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

The effect of dermal application of halofuginone-an inhibitor of collagen t ype I synthesis-on skin collagen and collagen alpha1(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-ski n mouse (Tsk) and skin biopsies were taken for collagen staining by sirius red and for collagen alpha1(I) gene expression by in situ hybridization. In addition, cell proliferation was evaluated by immunostaining for prolifera tion cell nuclear antigen (PCNA) alone or in combination with collagen alph a1(I) probe. The number of mast cells was assessed by toluidine blue. Derma l application of halofuginone (0.01%) for 60 days was as good as systemic a dministration (1 mug/mouse/day) in reducing collagen alpha1(I) gene express ion in skin biopsy and almost as good in reducing skin width. Halofuginone was stable and effective only at acidic pH. The effect of halofuginone (0.0 3%) was time-dependent. After 40 days of daily, treatment, a significant re duction in the collagen alpha1(I) gene expression was observed and further decrease was observed after 60 days. The reduction in collagen alpha1(I) ge ne expression and the reduction in the proliferation of dermal fibroblasts probably occur in the same subset of cells. No effect of halofuginone on th e proliferation of keratinocytes or on mast cell number was observed. These results suggest that target-oriented application of halofuginone may becom e a novel therapy for fibrotic disorders in general and for scleroderma in particular. (C) 2001 Elsevier Science Inc. All rights reserved.