Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

J Bone Miner Res. 2016 Oct;31(10):1791-1802. doi: 10.1002/jbmr.2869. Epub 2016 Jun 5.


Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/β-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/β-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost-/- mice. The high bone mass exhibited by Sost-/- mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost-/- mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/β-catenin pathway by decreasing the expression of genes associated with both anti-catabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost-/- mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/β-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/β-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/β-catenin signaling. © 2016 American Society for Bone and Mineral Research.


MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Female
  • Glucocorticoids / adverse effects*
  • Glucocorticoids / pharmacology
  • Glycoproteins / deficiency*
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Osteoporosis / chemically induced
  • Osteoporosis / genetics
  • Osteoporosis / metabolism*
  • Osteoporosis / pathology
  • Osteoprotegerin / genetics
  • Osteoprotegerin / metabolism
  • Wnt Signaling Pathway / drug effects*
  • Wnt Signaling Pathway / genetics*


  • Adaptor Proteins, Signal Transducing
  • Ccnd1 protein, mouse
  • Glucocorticoids
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Osteoprotegerin
  • Sost protein, mouse
  • Tnfrsf11b protein, mouse
  • Cyclin D1