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The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis.

ABSTRACT: Osteoporosis is an important clinical problem, affecting more than 50% of people over age 50 yr. Estrogen signaling is critical for maintaining proper bone density, and the identification of an endogenous selective estrogen receptor (ER) modulator, 27-hydroxycholesterol (27HC), suggests a mechanism by which nutritional/metabolic status can influence bone biology. With its levels directly correlated with cholesterol, a new possibility emerges wherein 27HC links estrogen and cholesterol signaling to bone homeostasis. In these studies, we found that increasing concentrations of 27HC, both by genetic and pharmacological means, led to decreased bone mineral density that was associated with decreased bone formation and increased bone resorption. Upon manipulation of endogenous estrogen levels, many of the responses to elevated 27HC were altered in such a way as to implicate ER as a likely mediator. In a model of postmenopausal bone loss, some pathologies associated with elevated 27HC were exacerbated by the absence of endogenous estrogens, suggesting that 27HC may act both in concert with and independently from classic ER signaling. These data provide evidence for interactions between estrogen signaling, cholesterol and metabolic disease, and osteoporosis. Patients with high cholesterol likely also have higher than average 27HC, perhaps putting them at a higher risk for bone loss and fracture. More studies are warranted to fully elucidate the mechanism of action of 27HC in bone and to identify ways to modulate this pathway therapeutically.

SUBMITTER: DuSell CD

PROVIDER: S-EPMC2940523 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis.

DuSell Carolyn D CD Nelson Erik R ER Wang Xiaojuan X Abdo Jennifer J Mödder Ulrike I UI Umetani Michihisa M Gesty-Palmer Diane D Javitt Norman B NB Khosla Sundeep S McDonnell Donald P DP

Endocrinology 20100525 8

Osteoporosis is an important clinical problem, affecting more than 50% of people over age 50 yr. Estrogen signaling is critical for maintaining proper bone density, and the identification of an endogenous selective estrogen receptor (ER) modulator, 27-hydroxycholesterol (27HC), suggests a mechanism by which nutritional/metabolic status can influence bone biology. With its levels directly correlated with cholesterol, a new possibility emerges wherein 27HC links estrogen and cholesterol signaling ...[more]

PMID: 20501668

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Project description:Despite the increased awareness of differences in the inflammatory response between men and women, only limited research has focused on the biological factors underlying these sex differences. The cholesterol derivative 27-hydroxycholesterol (27HC) has been shown to have opposite inflammatory effects in independent experiments using mouse models of atherosclerosis and non-alcoholic steatohepatitis (NASH), pathologies characterized by cholesterol-induced inflammation. As the sex of mice in these in vivo models differed, we hypothesized that 27HC exerts opposite inflammatory effects in males compared to females. To explore whether the sex-opposed inflammatory effects of 27HC translated to humans, plasma 27HC levels were measured and correlated with hepatic inflammatory parameters in obese individuals. To investigate whether 27HC exerts sex-opposed effects on inflammation, we injected 27HC into female and male Niemann-Pick disease type C1 mice (Npc1nih ) that were used as an extreme model of cholesterol-induced inflammation. Finally, the involvement of estrogen signaling in this mechanism was studied in bone marrow-derived macrophages (BMDMs) that were treated with 27HC and 17β-estradiol (E2). Plasma 27HC levels showed opposite correlations with hepatic inflammatory indicators between female and male obese individuals. Likewise, hepatic 27HC levels oppositely correlated between female and male Npc1nih mice. Twenty-seven hydroxycholesterol injections reduced hepatic inflammation in female Npc1nih mice in contrast to male Npc1nih mice, which showed increased hepatic inflammation after 27HC injections. Furthermore, 27HC administration also oppositely affected inflammation in female and male BMDMs cultured in E2-enriched medium. Remarkably, female BMDMs showed higher ERα expression compared to male BMDMs. Our findings identify that the sex-opposed inflammatory effects of 27HC are E2-dependent and are potentially related to differences in ERα expression between females and males. Hence, the individual's sex needs to be taken into account when 27HC is employed as a therapeutic tool as well as in macrophage estrogen research in general. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis.

Publications

The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis.

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