REGULATION OF GROWTH-PLATE CHONDROCYTES BY INSULIN-LIKE GROWTH-FACTOR I AND BASIC FIBROBLAST GROWTH-FACTOR

A study was performed in order to investigate the possible functional roles of insulin-like growth-factor I (IGF-I) and basic fibroblast growth factor (bFGF) in the regulation of mitotic and metabolic activity of growth-plate chondrocytes. Chondrocytes from the distal radial growth plates of calves and the costal physeal cartilage of rats were exposed to these factors, individually and in combination, in primary monolayer culture, to assess their effects. The data showed that bFGF had both a greater potency and a greater efficacy as a mitogen for bovine growth-plate chondrocytes than did IGF-I. The maximum incorporation of H-3-thymidine by bFGF was 8.3 times that in serum-free (control) cultures; the maximum stimulation of incorporation by IGF-I was 2.5 times that in the control medium. In contrast, IGF-I stimulated a maximum incorporation of S-35-sulfate into glycosaminoglycans that was 2.6 times that in the IGF-I se rum-free control cultures, while bFGF had no effect or was mildly inhibitory. When used together, these two factors acted synergistically. Incorporation of H-3-thymidine was more than two times greater than the sum of the effects of the growth factors when used alone and 20.5 times greater than that of the growth factor-free control cultures. Physeal chondrocytes from six-day-old rats were mitotically more responsive to bFGF than to IGF-I, but they were more responsive to IGF-I when they had been derived from twenty-eight-day-old rats. Interaction between bFGF and factors in the serum enhanced the mitotic activity of the rat chondrocytes, but bFGF did not interact with IGF-I under the same experimental conditions. In the presence of bFGF, there was a reduction in the stimulation by IGF-I of incorporation of S-35-sulfate and a decrease in the percentage of chondrocytes containing alkaline phosphatase. These growth factors also influenced cellular morphology in culture. In the presence of IGF-I or serum, the rat chondrocytes manifested the polygonal morphology typical of chondrocytes in culture, while bFGF promoted a more elongated spindle shape. Removal of bFGF and replacement by IGF-I restored the polygonal morphology, indicating that this transition is reversible. CLINICAL RELEVANCE: These results suggest that both IGF-I and bFGF participate in the regulation of skeletal growth and that they differ with regard to the specific cellular functions that they regulate. IGF-I stimulates both cellular mitotic activity and synthesis of extracellular matrix. Although bFGF appeared to be a more efficacious and more potent mitogen than IGF-I, it failed to stimulate the differentiated chondrocyte functions that were tested. These data are consistent with a general anabolic role for IGF-I in the growth plate and with the support of an immature, proliferative cellular phenotype for bFGF. The data also suggest that IGF-I and bFGF interact to regulate skeletal growth and development. Such interactions offer a more versatile means of regulation of growth than would be afforded by the two factors acting independently. Additional studies are needed to elucidate the mechanisms underlying these relationships and their application in vivo.