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.

Objective. Epidemiologic studies suggest a protective effect of estrogen replacement therapy (ERT) against the development of knee and hip osteoarthritis, but a potential mechanism for this effect is not known. The present study was done to determine if functional estrogen receptors (ERs) are present in adult articular cartilage and to determine if ERT in vivo affects the production of insulin-like growth factor binding proteins (IGFBPs). Methods. Reverse transcription-polymerase chain reaction, immunoblotting, and immunohisto-chemistry were used to measure messenger RNA (mRNA) and protein for ERs in adult monkey articular cartilage. Cultured chondrocytes transfected with a reporter construct containing the estrogen response element (ERE/luciferase) were stimulated with estrogen in vitro to determine functional activity of the ERs. IGFBP production was measured by ligand and immuno-blotting of conditioned media of cells cultured from control and estrogen-treated surgically menopausal monkeys. Proteoglycan (PG) synthesis was estimated by measurement of 35 SO 4 incorporation. Results. ER and ER mRNA were present in adult monkey articular cartilage, and ER protein was demonstrated by immunoblotting and immunohisto-chemistry. Estrogen treatment in vitro of cells trans-fected with the ERE/luciferase construct resulted in a 2.87-fold increase (P 0.0163) in reporter production over that of untreated cells. Compared with untreated controls, IGFBP-2 production was significantly increased (P < 0.008) in conditioned media of chondro-cytes cultured from monkeys that had received ERT in vivo. Increased IGFBP-2 in these cultures was associated with a 1.41-fold increase (P 0.02) in the level of sulfate incorporation. Conclusion. Transcriptionally functional ER are present in adult articular cartilage, and ERT increases the production of IGFBP-2 and the synthesis of PGs by chondrocytes from surgically menopausal monkeys. These results indicate that estrogen can have a direct effect on adult articular cartilage. The Framingham Osteoarthritis (OA) Study recently demonstrated that postmenopausal women who take estrogen replacement therapy (ERT) have lower odds of developing radiographic knee OA and that the protective effect was increased with increased duration of ERT treatment (1). Other epidemiologic studies have suggested a similar protective effect of ERT (2-5). Although data point to ERT as a possible treatment for modifying the increased risk and prevalence of OA seen in postmenopausal women, there is no biochemical data to illustrate a mechanism by which estrogen can directly or indirectly lead to a beneficial effect on joint metabolism .

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