F703 - F709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Finotto, M. Hausding, A. Doganci, J. H. Maxeiner, H. A. Lehr, C. Luft, P. R. Galle, and L. H. Glimcher Asthmatic changes in mice lacking T-bet are mediated by IL-13 Int. Immunol., August 1, 2005; 17(8): 993 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Quan, T. He, J. J. Voorhees, and G. J. Fisher Ultraviolet Irradiation Induces Smad7 via Induction of Transcription Factor AP-1 in Human Skin Fibroblasts J. Biol. Chem., March 4, 2005; 280(9): 8079 - 8085. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Jinnin, H. Ihn, K. Yamane, Y. Mimura, Y. Asano, and K. Tamaki {alpha}2(I) collagen gene regulation by protein kinase C signaling in human dermal fibroblasts Nucleic Acids Res., March 1, 2005; 33(4): 1337 - 1351. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
