Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids.
Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids.
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DOI：
10.1172/jci14538
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发表时间：
2002-04
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影响因子：
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通讯作者：
R. Weinstein;Jin-Ran Chen;Cara C. Powers;S. Stewart;Reid D. Landes;T. Bellido;R. Jilka;A. Parfitt;S. Manolagas
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文献类型：
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作者：
R. Weinstein;Jin-Ran Chen;Cara C. Powers;S. Stewart;Reid D. Landes;T. Bellido;R. Jilka;A. Parfitt;S. Manolagas
糖皮质激素通过抑制成骨细胞的生成和增加成骨细胞的凋亡来抑制骨形成。然而，骨吸收在糖皮质激素诱导的骨质疏松症的骨丢失特征的初始快速阶段中的作用尚不清楚，双膦酸盐在这种情况下有效的原因仍然未知。我们报告说，在小鼠破骨细胞培养，糖皮质激素延长破骨细胞的基线生存和拮抗双膦酸盐诱导的半胱天冬酶激活和凋亡的糖皮质激素受体介导的行动。与体外证据一致，在糖皮质激素诱导的骨质疏松症的小鼠模型中，松质骨破骨细胞的数量增加，即使破骨细胞祖细胞数量减少。此外，在接受糖皮质激素和双膦酸盐的小鼠中，双膦酸盐对破骨细胞的预期促凋亡作用被取消，如破骨细胞数量的维持和骨密度的损失所证明的。相比之下，二膦酸盐管理阻止糖皮质激素诱导的成骨细胞凋亡。这些结果表明，糖皮质激素过量引起的早期骨丢失是由于预先存在的破骨细胞寿命延长所致，这是双膦酸盐无法预防的一种作用。因此，这些药物的早期有益作用一定部分是由于延长了成骨细胞的寿命。
Glucocorticoids depress bone formation by inhibiting osteoblastogenesis and increasing osteoblast apoptosis. However, the role of bone resorption in the initial rapid phase of bone loss characteristic of glucocorticoid-induced osteoporosis is unexplained, and the reason for the efficacy of bisphosphonates in this condition remains unknown. We report that in murine osteoclast cultures, glucocorticoids prolonged the baseline survival of osteoclasts and antagonized bisphosphonate-induced caspase activation and apoptosis by a glucocorticoid receptor-mediated action. Consistent with the in vitro evidence, in a murine model of glucocorticoid-induced osteoporosis, the number of cancellous osteoclasts increased, even though osteoclast progenitor number was reduced. Moreover, in mice receiving both glucocorticoids and bisphosphonates, the expected proapoptotic effect of bisphosphonates on osteoclasts was abrogated, as evidenced by maintenance of osteoclast numbers and, additionally, loss of bone density. In contrast, bisphosphonate administration prevented glucocorticoid-induced osteoblast apoptosis. These results indicate that the early loss of bone with glucocorticoid excess is caused by extension of the life span of pre-existing osteoclasts, an effect not preventable by bisphosphonates. Therefore, the early beneficial effects of these agents must be due, in part, to prolonging the life span of osteoblasts.