אסיף מאגר המחקר החקלאי

Reduction in dermal fibrosis in the tight-skin (Tsk) mouse after local application of halofuginone

Year:

2001

Source of publication :

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Volume :

62

Co-Authors:

Pines, M., Institute of Animal Science, Agricultural Research Organization, the Volcani Center, Bet Dagan 50250, Israel
Domb, A., School of Pharmacy, Faculty of Medicine, the Hebrew University of Jerusalem, Jerusalem, Israel
Ohana, M., Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem 91120, Israel
Inbar, J., Collgard Biopharmaceuticals Ltd., Tel Aviv, Israel
Genina, O., Institute of Animal Science, Agricultural Research Organization, the Volcani Center, Bet Dagan 50250, Israel
Alexiev, R., Institute of Animal Science, Agricultural Research Organization, the Volcani Center, Bet Dagan 50250, Israel
Nagler, A., Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem 91120, Israel

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Abstract:

The effect of dermal application of halofuginone - an inhibitor of collagen type I synthesis - on skin collagen and collagen α1(I) gene expression in an animal model of scleroderma and chronic graft versus host disease (cGvHD) was evaluated. Halofuginone-containing cream was applied on the tight-skin mouse (Tsk) and skin biopsies were taken for collagen staining by sirius red and for collagen α1(I) gene expression by in situ hybridization. In addition, cell proliferation was evaluated by immunostaining for proliferation cell nuclear antigen (PCNA) alone or in combination with collagen α1(I) probe. The number of mast cells was assessed by toluidine blue. Dermal application of halofuginone (0.01%) for 60 days was as good as systemic administration (1 μg/mouse/day) in reducing collagen α1(I) gene expression in skin biopsy and almost as good in reducing skin width. Halofuginone was stable and effective only at acidic pH. The effect of halofuginone (0.03%) was time-dependent. After 40 days of daily treatment, a significant reduction in the collagen α1(I) gene expression was observed and further decrease was observed after 60 days. The reduction in collagen α1(I) gene expression and the reduction in the proliferation of dermal fibroblasts probably occur in the same subset of cells. No effect of halofuginone on the proliferation of keratinocytes or on mast cell number was observed. These results suggest that target-oriented application of halofuginone may become a novel therapy for fibrotic disorders in general and for scleroderma in particular. © 2001 Elsevier Science Inc. All rights reserved.

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