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-nondigestible proteins (NCDP), cell proliferation or collagen degradation. Halofuginone depressed specifically the expression of alpha 1 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 alpha 1(I) and alpha 1(II) mRNAs. A slight inhibition of the expression of alpha 2(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.
Granot
I
I
Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet Dagan, Israel.
Halevy
O
O
Hurwitz
S
S
Pines
M
M
D000818:Animals; D001717:Birds; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D003049:Coccidiostats / Q000494:pharmacology*; D003094:Collagen / Q000096:biosynthesis* / Q000235:genetics; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D005347:Fibroblasts; D015870:Gene Expression / Q000187:drug effects; D006132:Growth Plate; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D010880:Piperidines; D011392:Proline; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones; D051381:Rats; D013045:Species Specificity
D003049:Coccidiostats; D061965:Matrix Metalloproteinase Inhibitors; D010880:Piperidines; D011799:Quinazolines; D052999:Quinazolinones; D003094:Collagen; D011392:Proline; C010176:halofuginone