Functional estrogen receptors in adult articular cartilage: estrogen replacement therapy increases chondrocyte synthesis of proteoglycans and insulin-like growth factor binding protein 2.
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 immunohistochemistry 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 immunoblotting of conditioned media of cells cultured from control and estrogen-treated surgically menopausal monkeys. Proteoglycan (PG) synthesis was estimated by measurement of 35SO4 incorporation. RESULTS: ERa and ERbeta mRNA were present in adult monkey articular cartilage, and ER protein was demonstrated by immunoblotting and immunohistochemistry. Estrogen treatment in vitro of cells transfected 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 chondrocytes 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.