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

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 11β-hydroxysteroid dehydrogenase type 2, an enzyme that inactivates glucocorticoids. Osteoblast/osteocyte-specific expression was achieved by insertion of the 11β-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 apo...