Estrogen Modulates Parathyroid Hormone-Induced Interleukin-6 Production in Vivo and in Vitro*

Interleukin (IL)-6 promotes osteoclastogenesis and is thought to play a role in the bone loss that follows estrogen withdrawal. In vitro studies have demonstrated that IL-6 is produced in response to PTH by cells in the osteoblast lineage and that PTH-induced bone resorption is inhibited by a neutralizing antibody to the IL-6 receptor. In addition, we have recently reported that IL-6 plays a role in PTH-induced bone resorption in humans with chronic PTH excess and in experimental animals during the short-term infusion of PTH. In the current study, we examined whether estrogen withdrawal augments PTH-induced IL-6 production. When cultured in the absence of estrogen, human osteosarcoma cells (Saos-2) treated with PTH demonstrated significantly greater release of IL-6 than cells grown under estrogen-replete conditions, 30-fold vs. 15-fold (P = 0.005). A similar effect but of lesser magnitude was seen with primary human osteoblasts. In vivo, PTH induced IL-6 production was also increased in the estrogen-deficient state (ovx) such that at the end of a 5-day PTH infusion, the mean circulating level of IL-6 was significantly higher in ovx vs. sham/ovx mice (60.1 vs. 16.9 pg/ml; P < 0.0001). The greater increase in circulating levels of IL-6 in PTH-treated ovx mice was paralleled by a greater rise in bone resorption markers with the mean level of urine collagen cross-links in the PTH-treated ovx group being more than 2.5-fold higher than in the PTH-treated sham/ovx animals (236 vs. 88.5 microg/mmol creatinine, P < 0.0001). Mean serum collagen cross-link values were 17.4 microg/liter in PTH-treated ovx vs. 7.4 microg/liter in PTH-treated sham/ovx animals (P < 0.0001). Treatment of animals with estrogen prevented the exaggerated response to PTH infusion such that the increase in both circulating levels of IL-6 and bone turnover markers in estrogen-treated animals were similar to those observed in sham/ovx animals and significantly lower than those in PTH-treated ovx animals. These findings may help to explain the increased skeletal sensitivity to the resorbing effects of PTH seen in the estrogen-deficient state.