Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Activin-Smad Pathway Is Activated in Systemic Sclerosis
Takagi, Kae, Kawaguchi, Yasushi, Ota, Yuko, Gono, Takahisa, Tochimoto, Akiko, Katsumata, Yasuhiro, Fukasawa, Chikako
Systemic sclerosis is a chronic disease of unknown etiology characterized by autoimmunity, vascular damage, and progressive fibrosis of the skin and internal organs. However, it has not been elucidated how the fibrosis is achieved. The pathogenesis of fibrosis is not well understood and then there are not any effective treatments. It has been reported that overproduction of collagen, fibronectin, other many extracellular matrix and cytokines such as transforming growth factor b(TGF-b) and connective tissue growth factor (CTGF) in fibroblast cultured from SSc patients skin. TGF-b is thought to be the most important mediator, which induce fibrosis in SSc patient. Activin is a member of the TGF-b superfamily and initially discovered as inducers of follicle-stimulating hormone release. Recently wide varieties of functions of activins have been reported. Particularly, activin has the important functions to repair a tissue in acute and chronic inflammatory diseases, and to induce fibrosis in liver and renal tissue. Previous report was suggested the activin receptor 1B (ACR1B) also known as ALK4/5 mRNA was highly expressed in SSc patient. Then, we have investigated how activin is involved in the development of fibrosis in SSc.
Serum activin levels were measured by an ELISA assay. The expression of activin was determined by RT-PCR and immunohistochemistry in fibroblasts cultured from skin of SSc patients and healthy controls (HC). The production of procollagen type I was measured by an ELISA assay, and gene expression of COL1a was quantitated using real-time PCR. Ligand induced activation of the Smad signaling pathway was examined by Western blot analysis.
Serum activin levels were significantly higher in SSc patient than HC. Activin expression was also higher in cultured SSc fibroblasts. Activin stimulation induced phosphorylation of Smad2/3 and CTGF expression in SSc fibroblasts. Procollagen production and Col1a mRNA was also increased by activin stimulation. The basal level of Smad2/3 phosphorylation was higher in cultured SSc fibrobrast, and treatment of ALK4/5 inhibitor SB431542 abrogated phosphorylation of Smad2/3 and CTGF expression. Treatment of ALK4/5 inhibitor also attenuated collagen production induced by activin. The mechanism for activation of activin pathway in SSc fibroblast is speculated using autocrine activin production.
Activin play a critical role in collagen production of SSc fibroblast. Inhibition of activin-smad pathway would be a new approach for treatment of SSc.
To cite this abstract, please use the following information:
Takagi, Kae, Kawaguchi, Yasushi, Ota, Yuko, Gono, Takahisa, Tochimoto, Akiko, Katsumata, Yasuhiro, et al; Activin-Smad Pathway Is Activated in Systemic Sclerosis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1806