Regulation by IGF-I and TGF-beta 1 of swarm-rat chondrosarcoma chondrocytes

The growth factors transforming growth factor-beta 1 and insulin-like growt h factor-I influence a wide range of cellular actions, including the growth of several neoplastic cell types. Their role in the regulation of neoplast ic chondrocytes remains unclear. We tested the hypotheses that transforming growth factor-beta 1 and insulin-like growth factor-I differentially regul ate neoplastic chondrocytes and interact to modulate the mitotic and matrix synthetic activities of neoplastic chondrocytes. We used Swarm-rat chondro sarcoma chondrocytes to investigate the effect of each factor individually and of both factors in combination on [H-3]thymidine incorporation into DNA and on [S-35]sulfate incorporation into glycosaminoglycans. Each factor in creased [H-3]thymidine incorporation 2.7-fold; transforming growth factor-b eta 1 achieved this effect at a 20-fold lower concentration than insulin-li ke growth factor-I. In contrast, insulin-like growth factor-I stimulated [S -35]sulfate incorporation 3.5-fold; this was twice the maximal effect of tr ansforming growth factor-beta 1. Transforming growth factor-beta 1 and insu lin-like growth factor-I each decreased the proportion of newly synthesized glycosaminoglycans that were retained in the cells and pericellular matrix , indicating that the anabolic effect of these factors is only partly direc ted toward cell associated matrix production. The mitogenic and matrix synt hetic actions of insulin-like growth factor-I and transforming growth facto r-beta 1 were synergistic. In concert, they increased [H-3]thymidine incorp oration approximately 12-fold, an effect three times greater than the sum o f the maximal stimulation achieved by each factor individually. Similarly, transforming growth factor-beta 1 and insulin-like growth factor-I together increased glycosaminoglycan synthesis approximately two times more than th e sum of their maximal individual effects. Taken together, these data indic ate that these chondrosarcoma chondrocytes are positively regulated by insu lin-like growth factor-I and transforming growth factor-beta 1 and that the se growth factors interact to augment the mitotic and matrix synthetic acti ons of the chondrocytes. If supported in human models, the sensitivity to g rowth factors of these cells suggests that interventions directed toward gr owth factor inhibition may be of therapeutic value.