Reduction in the chondrocyte response to insulin-like growth factor 1 in aging and osteoarthritis: studies in a non-human primate model of naturally occurring disease.

OBJECTIVE Although the development of osteoarthritis (OA) is closely associated with aging, the mechanism for this association is not clear. This study was designed to determine the effects of aging and OA on the chondrocyte response to stimulation with insulin-like growth factor 1 (IGF-1) in a non-human primate model of naturally occurring OA. METHODS Chondrocytes were isolated from cartilage removed separately from the medial and lateral femoral condyles and tibial plateaus of cynomolgus monkeys at the time of necropsy. Each joint site was scored histologically on a scale of 0-7 for OA pathologic changes. Isolated chondrocytes were cultured in alginate in serum-free medium and stimulated with IGF-1 or des(1-3) IGF-1, which has a much lower affinity for IGF binding proteins (IGFBP) than IGF-1. Response was measured as the ability to stimulate sulfate and proline incorporation. RESULTS Cartilage samples from 34 monkeys ranging in age from 6.7 years to 27 years and with histologic scores ranging from 0 to 7 were analyzed. A significant decline in the response to IGF-1 was noted with both increasing age and increasing OA score. Controlling for the OA score, the estimated effect of age on IGF-1 response, measured by total sulfate incorporation, was a decline of 3.81% per year (P = 0.0001), or a 75% decline over 20 years as a monkey ages from young to older adult. Controlling for age, the effect of OA score was significant only for proline incorporation in the alginate matrix (estimated slope coefficient +/-standard error -15.9 +/- 7.2; P = 0.03), suggesting a negative effect of OA on retention of 3H-proline-labeled proteins in the matrix. There was a significantly reduced response to des(1-3) IGF-1 with increasing age, but no effect of OA score on response to des(1-3) IGF-1. There was no effect of age on cell viability. CONCLUSION These results demonstrate a significant age-related decline in the chondrocyte response to IGF-1. The finding that increasing OA score was associated with a reduced response to intact IGF-1 but not des(1-3) IGF-1 suggests a role of increased production of inhibitory IGFBP in OA. Since the cells from older animals had a reduced response to both forms of IGF-1, the mechanism of the reduced response with age cannot be attributed to changes in IGFBP. Age-related changes in IGF receptors or, more likely, age-related alterations in intracellular signal transduction may also be involved.