AGE-RELATED DECLINE IN CHONDROCYTE RESPONSE TO INSULIN-LIKE GROWTH-FACTOR-I - THE ROLE OF GROWTH-FACTOR BINDING-PROTEINS

The synthetic activity of chondrocytes in articular cartilage declines with age, possibly as a result of decreased sensitivity to anabolic g rowth factors such as insulin-like growth factor-I. The sensitivity of these cells to insulin-like growth factor-I is regulated, in part by the synthesis of insulin-like growth factor-I binding proteins. We hyp othesized that, as cartilage ages, an increase in the expression of th ese binding proteins suppresses the synthetic response of chondrocytes to insulin-like growth factor-I. To test this hypothesis, we measured proteoglycan synthesis (incorporation of [S-35]sulfate per cell) in a lginate cultures of chondrocytes from the articular cartilage of 1, 3, 12, and 24-month-old rats. A dose-response to insulin-like growth fac tor-I was determined for cells from each age group; incorporation of [ S-35]sulfate per cell declined with age, regardless of the dose. The s harpest decline was found between cells from the 1 and 3-month-old gro ups. Using the Western ligand blot technique, we then compared the exp ression of insulin-like growth factor-I binding protein in chondrocyte s from the 1 and 3-month-old rats and found that it was increased in t he cells from the older animals. Recombinant insulin-like growth facto r-3, when added to the cell cultures of the 1-month-old rats, inhibite d incorporation of [S-35]sulfate and blocked responses to insulin like growth factor-I. These findings suggest that the age-related decline in the synthetic response of chondrocytes to insulin-like growth facto r-I results, at least in part, from increased expression of insulin-li ke growth factor binding protein.