title: The estrogen receptor-alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone.
abstract: Estrogens attenuate osteoclastogenesis and stimulate osteoclast apoptosis, but the molecular mechanism and contribution of these effects to the overall antiosteoporotic efficacy of estrogens remain controversial. We selectively deleted the estrogen receptor (ER)alpha from the monocyte/macrophage cell lineage in mice (ERalpha(LysM)(-/-)) and found a 2-fold increase in osteoclast progenitors in the marrow and the number of osteoclasts in cancellous bone, along with a decrease in cancellous bone mass. After loss of estrogens these mice failed to exhibit the expected increase in osteoclast progenitors, the number of osteoclasts in bone, and further loss of cancellous bone. However, they lost cortical bone indistinguishably from their littermate controls. Mature osteoclasts from ERalpha(LysM)(-/-) were resistant to the proapoptotic effect of 17beta-estradiol. Nonetheless, the effects of estrogens on osteoclasts were unhindered in mice bearing an ERalpha knock-in mutation that prevented binding to DNA. Moreover, a polymeric form of estrogen that is not capable of stimulating the nuclear-initiated actions of ERalpha was as effective as 17beta-estradiol in inducing osteoclast apoptosis in cells with the wild-type ERalpha. We conclude that estrogens attenuate osteoclast generation and life span via cell autonomous effects mediated by DNA-binding-independent actions of ERalpha. Elimination of these effects is sufficient for loss of bone in the cancellous compartment in which complete perforation of trabeculae by osteoclastic resorption precludes subsequent refilling of the cavities by the bone-forming osteoblasts. However, additional effects of estrogens on osteoblasts, osteocytes, and perhaps other cell types are required for their protective effects on the cortical compartment, which constitutes 80% of the skeleton.
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205-7199, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Martin-Millan
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
authors.forename: Elena
authors.initials: E
authors.lastname: Ambrogini
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhao
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weinstein
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jilka
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015519:Bone Density; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D001862:Bone Resorption; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002678:Chimera; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D055879:Gene Knock-In Techniques; D018390:Gene Targeting; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009928:Organ Specificity; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010024:Osteoporosis / Q000517:prevention & control; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D012333:RNA, Messenger; D004958:Estradiol