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 rapid bone loss and increased fracture risk that can be reversed by estrogen replacement therapy. The bone-protective effects of estrogen may involve suppression of inflammatory cytokines that promote osteoclastogenesis and bone resorption, such as IL-1, TNF-alpha, and IL-6. We investigated whether estrogen modulates IL-1 actions on human osteoclasts (OCs) and other bone cell types. Isolated human OCs and primary bone marrow-derived OC-like cells expressed both the signaling (IL-1RI) and decoy (IL-1RII) IL-1 receptors, whereas only IL-1RI was detected in osteoblasts. IL-1RII/IL-1RI mRNA ratios and release of soluble IL-1RII (sIL-1RII) were lower in OC-like cells derived 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 reduced in vitro OC-like cell IL-1RI mRNA levels while increasing IL-1RII mRNA levels and sIL-1RII release. These estrogenic events were associated with inhibited IL-1-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 cells. We conclude that one novel mechanism by which estrogen exerts bone-protective effects may include a selective modulation of IL-1R isoform levels in OC or OC-like cells, thereby reducing their IL-1 responsiveness and cell survival. Conversely, this restraint on IL-1 actions may be lost as estrogen levels decline in aging women, contributing to an enhanced OC-mediated postmenopausal bone loss.
D000368:Aged; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology* / Q000502:physiology*; D015663:Osteoporosis, Postmenopausal / Q000209:etiology / Q000276:immunology / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D053573:Receptors, Interleukin-1 Type I; D053574:Receptors, Interleukin-1 Type II; D015398:Signal Transduction