title: 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.
authors.affiliation: Department of Pharmacology, Duke University Medical Center, Pharmacology and Cancer Biology, Durham, North Carolina 27710, USA.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: DuSell
authors.forename: Erik R
authors.initials: ER
authors.lastname: Nelson
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Abdo
authors.forename: Ulrike I
authors.initials: UI
authors.lastname: Mödder
authors.forename: Michihisa
authors.initials: M
authors.lastname: Umetani
authors.forename: Diane
authors.initials: D
authors.lastname: Gesty-Palmer
authors.forename: Norman B
authors.initials: NB
authors.lastname: Javitt
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism; D000072474:Cytochrome P450 Family 7; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006706:Homeostasis / Q000187:drug effects* / Q000235:genetics; D006888:Hydroxycholesterols / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism / Q000494:pharmacology*; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism
chemical_list: D006888:Hydroxycholesterols; D020845:Selective Estrogen Receptor Modulators; D004958:Estradiol; C076996:27-hydroxycholesterol; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C097207:Cyp7b1 protein, mouse; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse