Connexin 43 Is Required for the Anti-Apoptotic Effect of Bisphosphonates on Osteocytes and Osteoblasts In Vivo
Connexin 43 Is Required for the Anti-Apoptotic Effect of Bisphosphonates on Osteocytes and Osteoblasts In Vivo
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DOI：
10.1359/jbmr.080617
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发表时间：
2008-11-01
影响因子：
6.2
通讯作者：
Bellido, Teresita
中科院分区：
文献类型：
--
作者：
Plotkin, Lilian I.;Lezcano, Virginia;Bellido, Teresita
连接蛋白43是双膦酸盐体外抑制骨细胞和成骨细胞凋亡所必需的。本文所我们使用从骨细胞和成骨细胞中特异性缺失Cx43的小鼠（Cx43（Δ Ob-Ot/-）小鼠）评估了其对双膦酸盐体内作用的需求。Cx43的有效去除通过基因的缺失形式的存在以及通过从Cx43小鼠获得的成骨细胞和骨中的mRNA和蛋白质表达降低来证实。每天注射氨基二膦酸盐阿仑膦酸钠（2.3 μ mol/kg/d）给5月龄雌性小鼠（n = 6-11），持续31天。在植入释放糖皮质激素泼尼松龙（2.1mg/kg/d）的颗粒前3天开始。Cx46（Δ Ob-Ot/-）小鼠及其同窝出生的小鼠（Cx43（fl/-）、Cx43（Δ Ob-Ot/+）和Cx43（fl/+））以相似的动力学获得骨，并且从2至4.5月龄表现出相同的骨量，表明从骨细胞和成熟成骨细胞中缺失Cx43不会损害骨获取。此外，泼尼松龙在Cx43（Δ Ob-Ot/-）或对照Cx43（fl/-）同窝仔中诱导骨细胞和成骨细胞凋亡的类似增加。然而.阿仑膦酸钠在对照Cx43（fl/-）小鼠中阻止泼尼松龙诱导的细胞凋亡，而在Cx43（Delta Ob-Ot/-）小鼠中无效。相反。阿仑膦酸钠在两种类型的动物中均抑制糖皮质激素诱导的骨丢失，这表明抑制再吸收是阿仑膦酸钠对抗糖皮质激素诱导的骨丢失的早期阶段的主要作用。结合早期的体外实验证据。这些发现表明，Cx43是二膦酸盐对骨细胞和成骨细胞的抗凋亡作用所必需的。
Connexin (Cx)43 is required for inhibition of osteocyte and osteoblast apoptosis by bisphosphonates in vitro. Herein. we evaluated its requirement for the in vivo actions of bisphosphonates using mice in which Cx43 was deleted specifically from osteocytes and osteoblasts (Cx43(Delta Ob-Ot/-) mice). Effective removal of Cx43 was confirmed by the presence of the deleted form of the gene and by reduced mRNA and protein expression in osteoblastic cells and hones obtained from Cx43 mice. The amino-bisphosphonate alendronate (2.3) mu mol/kg/d) was Injected daily 5-mo-old female mice (n = 6-11) for 31 days. starting 3 days before implantation of pellets releasing the glucocorticoid prednisolone (2.1 mg/kg/d). Cx46(Delta Ob-Ot/-) mice and their littermates (Cx43(fl/-), Cx43(Delta Ob-Ot/+) and Cx43(fl/+)) gained bone with similar kinetics and exhibited identical bone mass from 2 to 4.5 mo of age, indicating that Cx43 deletion from osteocytes and mature osteoblasts does not Impair hone acquisition. In addition, prednisolone induced a similar increase in osteocyte and osteoblast apoptosis in Cx43(Delta Ob-Ot/-) or in control Cx43(fl/-) littermates. However. whereas alendronate prevented prednisolone-induced apoptosis in control Cx43(fl/-) mice, It was ineffective in Cx43(Delta Ob-Ot/-) mice. In contrast. alendronate inhibited glucocorticoid-induced bone loss in both type of animals, suggesting that inhibition of resorption is the predominant effect of alendronate against the early phase of glucocorticoid-induced induced bone loss. Taken together with earlier in vitro evidence. these findings show that Cx43 is required for the anti-apoptotic effect of bisphosphonates on osteocytes and osteoblasts.