Inhibition of Collagen Synthesis and Changes in Skin Morphology in Murine Graft-Versus-Host Disease and Tight Skin Mice: Effect of Halofuginone

Abstract

The effect of halofuginone, a plant alkaloid known to inhibit collagen type I synthesis, on skin collagen content and skin morphology was evaluated in two in vivo models of scleroderma: the murine chronic graft-versus-host disease (cGvHD) and the tight skin mouse. Skin collagen was assessed by hydroxyproline levels in skin biopsies and by immunohistochemistry using anti-collagen type I antibodies. Daily intraperitoneal injections of halofuginone (1 microgram/mouse) for 52 d starting 3 d before spleen cell transplantation, abrogated the increase in skin collagen and prevented the thickening of the dermis and the loss of the subdermal fat, all of which are characteristic of the cGvHD mice. Halofuginone had a minimal effect on collagen content of the control mice. The halofuginone-dependent decrease in skin collagen content was concentration-dependent and was not accompanied by changes in body weight in either the cGvHD or the control mice. Injections of halofuginone (1 microgram/mouse) for 45 d caused a decrease in the collagen content and dermis width in tight skin mice, but did not affect the dermis width of control mice. Collagen content determination from skin biopsies confirmed the immunohistochemical results in the same mice. The low concentration of halofuginone needed to prevent collagen deposition in fibrotic skin without affecting body weight suggests that halofuginone may serve as a novel and promising anti-fibrotic therapy.