Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength
Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength
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DOI：
10.1210/en.2003-0990
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发表时间：
2004-04-01
期刊：
影响因子：
4.8
通讯作者：
Weinstein, RS
中科院分区：
文献类型：
--
作者：
O'Brien, CA;Jia, D;Weinstein, RS
过量糖皮质激素对骨骼的负面影响是由于对骨细胞的直接影响，对骨骼外组织的间接影响，还是两者兼而有之尚不清楚。为了确定糖皮质激素在体内对成骨细胞/骨细胞的直接作用的贡献，我们通过11 β-羟基类固醇脱氢酶2型（一种使糖皮质激素失活的酶）的转基因表达来阻断糖皮质激素对这些细胞的作用。通过在成骨细胞特异性骨钙素启动子下游插入11 β-羟基类固醇脱氢酶2型cDNA实现成骨细胞/骨细胞特异性表达。成年转基因动物和野生型动物的骨密度、强度和组织形态计量学相同，证明转基因不影响正常的骨发育或骨转换。在野生型和转基因小鼠中，过量的糖皮质激素诱导了同等的骨丢失。正如预期的那样，松质骨破骨细胞不受转基因的影响。然而，在野生型小鼠中发生的成骨细胞凋亡的增加在转基因小鼠中被阻止。与此一致，糖皮质激素处理的转基因小鼠与糖皮质激素处理的野生型小鼠相比，成骨细胞，类骨质面积和骨形成率显着较高。在转基因小鼠中，糖皮质激素诱导的骨细胞凋亡也被阻止。引人注目的是，在糖皮质激素治疗的野生型小鼠中观察到的椎骨压缩强度的损失在转基因小鼠中得到了预防，尽管骨损失相当。这些结果首次证明过量的糖皮质激素直接影响体内骨形成细胞。此外，我们的研究结果表明，糖皮质激素诱导的骨强度损失的结果部分增加死亡的骨细胞，独立的骨丢失。
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.