Glucocorticoids Act Directly on Osteoblasts and Osteocytes to Induce Their Apoptosis and Reduce Bone Formation and Strength

Abstract

Whether the negative impact of excess glucocorticoids on the skeleton is due to direct effects on bone cells, indirect effects on extraskeletal tissues, or both is unknown. To determine the contribution of direct effects of glucocorticoids on osteoblastic/osteocytic cells in vivo, we blocked glucocorticoid action on these cells via transgenic expression of 11beta-hydroxysteroid dehydrogenase type 2, an enzyme that inactivates glucocorticoids. Osteoblast/osteocyte-specific expression was achieved by insertion of the 11beta-hydroxysteroid dehydrogenase type 2 cDNA downstream from the osteoblast-specific osteocalcin promoter. The transgene did not affect normal bone development or turnover as demonstrated by identical bone density, strength, and histomorphometry in adult transgenic and wild-type animals. Administration of excess glucocorticoids induced equivalent bone loss in wild-type and transgenic mice. As expected, cancellous osteoclasts were unaffected by the transgene. However, the increase in osteoblast apoptosis that occurred in wild-type mice was prevented in transgenic mice. Consistent with this, osteoblasts, osteoid area, and bone formation rate were significantly higher in glucocorticoid-treated transgenic mice compared with glucocorticoid-treated wild-type mice. Glucocorticoid-induced osteocyte apoptosis was also prevented in transgenic mice. Strikingly, the loss of vertebral compression strength observed in glucocorticoid-treated wild-type mice was prevented in the transgenic mice, despite equivalent bone loss. These results demonstrate for the first time that excess glucocorticoids directly affect bone forming cells in vivo. Furthermore, our results suggest that glucocorticoid-induced loss of bone strength results in part from increased death of osteocytes, independent of bone loss.

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

“…3E), consistent with the relationship between decreased bone formation and promotion of osteoblast (and osteocyte) apoptosis by glucocorticoids. (18,20,32) Moreover, addition of the glucocorticoid dexamethasone to cultured primary calvarial osteoblasts decreased mineral deposition in cells isolated from WT or Sost -/-mice (Fig. 3F).…”

Advanced glycation end products stimulate osteoblast apoptosis via the MAP kinase and cytosolic apoptotic pathways

“…However, AGEs do not represent the only mechanism for diabetes-enhanced osteoblast apoptosis as inhibition of TNF in vivo also reduces apoptosis of periosteal cells and promotes new bone formation (31). These and other reports underscore the potential importance of osteoblast apoptosis as a mechanism for impaired bone formation in diabetic and aged individuals (5,34,35). A. CML-collagen (100 μg) or control unmodified collagen (100 μg) was injected into the scalp as described in Materials and Methods and mice were euthanized 24 hours later.…”

Fracture risk with intermittent high‐dose oral glucocorticoid therapy

“…However, the risk of fracture in patients receiving oral GCs is partially independent of decreased bone mass (1), and the increased fracture risk associated with GCs may occur 3 months after treatment is initiated (2). Increased apoptosis of osteoblasts and osteocytes and decreased osteocyte viability may lead to bone microdamage and, ultimately, bone fragility (16)(17)(18)(19). Damage to the microarchitecture of trabecular bone has been shown to be a risk factor for vertebral deformities (20).…”