Journal
ENDOCRINOLOGY
Volume 152, Issue 12, Pages 4691-4705Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/en.2011-1298
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Funding
- National Institutes of Health [R37DK048807, AG004875]
- National Institute of Diabetes and Digestive and Kidney Diseases [1P30DK079328]
- Arthritis Foundation
- Department of Defense [W81XWH-09-1-0613]
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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. (Endocrinology 152: 4691-4705, 2011)
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