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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Nelson, ER; DuSell, CD; Wang, X; Howe, MK; Evans, G; Michalek, RD; Umetani, M; Rathmell, JC; Khosla, S; Gesty-Palmer, D; McDonnell, DP

Published Date

  • December 2011

Published In

Volume / Issue

  • 152 / 12

Start / End Page

  • 4691 - 4705

PubMed ID

  • 21933863

Pubmed Central ID

  • 21933863

Electronic International Standard Serial Number (EISSN)

  • 1945-7170

Digital Object Identifier (DOI)

  • 10.1210/en.2011-1298

Language

  • eng

Conference Location

  • United States