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

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/beta-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/beta-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/beta-catenin pathway by decreasing the expression of genes associated with both anticatabolism, 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/beta-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/beta-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/beta-catenin signaling. (C) 2016 American Society for Bone and Mineral Research.