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-1RII/IL-1RI steady-state mRNA ratios in hOCL cells decrease with incr...
IL-1RII/IL-1RI steady-state mRNA ratios in hOCL cells decrease with increasing age of female, but not male, bone marrow donors. Steady-state mRNA levels for IL-1RI, IL-1RII, and the internal control GAPDH were measured in hOCL cells generated from 11 women ranging from 51 to 72 years of age (a), and from 11 men ranging from 40 to 68 years of age (b), as described in Figure 3b. No bone marrow samples were available from female donors of 40 to 50 years of age. The IL-1RII/IL-1RI mRNA ratios were calculated as follows: the signal intensity of each IL-1R protected band was divided by the signal intensity of the corresponding internal GAPDH control for that reaction, and the normalized value for IL-1RII was then divided by the normalized value for IL-1RI (Table 1). P, statistical significance as determined by ANOVA; r, correlation coefficient. Typically, as many RNA samples as possible were run in a single RPA (using the same gel and probes) to enable direct comparisons. In addition, RNA obtained from 2 different hOCL cell cultures each was reanalyzed in 3 separate RPA trials to calculate the variances associated with determining the IL-1RII/IL-1RI mRNA ratios across independent RPA experiments. Thus, independent assessments of the IL-1RII/IL-1RI ratio for hOCL cells derived from a 72-year-old woman yielded values of 0.28, 0.3, and 0.32 with a variance of 0.0004, and hOCL cells from a 51-year-old woman yielded ratios of 2.4, 1.8, and 2.0 with a variance of 0.093.