Cell-cycle-dependent expression of transforming growth factor beta type I receptor correlates with differential proliferative effects of TGFbeta1 in articular chondrocytes.

We previously found that transforming growth factor beta type 1 (TGFbeta1) had bifunctional effects on articular chondrocytes in culture depending on the proliferative state of the cells. Here, TGFbeta1 responses and the expression of TGFbeta receptors I and II were investigated as a function of growth state in rabbit articular chondrocytes (RAC) and Mv1Lu cells, a cell line which is growth inhibited by TGFbeta1. In contrast to these latter cells, in which DNA synthesis was decreased by TGFbeta1 independently of the cell cycle phases, exponentially growing RAC responded with a stimulation of DNA synthesis while confluent or quiescent cells were growth inhibited. Using synchronized RAC cultures, we showed that inhibitory responses were associated with the G0/G1 phase, whereas proliferative effects were S-phase dependent. Type I receptor mRNA level was severalfold greater in quiescent and slowly proliferating than in exponentially growing cells. In contrast, the expression of type II mRNA did not change. 125I-TGFbeta1 binding to RI in G0/G1-arrested cells was greater than in S-phase, suggesting a correlation with the growth-inhibitory effect of TGFbeta1. Transfection of an RI expression vector in exponentially growing RAC, which normally are growth stimulated by TGFbeta1, induced an inhibitory response, supporting the idea that this effect was due to increased RI expression. These results indicate that the ratio of type I to type II levels is cell cycle dependent and could lead to either negative or positive proliferative responses. In contrast, no influence on the TGFbeta1-induced stimulation of matrix gene transcriptional activity was seen, confirming that TGFbeta cell growth and matrix effects are controlled by separate pathways.