title: Effects of chronic estrogen treatment on modulating age-related bone loss in female mice.
abstract: While female mice do not have the equivalent of a menopause, they do undergo reproductive senescence. Thus, to dissociate the effects of aging versus estrogen deficiency on age-related bone loss, we sham-operated, ovariectomized, or ovariectomized and estrogen-replaced female C57/BL6 mice at 6 months of age and followed them to age 18 to 22 months. Lumbar spines and femurs were excised for analysis, and bone marrow hematopoietic lineage negative (lin-) cells (enriched for osteoprogenitor cells) were isolated for gene expression studies. Six-month-old intact control mice were euthanized to define baseline parameters. Compared with young mice, aged/sham-operated mice had a 42% reduction in lumbar spine bone volume/total volume (BV/TV), and maintaining constant estrogen levels over life in ovariectomized/estrogen-treated mice did not prevent age-related trabecular bone loss at this site. By contrast, lifelong estrogen treatment of ovariectomized mice completely prevented the age-related reduction in cortical volumetric bone mineral density (vBMD) and thickness at the tibial diaphysis present in the aged/sham-operated mice. As compared with cells from young mice, lin- cells from aged/sham-operated mice expressed significantly higher mRNA levels for osteoblast differentiation and proliferation marker genes. These data thus demonstrate that, in mice, age-related loss of cortical bone in the appendicular skeleton, but not loss of trabecular bone in the spine, can be prevented by maintaining constant estrogen levels over life. The observed increase in osteoblastic differentiation and proliferation marker gene expression in progenitor bone marrow cells from aged versus young mice may represent a compensatory mechanism in response to ongoing bone loss.
authors.affiliation: Endocrine Research Unit, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Farhan A
authors.initials: FA
authors.lastname: Syed
authors.forename: Ulrike Il
authors.initials: UI
authors.lastname: Mödder
authors.forename: Matthew
authors.initials: M
authors.lastname: Roforth
authors.forename: Ira
authors.initials: I
authors.lastname: Hensen
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Fraser
authors.forename: James M
authors.initials: JM
authors.lastname: Peterson
authors.forename: Merry Jo
authors.initials: MJ
authors.lastname: Oursler
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000188:drug therapy*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013131:Spine / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D014057:Tomography, X-Ray Computed
chemical_list: D004967:Estrogens; D012333:RNA, Messenger