title: The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors.
abstract: Osteoporosis and age-related bone loss are important public health concerns. Therefore, there is a high level of interest in the development of medical interventions and lifestyle changes that reduce the incidence of osteoporosis and age-related bone loss. Decreased bone mineral density is associated with high cholesterol, and patients on statins have increased bone mineral densities, strongly implicating cholesterol as a negative regulator of bone homeostasis. In this study, using both molecular and pharmacological approaches, we have been able to demonstrate that the primary cholesterol metabolite, 27-hydroxycholesterol, through its actions on both estrogen receptors and liver X receptors, decreases osteoblast differentiation and enhances osteoclastogenesis, resulting in increased bone resorbtion in mice. Induction of the short heterodimer partner protein by estrogens in osteoblasts can attenuate the liver X receptor-mediated actions of 27-hydroxycholesterol in bone. These data establish a mechanistic link between cholesterol and bone quality, highlight an unexpected target of estrogens in osteoblasts, and define a signaling axis, the therapeutic exploitation of which is likely to yield novel antiosteoporotic drugs.
authors.affiliation: Pharmacology and Cancer Biology, Duke University Medical Center, P.O. Box 3813, Durham, North Carolina 27710, USA.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Nelson
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: DuSell
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wang
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Howe
authors.forename: Glenda
authors.initials: G
authors.lastname: Evans
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Michalek
authors.forename: Michihisa
authors.initials: M
authors.lastname: Umetani
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Rathmell
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
authors.forename: Diane
authors.initials: D
authors.lastname: Gesty-Palmer
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D006706:Homeostasis; D006888:Hydroxycholesterols / Q000494:pharmacology*; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000187:drug effects* / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D011987:Receptors, Steroid; D013261:Sterols; D000098825:Oxysterol Binding Proteins
chemical_list: D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011960:Receptors, Estrogen; D011987:Receptors, Steroid; D013261:Sterols; D000098825:Oxysterol Binding Proteins; C076996:27-hydroxycholesterol; D002784:Cholesterol