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

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

ASJC Scopus subject areas

  • Endocrinology

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    Nelson, E. R., DuSell, C. D., Wang, X., Howe, M. K., Evans, G., Michalek, R. D., Umetani, M., Rathmell, J. C., Khosla, S., Gesty-Palmer, 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