Transforming Growth Factor Beta: An Autocrine Regulator of Chondrocytes

Transforming growth factor beta (TGF-β) is a ubiquitous regulator of cellular growth and differentiation. The present study investigated the effects of TGF-β on chick growth plate chondrocyte proliferation, matrix synthesis, and alkaline phosphatase activity in short term cultures. TGF-β markedly stimulated DNA synthesis in a dose-dependent manner, while collagen synthesis and cellular and matrix vesicle alkaline phosphatase activity were inhibited. Biologic effects of TGF-β were correlated with binding to specific receptors, and both high and low affinity receptors were identified. Countercurrent centrifugal elutriation was used to fractionate growth plate chondrocytes to obtain populations of cells in different stages of maturation (effectively from different zones of the growth plate). TGF-β showed increasing mitogenicity with increasing cellular maturation in the growth plate, with maximal stimulation in the proliferating and early hypertrophic cells. The smallest cells expressed only the high affinity receptor, while with hypertrophy there was increasing expression of the low affinity receptor and a progressive increase in the number of both receptors per cell. Furthermore, the dose-response curves for TGF-β-stimulated DNA synthesis were not biphasic in the smaller cells, but became progressively more biphasic with cellular hypertrophy and expression of the low affinity receptor. Finally, TGF-β activity was identified in partially purified chondrocyte conditioned medium by specific bioassay, indicating TGF-β production by growth plate chondrocytes. The data suggests a potentially important autocrine function for TGF-B in modulating chondrocyte proliferation and matrix synthesis in endochondral calcification.