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

Abstract

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-α, 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. IL-1 is a potent in vivo and in vitro stimulator of bone resorption owing to its promotion of OC differentiation, OC-resorptive activity (34,35), and OC cell survival (36,37). It has been postulated that IL-1 acts indirectly on OCs through the release of soluble factor(s) from osteoblasts and other marrow cells (38). For example, high-affinity binding of IL-1 to IL-1 signaling receptors expressed on osteoblasts leads to a paracrine modulation of OC development and activity (34). However, some evidence also exists for a direct effect of IL-1 on OCs. IL-1 has been shown to raise intracellular Ca 2+ levels in isolated individual rabbit OCs (39) and to activate NF-κB-like transcription factors in purified murine OC-like cells (40); IL-1 receptor mRNA has been detected in rodent OCs by in situ hybridization (41); and IL-1 treatment of purified human OC-like cells has stimulated the release of 43). The biologic effects of IL-1 on bone depend on complex interactions among many factors, including IL-1α, IL-1β, IL-1Ra, IL-1 receptors, and IL-1 receptor accessory protein. Two distinct IL-1 receptors are known: the type I, or signaling, receptor (IL-1RI) that mediates cellular responses to IL-1 and binds equally well IL-1 agonist and antagonist; and the type II, or decoy, receptor (IL-1RII) that preferentially b...

Protective effects of estradiol on TRAIL-induced apoptosis in a human oligodendrocytic cell line: evidence for multiple sites of interactions

“…18 Thus, the subsequent activation of TRAIL surface death receptors DR4 and DR5 may finally trigger an apoptosis program in oligodendrocytic cells. Our data are in accordance with the general concept that cytokines can regulate their own receptors, [33][34][35][36] in either a paracrine or an autocrine manner, and with the observation that oligodendrocytes remain sensitive to TRAIL-induced apoptosis, in conditions where other cells, such as microglia, become insensitive to it. In fact, TRAIL upregulates its own decoy receptors in the latter cell type, thus neutralizing the effects of the molecule.…”

Hormonal regulation of immune modulators in human breast tissue

“…IL-1RI was deceased by estrogen exposure and increased by both tamoxifen and fulvestrand treatment in both breast cancer cell lines. This result is consistent with other studies showing negative regulation of mRNA IL-1RI by estrogen in human osteoclasts-like cells (244).…”

Sex Steroids and Bone

“…IL-6 and IL-11 may influence osteoclastogenesis by stimulating the self-renewal and inhibiting the apoptosis of osteoclast progenitors (Girasole et al, 1994;Jilka, 1998). Estrogen loss also may increase the sensitivity of osteoclasts to IL-1 by increasing the ratio of the IL-1RI over the IL-1 decoy receptor (IL-RII) (Sunyer et al, 1999) or increasing the number of TNF-synthesizing lymphocytes (Cenci et al, 2000). As in the case of IL-6, the effects of estrogen on TNF and M-CSF are mediated via protein-protein interactions between the ER and other transcription factors (Table I).…”