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

Carolyn D. DuSell, Erik R. Nelson, Xiaojuan Wang, Jennifer Abdo, Ulrike I. Mödder, Michihisa Umetani, Diane Gesty-Palmer, Norman B. Javitt, Sundeep Khosla, Donald P. McDonnell

Research output: Contribution to journalArticle

59 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3675-3685
Number of pages11
JournalEndocrinology
Volume151
Issue number8
DOIs
StatePublished - Aug 2010

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Selective Estrogen Receptor Modulators
Homeostasis
Bone and Bones
Estrogens
Cholesterol
Estrogen Receptors
Bone Density
Osteoporosis
Postmenopausal Osteoporosis
27-hydroxycholesterol
Metabolic Diseases
Bone Fractures
Bone Resorption
Nutritional Status
Osteogenesis
Pharmacology
Pathology

ASJC Scopus subject areas

  • Endocrinology

Cite this

DuSell, C. D., Nelson, E. R., Wang, X., Abdo, J., Mödder, U. I., Umetani, M., ... McDonnell, D. P. (2010). The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis. Endocrinology, 151(8), 3675-3685. https://doi.org/10.1210/en.2010-0080

The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis. / DuSell, Carolyn D.; Nelson, Erik R.; Wang, Xiaojuan; Abdo, Jennifer; Mödder, Ulrike I.; Umetani, Michihisa; Gesty-Palmer, Diane; Javitt, Norman B.; Khosla, Sundeep; McDonnell, Donald P.

In: Endocrinology, Vol. 151, No. 8, 08.2010, p. 3675-3685.

Research output: Contribution to journalArticle

DuSell, CD, Nelson, ER, Wang, X, Abdo, J, Mödder, UI, Umetani, M, Gesty-Palmer, D, Javitt, NB, Khosla, S & McDonnell, DP 2010, 'The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis', Endocrinology, vol. 151, no. 8, pp. 3675-3685. https://doi.org/10.1210/en.2010-0080
DuSell, Carolyn D. ; Nelson, Erik R. ; Wang, Xiaojuan ; Abdo, Jennifer ; Mödder, Ulrike I. ; Umetani, Michihisa ; Gesty-Palmer, Diane ; Javitt, Norman B. ; Khosla, Sundeep ; McDonnell, Donald P. / The endogenous selective estrogen receptor modulator 27-hydroxycholesterol is a negative regulator of bone homeostasis. In: Endocrinology. 2010 ; Vol. 151, No. 8. pp. 3675-3685.
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