Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-15997
Distler, J H W; Jüngel, A; Huber, L C; Schulze-Horsel, U; Zwerina, J; Gay, R E; Michel, B A; Hauser, T; Schett, G; Gay, S; Distler, O (2007). Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis and Rheumatism, 56(1):311-322.
- Registered users only
View at publisher
OBJECTIVE: Imatinib mesylate is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc). METHODS: The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycin-induced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo. RESULTS: Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGFbeta and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects. CONCLUSION: These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.
0 downloads since deposited on 22 Mar 2009
0 downloads since 12 months
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Center for Integrative Human Physiology|
|Dewey Decimal Classification:||570 Life sciences; biology
610 Medicine & health
|Deposited On:||22 Mar 2009 11:16|
|Last Modified:||27 Nov 2013 23:25|
|Additional Information:||Comment in: Arthritis Rheum. 2007 Jan;56(1):9-12.|
Users (please log in): suggest update or correction for this item
Repository Staff Only: item control page