Halofuginone: An inhibitor of collagen type I synthesis

The effect of halofuginone - a plant alkaloid used as a coccidiostat in birds - on collagen metabolism was studied in various avian and mammalian cell cultures. In avian skin fibroblasts halofuginone attenuated the incorporation of [³H]proline into collagenase-digestible proteins (CDP) at concentrations as low as 10^-11 M, without affecting production of [³H]collagenase-non-digestible proteins (NCDP), cell proliferation or collagen degradation. Halofuginine depressed specifically the expression of α1 gene of collagen type I but not that of collagen type II. This was demonstrated in skin fibroblasts and growth-plate chondrocytes using probes containing inserts sequences corresponding to the α1(I) and α1(II) mRNAs. A slight inhibition of the expression of α2(I) was observed in avian skin fibroblasts but not in growth-plate chondrocytes. The inhibition of gene expression of both polypeptides of collagen type I in skin fibroblasts resulted in a decrease in synthesis, as demonstrated by immunoprecipitation with specific type I collagen antiserum. In primary cultures of mouse skin fibroblasts, avian epiphyseal growth plate chondrocytes and a rat embryo cell line - all of which produce and secrete collagen type I - halofuginone inhibited the incorporation of [³H]proline into CDP, the Rat-1 line being the most sensitive to the drug. These results suggest that halofuginone affects specifically type I collagen synthesis by repressing gene-expression. The need for extremely low concentrations of halofuginone to inhibit collagen type I synthesis, regardless of the tissue or animal species, contributes to the potential usefulness of the substance in studying collagen metabolism.