Estrogen modulates parathyroid hormone-induced interleukin-6 production invivo and in vitro

Interleukin (IL)-6 promotes osteoclastogenesis and is thought to play a rol e 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 osteo blast lineage and that PTH-induced bone resorption is inhibited by a neutra lizing antibody to the IL-6 receptor. In addition, we have recently reporte d that IL-6 plays a role in PTH-induced bone resorption in humans with chro nic PTH excess and in experimental animals during the short-term infusion o f PTH. In the current study, we examined whether estrogen withdrawal augmen ts PTH-induced IL-6 production. When cultured in the absence of estrogen, h uman osteosarcoma cells (Saos-2) treated with PTH demonstrated significantl y greater release of IL-6 than cells grown under estrogen-replete condition s, 30-fold vs. 15-fold (P = 0.005). A similar effect but of lesser magnitud e was seen with primary human osteo-blasts. In vivo, PTH induced IL-6 produ ction was also increased in the estrogen-deficient state (ovx) such that at the end of a B-day PTH infusion, the mean circulating level of IL-6 was si gnificantly higher in ovx us. sham/ovx mice (60.1 vs. 16.9 pg/ml; P < 0.000 1). The greater increase in circulating levels of IL-6 in PTH-treated ovx m ice was paralleled by a greater rise in bone resorption markers with the me an level of urine collagen cross-links in the PTH-treated ovx group being m ore than 2.5-fold higher than in the PTH-treated sham/ovx animals (236 vs. 88.5 mu g/mmol creatinine, P < 0.0001). Mean serum collagen cross-link valu es were 17.4 mu g/liter in PTN-treated ovx vs. 7.4 mu g/liter in PTH-treate d sham/ovx animals (P ( 0.0001). Treatment of animals with estrogen prevent ed the exaggerated response to PTH infusion such that the increase in both circulating levels of IL-6 and hone turnover markers in estrogen-treated an imals were similar to those observed in sham/ovx animals and significantly lower than those in PTH-treated ovx animals. These findings may help to exp lain the increased skeletal sensitivity to the resorbing effects of PTH see n in the estrogen-deficient state.