The Endogenous Selective Estrogen Receptor Modulator 27-Hydroxycholesterol Is a Negative Regulator of Bone Homeostasis

摘要

Osteoporosis is an important clinical problem, affecting more than 50% of people over age 50 yr. Estrogen signaling is critical for maintaining proper bone density, andthe identification of an endogenous selective estrogen receptor (ER) modulator, 27-hydroxycholesterol (27HC), suggests a mechanism by which nutritional/metabolicstatus can influence bone biology. With its levels directly correlated with cholesterol, a new possibility emerges wherein 27HC links estrogen and cholesterol signalingtobonehomeostasis.Inthesestudies,wefoundthatincreasingconcentrationsof27HC,bothbygeneticandpharmacologicalmeans,ledtodecreasedbonemineraldensitythatwasassociatedwithdecreasedboneformationandincreasedboneresorption.Uponmanipulationofendogenousestrogenlevels,manyoftheresponsestoelevated27HC were altered in such a way as to implicate ER as a likely mediator. In a model of postmenopausal bone loss, some pathologies associated with elevated 27HC wereexacerbatedbytheabsenceofendogenousestrogens,suggestingthat27HCmayactbothinconcertwithandindependentlyfromclassicERsignaling.Thesedataprovideevidence for interactions between estrogen signaling, cholesterol and metabolic disease, and osteoporosis. Patients with high cholesterol likely also have higher thanaverage 27HC, perhaps putting them at a higher risk for bone loss and fracture. More studies are warranted to fully elucidate the mechanism of action of 27HC in boneand to identify ways to modulate this pathway therapeutically.