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

Endocrinology. 2011 Dec;152(12):4691-705. doi: 10.1210/en.2011-1298. Epub 2011 Sep 20.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bone Resorption / chemically induced
  • Bone and Bones / metabolism*
  • Cell Differentiation / drug effects
  • Cholesterol / metabolism*
  • Homeostasis*
  • Hydroxycholesterols / pharmacology*
  • Liver X Receptors
  • Mice
  • Orphan Nuclear Receptors / drug effects*
  • Orphan Nuclear Receptors / metabolism
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Receptors, Estrogen / drug effects*
  • Receptors, Estrogen / metabolism
  • Receptors, Steroid
  • Sterols


  • Hydroxycholesterols
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Receptors, Estrogen
  • Receptors, Steroid
  • Sterols
  • oxysterol binding protein
  • 27-hydroxycholesterol
  • Cholesterol