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


CONCLUSIONS
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.
Distler
Jörg H W
JH
University of Erlangen-Nuremberg, Erlangen, Germany. joerg.distler@med3.imed.uni-erlangen.de
Jüngel
Astrid
A
Huber
Lars C
LC
Schulze-Horsel
Ursula
U
Zwerina
Jochen
J
Gay
Renate E
RE
Michel
Beat A
BA
Hauser
Thomas
T
Schett
Georg
G
Gay
Steffen
S
Distler
Oliver
O
D000368:Aged; D000818:Animals; D001549:Benzamides; D001761:Bleomycin / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000209:etiology / Q000276:immunology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013047:Specific Pathogen-Free Organisms
D001549:Benzamides; D016326:Extracellular Matrix Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D001761:Bleomycin; D000068877:Imatinib Mesylate