| Osteoprotegerin prevents glucocorticoid-induced osteocyte apoptosis in mice. | |
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MedLine Citation:
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PMID: 21771887 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The adverse skeletal effects of glucocorticoid excess are due to increased osteoclast survival, decreased production of osteoblasts, and increased apoptosis of osteoblasts and osteocytes, but it remains unknown which of these is the principle cause of the decrease in bone strength. Previous studies suggested that osteocytes contribute to bone strength independently of changes in bone mass. Administration of the receptor activator for nuclear factor κB ligand (RANKL) antagonist osteoprotegerin (OPG) rapidly decreases osteoclasts followed by a decrease in osteoblasts but should not affect the long-lived osteocytes. Therefore, to distinguish between glucocorticoid effects on osteoclasts, osteoblasts, or osteocytes, we administered glucocorticoids, alone or in combination with OPG with the fragment crystallizable region of Ig heavy chains (OPG-Fc), to mice. The suppressive effect of glucocorticoids on spinal bone mineral density, cortical thickness, and strength was prevented by OPG-Fc. OPG-Fc, with or without glucocorticoids, profoundly reduced osteoclasts, osteoblasts, and bone formation. Unexpectedly, OPG-Fc prevented the glucocorticoid-induced increase in osteocyte apoptosis and reduction in solute transport from the systemic circulation to the osteocyte-lacunar-canalicular network. The fluid in the osteocyte-lacunar-canalicular network was inversely related to osteocyte apoptosis and directly related to bone mineral density. Consistent with the in vivo findings, Both OPG-Fc and OPG decreased glucocorticoid-induced apoptosis of MLO-Y4 osteocytic cells. OPG can also bind and antagonizes the activity of the TNF-related apoptosis-inducing ligand (TRAIL), but glucocorticoids did not change TRAIL expression, and knockdown of TRAIL did not prevent OPG-Fc from reducing glucocorticoid-induced osteocyte apoptosis. Based on these results, we conclude that at least part of the OPG-induced preservation of bone strength is due to the maintenance of osteocyte viability and the lacunar-canalicular network. |
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Authors:
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Robert S Weinstein; Charles A O'Brien; Maria Almeida; Haibo Zhao; Paula K Roberson; Robert L Jilka; Stavros C Manolagas |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2011-07-19 |
Journal Detail:
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Title: Endocrinology Volume: 152 ISSN: 1945-7170 ISO Abbreviation: Endocrinology Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-08-24 Completed Date: 2011-10-31 Revised Date: 2012-05-01 |
Medline Journal Info:
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Nlm Unique ID: 0375040 Medline TA: Endocrinology Country: United States |
Other Details:
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Languages: eng Pagination: 3323-31 Citation Subset: AIM; IM |
Affiliation:
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Division of Endocrinology and Metabolism, Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. weinsteinroberts@uams.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects* Bone Density / drug effects Cell Line Cells, Cultured Glucocorticoids / pharmacology* Mice Osteoclasts / drug effects, metabolism Osteocytes / drug effects*, metabolism Osteoprotegerin / metabolism, pharmacology* Prednisolone / pharmacology* TNF-Related Apoptosis-Inducing Ligand / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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P01-AG13918/AG/NIA NIH HHS; R01 AR049794/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Glucocorticoids; 0/Osteoprotegerin; 0/TNF-Related Apoptosis-Inducing Ligand; 50-24-8/Prednisolone |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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