The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors

Erik R. Nelson, Carolyn D. DuSell, Xiaojuan Wang, Matthew K. Howe, Glenda Evans, Ryan D. Michalek, Michihisa Umetani, Jeffrey C. Rathmell, Sundeep Khosla, Diane Gesty-Palmer, Donald P. McDonnell

Research output: Contribution to journalArticle

58 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4691-4705
Number of pages15
JournalEndocrinology
Volume152
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Osteoporosis
Estrogens
Homeostasis
Osteoblasts
Cholesterol
Bone and Bones
Bone Density
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Osteogenesis
Estrogen Receptors
Life Style
Public Health
Pharmacology
Oxysterols
Liver X Receptors
27-hydroxycholesterol
Incidence
Pharmaceutical Preparations
Proteins
Therapeutics

ASJC Scopus subject areas

  • Endocrinology

Cite this

Nelson, E. R., DuSell, C. D., Wang, X., Howe, M. K., Evans, G., Michalek, R. D., ... McDonnell, D. P. (2011). The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors. Endocrinology, 152(12), 4691-4705. https://doi.org/10.1210/en.2011-1298

The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors. / Nelson, Erik R.; DuSell, Carolyn D.; Wang, Xiaojuan; Howe, Matthew K.; Evans, Glenda; Michalek, Ryan D.; Umetani, Michihisa; Rathmell, Jeffrey C.; Khosla, Sundeep; Gesty-Palmer, Diane; McDonnell, Donald P.

In: Endocrinology, Vol. 152, No. 12, 12.2011, p. 4691-4705.

Research output: Contribution to journalArticle

Nelson, ER, DuSell, CD, Wang, X, Howe, MK, Evans, G, Michalek, RD, Umetani, M, Rathmell, JC, Khosla, S, Gesty-Palmer, D & McDonnell, DP 2011, 'The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors', Endocrinology, vol. 152, no. 12, pp. 4691-4705. https://doi.org/10.1210/en.2011-1298
Nelson, Erik R. ; DuSell, Carolyn D. ; Wang, Xiaojuan ; Howe, Matthew K. ; Evans, Glenda ; Michalek, Ryan D. ; Umetani, Michihisa ; Rathmell, Jeffrey C. ; Khosla, Sundeep ; Gesty-Palmer, Diane ; McDonnell, Donald P. / The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors. In: Endocrinology. 2011 ; Vol. 152, No. 12. pp. 4691-4705.
@article{8fdce8f0feb549d5b1dced944f5cd85c,
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.",
author = "Nelson, {Erik R.} and DuSell, {Carolyn D.} and Xiaojuan Wang and Howe, {Matthew K.} and Glenda Evans and Michalek, {Ryan D.} and Michihisa Umetani and Rathmell, {Jeffrey C.} and Sundeep Khosla and Diane Gesty-Palmer and McDonnell, {Donald P.}",
year = "2011",
month = "12",
doi = "10.1210/en.2011-1298",
language = "English (US)",
volume = "152",
pages = "4691--4705",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "12",

}

TY - JOUR

T1 - The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver X receptors

AU - Nelson, Erik R.

AU - DuSell, Carolyn D.

AU - Wang, Xiaojuan

AU - Howe, Matthew K.

AU - Evans, Glenda

AU - Michalek, Ryan D.

AU - Umetani, Michihisa

AU - Rathmell, Jeffrey C.

AU - Khosla, Sundeep

AU - Gesty-Palmer, Diane

AU - McDonnell, Donald P.

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=82355163429&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=82355163429&partnerID=8YFLogxK

U2 - 10.1210/en.2011-1298

DO - 10.1210/en.2011-1298

M3 - Article

VL - 152

SP - 4691

EP - 4705

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 12

ER -