Estrogen’s bone-protective effects may involve differential IL-1 receptor regulation in human osteoclast-like cells
Teresa Sunyer, … , Patricia Collin-Osdoby, Philip Osdoby
Teresa Sunyer, … , Patricia Collin-Osdoby, Philip Osdoby
Published May 15, 1999
Citation Information: J Clin Invest. 1999;103(10):1409-1418. https://doi.org/10.1172/JCI4682.
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Article

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.

Authors

Teresa Sunyer, Jennifer Lewis, Patricia Collin-Osdoby, Philip Osdoby

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IL-1 induction of IL-8 in hOCL cells is mediated by the signaling IL-1RI...
IL-1 induction of IL-8 in hOCL cells is mediated by the signaling IL-1RI. Bone marrow–derived hOCL cells were preincubated for 1 hour in the absence (0) or presence of neutralizing antibodies to the signaling IL-1RI (5 or 50 μg/mL) or the decoy IL-1RII (1 or 5 μg/mL) at concentrations that represent approximately 1–10 times their ND50 (antibody concentration required for half-maximal inhibition of IL-1 activity as determined by the manufacturer). Cell cultures were then treated for 16 hours with 10–9 M IL-1β (+) or vehicle (–), and the cells were harvested for protein determination. IL-8 cytokine release was measured in the conditioned medium, normalized by the total cellular protein in each culture dish, and expressed as the mean ± SEM of nanograms of IL-8 released per milligrams of cell protein. Significant differences from control cultures: **P < 0.01. Significant differences from IL-1–treated cultures: +P < 0.05. Determined by Bonferroni post-ANOVA test for multiple comparisons.