Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin
Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin
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DOI：
10.1172/jci6800
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发表时间：
1999-11-01
影响因子：
15.9
通讯作者：
Bellido, T
中科院分区：
文献类型：
--
作者：
Plotkin, LI;Weinstein, RS;Bellido, T
糖皮质激素诱导的骨质疏松症可能部分是由于骨细胞和成骨细胞的凋亡增加，双膦酸盐（BP）在这种情况下的管理是有效的。我们已经验证了BP抑制这些细胞类型凋亡的假设。在10（-9）至10（-6）M浓度下，依替膦酸盐、阿仑膦酸盐、帕米膦酸盐、奥帕膦酸盐或氨基奥帕膦酸盐（IG 9402，一种缺乏抗吸收活性的双膦酸盐）可阻止小鼠骨细胞MLO-Y 4细胞凋亡，无论其是由依托泊苷、TNF-α还是合成糖皮质激素地塞米松诱导。BPs还抑制从颅骨分离的原代小鼠成骨细胞的凋亡。纳摩尔浓度的肽激素降钙素对MLO-Y 4和成骨细胞也有类似的抗凋亡作用。BPs和降钙素的抗凋亡作用与细胞外信号调节激酶（ERK）磷酸化部分的快速增加相关，并被ERK激活的特异性抑制剂阻断。与这些体外结果一致，阿仑膦酸钠消除了泼尼松龙给药后小鼠椎体松质骨细胞和成骨细胞凋亡发生率的增加。这些结果表明，BPs或降钙素在糖皮质激素诱导的骨质疏松症等疾病中的治疗效果可能部分归因于其预防骨细胞和成骨细胞凋亡的能力。
Glucocorticoid-induced osteoporosis may be due, in part, to increased apoptosis of osteocytes and osteoblasts, and bisphosphonates (BPs) are effective in the management of this condition. We have tested the hypothesis that BPs suppress apoptosis in these cell types. Etidronate, alendronate, pamidronate, olpadronate, or amino-olpadronate (IG9402, a bisphosphonate that lacks antiresorptive activity) at 10(-9) to 10(-6) M prevented apoptosis of murine osteocytic MLO-Y4 cells, whether it was induced by etoposide, TNF-alpha, or the synthetic glucocorticoid dexamethasone. BPs also inhibited apoptosis of primary murine osteoblastic cells isolated from calvaria. Similar antiapoptotic effects on MLO-Y4 and osteoblastic cells were seen with nanomolar concentrations of the peptide hormone calcitonin. The antiapoptotic effect of BPs and calcitonin was associated with a rapid increase in the phosphorylated fraction of extracellular signal regulated kinases (ERKs) and was blocked by specific inhibitors of ERK activation. Consistent with these in vitro results, alendronate abolished the increased prevalence of apoptosis in vertebral cancellous bone osteocytes and osteoblasts that follows prednisolone administration to mice. These results suggest that the therapeutic efficacy of BPs or calcitonin in diseases such as glucocorticoid-induced osteoporosis may be due, in part, to their ability to prevent osteocyte and osteoblast apoptosis.