Cell-cycle-dependent expression of transforming growth factor β type I receptor correlates with differential proliferative effects of TGFβ1 in articular chondrocytes

We previously found that transforming growth factor beta type 1 (TGF beta(1)) had bifunctional effects on articular chondrocytes in culture depending on the proliferative state of the cells. Here, TGF beta(1) responses and the expression of TGF beta 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 TGF beta(1). In contrast to these latter cells, in which DNA synthesis was decreased by TGF beta(1) 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 G(0)/G(1) 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. I-125-TGF beta(1) binding to RI in G(0)/G(1)-arrested cells was greater than in S-phase, suggesting a correlation with the growth-inhibitory effect of TGF beta(1). Transfection of an RI expression vector in exponentially growing RAC, which normally are growth stimulated by TGF beta(1), 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 TGF beta(1)-induced stimulation of matrix gene transcriptional activity was seen, confirming that TGF beta cell growth and matrix effects are controlled by separate pathways. (C) 1998 Academic Press.