ONCOSTATIN-M STIMULATES COLLAGEN AND GLYCOSAMINOGLYCAN PRODUCTION BY CULTURED NORMAL DERMAL FIBROBLASTS - INSENSITIVITY OF SCLERODERMAL ANDKELOIDAL FIBROBLASTS

It is thought that normal fibrotic repair progresses to dermal fibrosi s when fibroblasts are activated persistently by chronic exposure to c ytokines such as transforming growth factor-beta. However, additional cytokines and mechanisms may play a role in the development of fibrosi s. Thus, we examined a recently described T-lymphocyte/macrophage-deri ved cytokine, oncostatin M, for its effect on the production of collag en and glycosaminoglycan by microcultures of normal dermal, scleroderm al, and keloidal fibroblasts. Treatment with oncostatin M for 48 h ind uced dose-dependent (1-100 ng/ml) increases in the collagen and glycos aminoglycan production of nine normal fibroblast strains, which in the absence of fetal bovine serum at 100 ng/ml averaged 196% and 244%, re spectively. Oncostatin M treatment increased both types I and III proc ollagens and their mRNA transcripts, as well as levels of hyaluronic a cid, chondroitin-4/6 sulfates, and dermatan sulfate, but not fibronect in or general noncollagenous protein synthesis. In contrast, the colla gen production of six of eight sclerodermal and keloidal fibroblast st rains was essentially unresponsive to oncostatin M treatment, with 100 ng/ml inducing an average increase of only 34% for the eight fibrotic strains. Oncostatin M stimulation of fibrotic fibroblast glycosaminog lycan production was also hyporesponsive, as 100 ng/ml of oncostatin M induced an average increase of only 101%. These results indicate that oncostatin M could function as a stimulator of normal fibrotic repair via activation of fibroblast collagen and glycosaminoglycan synthesis and that the persistent activation of sclerodermal and keloidal fibro blasts is accompanied by a loss of sensitivity to oncostatin M stimula tion.