Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis - PubMed (original) (raw)
Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis
Jörg H W Distler et al. Arthritis Rheum. 2007 Jan.
Free article
Abstract
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.
Comment in
- Treatment of pulmonary fibrosis in systemic sclerosis: light at the end of the tunnel?
Wollheim FA. Wollheim FA. Arthritis Rheum. 2007 Jan;56(1):9-12. doi: 10.1002/art.22315. Arthritis Rheum. 2007. PMID: 17195185 No abstract available.
Similar articles
- Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin-induced skin fibrosis.
Huber LC, Distler JH, Moritz F, Hemmatazad H, Hauser T, Michel BA, Gay RE, Matucci-Cerinic M, Gay S, Distler O, Jüngel A. Huber LC, et al. Arthritis Rheum. 2007 Aug;56(8):2755-64. doi: 10.1002/art.22759. Arthritis Rheum. 2007. PMID: 17665426 - Src kinases in systemic sclerosis: central roles in fibroblast activation and in skin fibrosis.
Skhirtladze C, Distler O, Dees C, Akhmetshina A, Busch N, Venalis P, Zwerina J, Spriewald B, Pileckyte M, Schett G, Distler JH. Skhirtladze C, et al. Arthritis Rheum. 2008 May;58(5):1475-84. doi: 10.1002/art.23436. Arthritis Rheum. 2008. PMID: 18438865 - Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis.
Avouac J, Palumbo K, Tomcik M, Zerr P, Dees C, Horn A, Maurer B, Akhmetshina A, Beyer C, Sadowski A, Schneider H, Shiozawa S, Distler O, Schett G, Allanore Y, Distler JH. Avouac J, et al. Arthritis Rheum. 2012 May;64(5):1642-52. doi: 10.1002/art.33501. Arthritis Rheum. 2012. PMID: 22139817 - Tyrosine kinase inhibitors for the treatment of fibrotic diseases such as systemic sclerosis: towards molecular targeted therapies.
Distler JH, Distler O. Distler JH, et al. Ann Rheum Dis. 2010 Jan;69 Suppl 1:i48-51. doi: 10.1136/ard.2009.120196. Ann Rheum Dis. 2010. PMID: 19995744 Review. - A potential role for imatinib and other small molecule tyrosine kinase inhibitors in the treatment of systemic and localized sclerosis.
Bibi Y, Gottlieb AB. Bibi Y, et al. J Am Acad Dermatol. 2008 Oct;59(4):654-8. doi: 10.1016/j.jaad.2008.04.034. Epub 2008 Jun 20. J Am Acad Dermatol. 2008. PMID: 18571768 Review.
Cited by
- Use of a pH-responsive imatinib mesylate sustained-release hydrogel for the treatment of tendon adhesion by inhibiting PDGFRβ/CLDN1 pathway.
Pang S, Wu R, Lv W, Zou J, Li Y, Li Y, Zhang P, Ma X, Wang Y, Liu S. Pang S, et al. Bioact Mater. 2024 Apr 25;38:124-136. doi: 10.1016/j.bioactmat.2024.04.012. eCollection 2024 Aug. Bioact Mater. 2024. PMID: 38699245 Free PMC article. - Perspective to precision medicine in scleroderma.
Komura K, Yanaba K, Bouaziz JD, Yoshizaki A, Hasegawa M, Varga J, Takehara K, Matsushita T. Komura K, et al. Front Immunol. 2024 Jan 18;14:1298665. doi: 10.3389/fimmu.2023.1298665. eCollection 2023. Front Immunol. 2024. PMID: 38304250 Free PMC article. - Recent Advances in Treatment of Systemic Sclerosis and Morphea.
Teske N, Fett N. Teske N, et al. Am J Clin Dermatol. 2024 Mar;25(2):213-226. doi: 10.1007/s40257-023-00831-2. Epub 2023 Dec 12. Am J Clin Dermatol. 2024. PMID: 38087156 Review. - ACSL4 inhibition prevents macrophage ferroptosis and alleviates fibrosis in bleomycin-induced systemic sclerosis model.
Cao D, Zheng J, Li Z, Yu Y, Chen Z, Wang Q. Cao D, et al. Arthritis Res Ther. 2023 Oct 26;25(1):212. doi: 10.1186/s13075-023-03190-9. Arthritis Res Ther. 2023. PMID: 37884942 Free PMC article. - Oral Submucous Fibrosis and Scleroderma: A Review of the Etiopathogenesis, Clinicopathological Correlation, and Management Aspects.
J S, S L, Nair MV, R KT, Ramani P. J S, et al. Cureus. 2023 Aug 31;15(8):e44502. doi: 10.7759/cureus.44502. eCollection 2023 Aug. Cureus. 2023. PMID: 37791189 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous