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 growth 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 hypothesized that, as cartilage ages, an increase in the expression of these binding proteins suppresses the synthetic response of chondrocytes to insulin-like growth factor-I. To test this hypothesis, we measured proteoglycan synthesis (incorporation of [35S]sulfate per cell) in alginate cultures of chondrocytes from the articular cartilage of 1, 3, 12, and 24-month-old rats. A dose-response to insulin-like growth factor-I was determined for cells from each age group; incorporation of [35S]sulfate per cell declined with age, regardless of the dose. The sharpest decline was found between cells from the 1 and 3-month-old groups. Using the Western ligand blot technique, we then compared the expression of insulin-like growth factor-I binding protein in chondrocytes from the 1 and 3-month-old rats and found that it was increased in the cells from the older animals. Recombinant insulin-like growth factor-3, when added to the cell cultures of the 1-month-old rats, inhibited incorporation of [35S]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 factor-I results, at least in part, from increased expression of insulin-like growth factor binding protein.