Estrogen replacement therapy modulation of the insulin-like growth factor system in monkey knee joints

Objective. Epidemiologic studies have suggested that estrogen replacement t herapy may lower the risk of osteoarthritis in women, but the mechanism of this effect is unknown. Since estrogen acts in other tissues in part throug h regulation of the insulin-like growth factor (IGF) system as well as cyto kines including interleukin-6 (IL-6), we determined whether estrogen replac ement regulates the levels of these factors in synovial fluid (SF). Methods. Levels of IGF-1, IGF-2, IGF binding proteins (IGFBP) 1-3, and IL-6 were measured in SF samples obtained from 67 female adult cynomolgus monke ys that had been ovariectomized and treated for 30 months in 1 of 3 groups. Group 1 (n = 24) had no estrogen replacement (control), group 2 (n = 22) I received estrogen (Premarin) at the human equivalent of 0.625 mg/day, and group 3 (n = 21) received estrogen at the same dose as group 2, plus proges terone (Provera) at the equivalent of 2.5 mg/day, Results. Compared with controls, estrogen-treated monkeys had 2-fold higher SF levels of IGF-1 (P < 0.001), 1.7-fold higher IGF-2 (P < 0.006), 5.9-fol d higher IGFBP- 1 (P < 0.02), and 2.5-fold higher IGFBP-3 (P < 0.001). Estr ogen plus progesterone-treated monkeys had SF levels of IGF-1, IGF-2, IGFBP -1, and IGFBP-3 that were intermediate between the levels in the control an d estrogen groups, except that the level of IGFBP-3 was significantly great er than that in the control group (P < 0.001), SF levels of IGFBP-2 and IL- 6 did not differ by treatment group. Treatment group did not affect the ser um levels of IGF-1 and IL-6, but IGF-2 and IGFBP-3 were increased by 1.6- a nd 1.8-fold, respectively, in the estrogen group (P < 0.001), There was no correlation between changes in serum and SF levels of IGF components, excep t for a weak correlation for IGFBP-3 levels from control (r = 0.464, P = 0. 04) and estrogen-treated (r = 0.577, P = 0.008) animals. Conclusion. This study demonstrates a significant effect of estrogen replac ement on IGF system components in synovial fluid, of which at least some ar e distinct from any systemic changes observed. The results indicate a poten tial stimulatory effect of estrogen on joint tissues in vivo.