Estrogen's bone-protective effects may involve differential IL-1 receptor regulation in human osteoclast-like cells

Declining estrogen levels during the first postmenopausal decade lead to ra pid bone loss and increased fracture risk that can be reversed by estrogen replacement therapy. The bone-protective effects of estrogen may involve su ppression of inflammatory cytokines that promote osteoclastogenesis and bon e resorption, such as IL-1, TNF-alpha, and IL-6. We investigated whether es trogen modulates IL-1 actions on human osteoclasts (OCs) and other bone cel l types. Isolated human OCs and primary bone marrow-derived CC-like cells e xpressed both the signaling (IL-1RI) and decoy (IL-1RII) IL-1 receptors, wh ereas only IL-1RI was detected in osteoblasts. IL-1RII/IL-1RI mRNA ratios a nd release of soluble IL-1RII (sIL-1RII) were lower in OC-like cells derive d from women in the late postmenopausal period compared with younger women, but were unrelated to male donor age, suggesting that estrogen might play a role in regulating IL-1 receptor levels in vivo. Estrogen directly reduce d in vitro OC-like cell IL-1RI mRNA levels while increasing IL-1RII mRNA le vels and sIL-1RII release. These estrogenic events were associated with inh ibited IL-l-mediated cytokine (IL-8) mRNA induction and cell survival, i.e. , increased apoptosis. In contrast, estrogen did not alter IL-1R levels or IL-1 responsiveness in primary human osteoblasts or bone marrow stromal cel ls. We conclude that one novel mechanism by which estrogen exerts bone-prot ective effects may include a selective modulation of IL-1R isoform levels i n OC or CC-like cells, thereby reducing their IL-1 responsiveness and cell survival. Conversely, this restraint on IL-1 actions may be lost as estroge n levels decline in aging women, contributing to an enhanced CC-mediated po stmenopausal bone loss.