Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

✍ Scribed by Jörg H. W. Distler; Astrid Jüngel; Lars C. Huber; Ursula Schulze-Horsel; Jochen Zwerina; Renate E. Gay; Beat A. Michel; Thomas Hauser; Georg Schett; Steffen Gay; Oliver Distler

• Book ID: 101651737
• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 437 KB
• Volume: 56
• Category: Article
• ISSN: 0004-3591
• DOI: 10.1002/art.22314

✦ Synopsis

Objective. Imatinib mesylate is a clinically welltolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor ␤ (TGF␤) 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. Bleomycininduced 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 TGF␤ 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.

Systemic sclerosis (SSc; scleroderma) is a chronic fibrotic disorder of unknown etiology that affects the skin and various internal organs including the heart, lungs, and gastrointestinal tract. Histopathologic hallmarks of early-stage SSc are perivascular inflammatory infiltration and reduced capillary density. Later stages of the disease are characterized by excessive accumulation of extracellular matrix (ECM) components (1,2). The resulting fibrosis disrupts the physiologic structure of the affected tissues and frequently leads to dysfunction of the affected organs. Tissue fibrosis not only causes significant morbidity, but is also the major cause of death in SSc patients (3).

The overproduction of ECM components in SSc