title: Chronic Mild Stress Causes Bone Loss via an Osteoblast-Specific Glucocorticoid-Dependent Mechanism.
abstract: Chronic stress and depression are associated with alterations in the hypothalamic-pituitary-adrenal signaling cascade and considered a risk factor for bone loss and fractures. However, the mechanisms underlying the association between stress and poor bone health are unclear. Using a transgenic (tg) mouse model in which glucocorticoid signaling is selectively disrupted in mature osteoblasts and osteocytes [11β-hydroxysteroid-dehydrogenase type 2 (HSD2)OB-tg mice], the present study examines the impact of chronic stress on skeletal metabolism and structure. Eight-week-old male and female HSD2OB-tg mice and their wild-type (WT) littermates were exposed to chronic mild stress (CMS) for the duration of 4 weeks. At the endpoint, L3 vertebrae and tibiae were analyzed by micro-computed tomography and histomorphometry, and bone turnover was measured biochemically. Compared with nonstressed controls, exposure to CMS caused an approximately threefold increase in serum corticosterone concentrations in WT and HSD2OB-tg mice of both genders. Compared with controls, CMS resulted in loss of vertebral trabecular bone mass in male WT mice but not in male HSD2OB-tg littermates. Furthermore, both tibial cortical area and area fraction were reduced in stressed WT but not in stressed HSD2OB-tg male mice. Osteoclast activity and bone resorption marker were increased in WT males following CMS, features absent in HSD2OB-tg males. Interestingly, CMS had little effect on vertebral and long-bone structural parameters in female mice. We conclude that in male mice, bone loss during CMS is mediated via enhanced glucocorticoid signaling in osteoblasts (and osteocytes) and subsequent activation of osteoclasts. Female mice appear resistant to the skeletal effects of CMS.
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia.
authors.forename: Holger
authors.initials: H
authors.lastname: Henneicke
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia.|Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environmental Biophysics, School of Life Sciences, Northwestern Polytechnical University, Shaanxi 710000, China.
authors.forename: Jingbao
authors.initials: J
authors.lastname: Li
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kim
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia.
authors.forename: Sylvia J
authors.initials: SJ
authors.lastname: Gasparini
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia.|Department of Endocrinology and Metabolism, Concord Hospital, University of Sydney, Sydney, New South Wales 2139, Australia.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Seibel
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia.|Department of Endocrinology and Metabolism, Concord Hospital, University of Sydney, Sydney, New South Wales 2139, Australia.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics; D000818:Animals; D015519:Bone Density / Q000187:drug effects / Q000235:genetics; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology*; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013315:Stress, Psychological / Q000150:complications* / Q000473:pathology
chemical_list: D005938:Glucocorticoids; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2