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

Robert S. Weinstein, Chao Wan, Qinglan Liu, Ying Wang, Maria Almeida, Charles A. O'Brien, Jeff Thostenson, Paula K. Roberson, Adele L. Boskey, Thomas L. Clemens, Stavros C. Manolagas

Research output: Contribution to journalArticle

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 11β-hydroxysteroid dehydrogenase (11β-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 11β-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-1α 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.

Original languageEnglish (US)
Pages (from-to)147-161
Number of pages15
JournalAging Cell
Volume9
Issue number2
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

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Keywords

  • 11β-hydroxysteroid dehydrogenase
  • Aging
  • Angiogenesis
  • Apoptosis
  • Bone histomorphometry
  • Glucocorticoids
  • Hydraulic support
  • Osteoporosis

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Weinstein, R. S., Wan, C., Liu, Q., Wang, Y., Almeida, M., O'Brien, C. A., Thostenson, J., Roberson, P. K., Boskey, A. L., Clemens, T. L., & Manolagas, S. C. (2010). Endogenous glucocorticoids decrease skeletal angiogenesis, vascularity, hydration, and strength in aged mice. Aging Cell, 9(2), 147-161. https://doi.org/10.1111/j.1474-9726.2009.00545.x