Osteocyte apoptosis and control of bone resorption following ovariectomy in mice.
Osteocyte apoptosis and control of bone resorption following ovariectomy in mice.
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DOI：
10.1016/j.bone.2009.11.006
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发表时间：
2010-03
期刊：
影响因子：
4.1
通讯作者：
Schaffler, M. B.
中科院分区：
文献类型：
--
作者：
Emerton, K. B.;Hu, B.;Woo, A. A.;Sinofsky, A.;Hernandez, C.;Majeska, R. J.;Jepsen, K. J.;Schaffler, M. B.
引言骨细胞凋亡与雌激素耗竭和其他骨吸收刺激引起的骨吸收有关，然而，这两个事件之间精确的空间和时间关系尚未明确建立。本研究的目的是描述卵巢切除术后与骨吸收相关的骨细胞凋亡模式，以测试骨细胞凋亡是否优先发生在已知激活骨吸收的区域。此外，我们报告，骨细胞凋亡是必要的，启动皮质内重塑响应雌激素withdraw.MATERIALS和METHODSAdult女性C57 BL/6 J小鼠（17周龄）进行双侧卵巢切除术（OVX），或假手术（SHAM），并在第3天，第7天，第14天，或第21天OVX后安乐死。通过免疫组织化学染色骨干横截面的活化半胱天冬酶-3作为细胞凋亡的标志物。Caspase阳性染色骨细胞（Casp+Ot.）测量股骨干周围沿着长轴和短轴的骨吸收面积，以评估雌激素丢失后骨细胞凋亡的分布;测量相邻皮质内区域的骨吸收面积。在第二项研究中，测试骨细胞凋亡是否在骨吸收的起始中起调节作用，一组OVX小鼠接受泛半胱天冬酶抑制剂QVDOPh以抑制骨细胞凋亡。剩余的实验组和假手术组接受QVD或赋形剂。TSOVX增加了骨细胞凋亡，在整个股骨骨干中呈不均匀分布。Casp+骨细胞的增加主要位于后骨干皮质。在此，到OVX后第3天，凋亡骨细胞的数量比假手术对照组高4- 7倍（p<0.005），并保持升高。OVX后骨吸收的增加也发生在沿着骨细胞凋亡区域的后皮质内表面，但这些增加仅发生在OVX后14和21天（p<0.002），远远晚于骨细胞凋亡的增加。在OVX动物中用QVD处理抑制骨细胞凋亡，QVD处理的样品中的水平相当于基线。此外，增加骨细胞再吸收后，通常观察到雌激素的损失没有发生在OVX小鼠治疗QVD.CONCLUSIONSThe的结果，这项研究表明，骨细胞凋亡后雌激素的损失发生区域，而不是均匀的整个皮质。我们还发现雌激素的丢失增加了骨细胞的凋亡。凋亡骨细胞绝大多数位于后皮质区，在卵巢切除小鼠中，该位置随后激活了皮质内吸收。最后，通常在雌激素停药后观察到的骨细胞再吸收的增加在骨细胞凋亡的情况下没有发生，表明这种凋亡是雌激素损失后激活皮质内重塑所必需的。
INTRODUCTIONOsteocyte apoptosis has been linked to bone resorption resulting from estrogen depletion and other resorptive stimuli; however, precise spatial and temporal relationships between the two events have not been clearly established. The purpose of this study was to characterize the patterns of osteocyte apoptosis in relation to bone resorption following ovariectomy to test whether osteocyte apoptosis occurs preferentially in areas known to activate resorption. Moreover, we report that osteocyte apoptosis is necessary to initiate endocortical remodeling in response to estrogen withdrawal.MATERIALS AND METHODSAdult female C57BL/6J mice (17 weeks old) underwent either bilateral ovariectomy (OVX), or sham surgery (SHAM) and were euthanized on days 3, 7, 14, or 21 days after OVX. Diaphyseal cross-sections were stained by immunohistochemistry for activated caspase-3 as a marker of apoptosis. The percentages of caspase-positive stained osteocytes (Casp+Ot.) were measured along major and minor anatomical axes around the femoral diaphysis to evaluate the distribution of osteocyte apoptosis after estrogen loss; resorption surface was measured at the adjacent endocortical regions. In a second study to test whether osteocyte apoptosis plays a regulatory role in the initiation of bone resorption, a group of OVX mice received the pan-caspase inhibitor, QVDOPh, to inhibit osteocyte apoptosis. Remaining experimental and sham groups received either QVD or Vehicle.RESULTSOVX increased osteocyte apoptosis in a non-uniform distribution throughout the femoral diaphyses. Increases in Casp+osteocytes were predominately located in the posterior diaphyseal cortex. Here, the number of apoptotic osteocytes 4- to 7-fold higher than sham controls (p<0.005) by day 3 post-OVX and remained elevated. Increases in resorption post-OVX also occurred along the posterior endocortical surface overlying the region of osteocyte apoptosis, but these increases occurred only at 14 and 21 days post-OVX (p<0.002) well after the increases in osteocyte apoptosis. Treatment with QVD in OVX animals suppressed osteocyte apoptosis, with levels in QVD-treated samples equivalent to baseline. Moreover, the increases in osteoclastic resorption normally observed after estrogen loss did not occur in OVX mice treated with QVD.CONCLUSIONSThe results of this study demonstrate that osteocyte apoptosis following estrogen loss occur regionally, rather than uniformly throughout the cortex. We also showed that estrogen loss increased osteocyte apoptosis. Apoptotic osteocytes were overwhelmingly localized within the posterior cortical region, the location where endocortical resorption was subsequently activated in ovariectomized mice. Finally, the increases in osteoclastic resorption normally observed after estrogen withdrawal did not occur in the absence of osteocyte apoptosis indicating that this apoptosis is necessary to activate endocortical remodeling following estrogen loss.
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