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Aging Cell. 2010 Apr;9(2):147-61. doi: 10.1111/j.1474-9726.2009.00545.x. Epub 2009 Dec 28.

Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice.

Author information

1
Center for Osteoporosis and Metabolic Bone Diseases, Department of Internal Medicine, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, USA. weinsteinroberts@uams.edu

Abstract

Aging or glucocorticoid excess decrease bone strength more than bone mass in humans and mice, but an explanation for this mismatch remains elusive. We report that aging in C57BL/6 mice was associated with an increase in adrenal production of glucocorticoids as well as bone expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1, the enzyme that activates glucocorticoids. Aging also decreased the volume of the bone vasculature and solute transport from the peripheral circulation to the lacunar-canalicular system. The same changes were reproduced by pharmacologic hyperglucocorticoidism. Furthermore, mice in which osteoblasts and osteocytes were shielded from glucocorticoids via cell-specific transgenic expression of 11beta-HSD type 2, the enzyme that inactivates glucocorticoids, were protected from the adverse effects of aging on osteoblast and osteocyte apoptosis, bone formation rate and microarchitecture, crystallinity, vasculature volume, interstitial fluid, and strength. In addition, glucocorticoids suppressed angiogenesis in fetal metatarsals and hypoxia inducible factor-1alpha transcription and vascular endothelial growth factor production in osteoblasts and osteocytes. These results, together with the evidence that dehydration of bone decreases strength, reveal that endogenous glucocorticoids increase skeletal fragility in old age as a result of cell autonomous effects on osteoblasts and osteocytes leading to interconnected decrements in bone angiogenesis, vasculature volume, and osteocyte-lacunar-canalicular fluid.

KEYWORDS:

11β-hydroxysteroid dehydrogenase; Aging; angiogenesis; apoptosis; bone histomorphometry; glucocorticoids; hydraulic support; osteoporosis

PMID:
20047574
PMCID:
PMC2858771
DOI:
10.1111/j.1474-9726.2009.00545.x
[Indexed for MEDLINE]
Free PMC Article

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