Accentuated ovariectomy-induced bone loss and altered osteogenesis in heterozygous N-cadherin null mice
Accentuated ovariectomy-induced bone loss and altered osteogenesis in heterozygous N-cadherin null mice
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DOI：
10.1359/jbmr.060906
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发表时间：
2006-12-01
影响因子：
6.2
通讯作者：
Civitelli, Roberto
中科院分区：
文献类型：
--
作者：
Lai, Chung Fang;Cheng, Su-Li;Civitelli, Roberto
卵巢切除术诱导的骨丢失在具有生殖系Cdh 2单倍不足的小鼠中加重，这是在正常破骨细胞数量的情况下成骨细胞生成减少的结果。这些小鼠中N-钙粘蛋白丰度的降低降低了细胞间粘附并改变了成骨细胞定型和分化的重要信号通路，从而提供了体内证据表明N-钙粘蛋白介导的细胞间相互作用参与了对骨重塑增加的稳态反应。我们已经表明，靶向表达显性负性截短形式的N-钙粘蛋白（Cdh 2）延迟小鼠峰值骨量的获得和延迟成骨细胞分化。我们测试了这种分子在生殖系Cdh 2单倍不足小鼠卵巢切除后骨骼稳态反应中的作用。材料与方法：将杂合Cdh 2 null（Cdh 2（+/-））和野生型小鼠卵巢切除，并通过体内放射密度测定和离体组织学评估骨量和转换随访13周。从野生型和Cdh 2（+/-）小鼠分离的细胞被用来确定骨细胞功能的改变所产生的部分损失的N-钙粘蛋白。结果：骨质量之间没有显着差异Cdh 2（+/-）和野生型同窝仔，但卵巢切除术，在Cdh 2（+/-）小鼠的骨丢失最初较慢，但随着时间的推移，它变得显着大于野生型小鼠。这种加重的骨丢失与成骨细胞数量和血清骨钙素水平降低有关，骨吸收没有差异。虽然从Cdh 2（+/-）小鼠分离的颅盖骨细胞中钙化结节的发育相对于Cdh 2（+/+）细胞更快，但前者的骨髓成骨前体细胞低于后者基因型。Cdh 2表达下调与野生型颅骨细胞的分化，而钙粘蛋白-11丰度保持不变。此外，细胞-细胞粘附（汇合后）减少杂合子颅盖细胞，是细胞增殖（汇合前），相对于野生型细胞。最后，β-连环蛋白的丰度和细胞分布在Cdh 2（+/-）细胞中最低限度地降低，而丝裂原活化蛋白激酶（MAPK）信号转导在Cdh 2不足cells.Conclusions中更活跃：Cdh 2参与卵巢切除术后稳态骨形成反应，推测是通过稳定细胞-细胞粘附和/或信号转导调节骨祖细胞的数量和分化。
Ovariectomy-induced bone loss is accentuated in mice with germline Cdh2 haploinsufficiency, the result of a decreased osteoblastogenesis in the face of normal osteoclast number. Reduced N-cadherin abundance in these mice decreases cell-cell adhesion and alters signaling pathways important for osteoblast commitment and differentiation, thus providing in vivo evidence that N-cadherin-mediated cell-cell interactions are involved in homeostatic responses to increased bone remodeling.Introduction: We have shown that targeted expression of a dominant negative truncated form of N-cadherin (Cdh2) delays acquisition of peak bone mass in mice and retards osteoblast differentiation. We tested the role of this molecule in the skeletal homeostatic response to ovariectomy in mice with germline Cdh2 haploinsufficiency. Materials and Methods: Heterozygous Cdh2 null (Cdh2(+/-)) and wildtype mice were ovariectomized and followed up to 13 weeks by in vivo radiodensitometric and ex vivo histologic assessment of bone mass and turnover. Cells isolated from wildtype and Cdh2(+/-) mice were used to determine the alterations in bone cell function produced by partial loss of N-cadherin.Results: Bone mass was not significantly different between Cdh2(+/-) and wildtype littermates, but on ovariectomy, bone loss in Cdh2(+/-) mice was initially slower, but with time it became significantly greater than in wildtype mice. This accentuated bone loss was associated with lower osteoblast number and serum osteocalcin levels, with no differences in bone resorption. Although development of calcified nodules was faster in calvaria cells isolated from Cdh2(+/-) mice relative to Cdh2(+/+) cells, bone marrow osteogenic precursors were lower in the former than in the latter genotypes. Cdh2 expression was downregulated with differentiation in wildtype calvaria cells, whereas cadherin-11 abundance remained unchanged. Furthermore, cell-cell adhesion (postconfluence) was decreased among heterozygous calvaria cells, as was cell proliferation (preconfluence), relative to wildtype cells. Finally, the abundance and cellular distribution of beta-catenin was minimally decreased in Cdh2(+/-) cells, whereas mitogen-activated protein kinase (MAPK) signaling was more active in Cdh2 insufficient cells.Conclusions: Cdh2 is involved in the homeostatic bone formation response to ovariectomy, presumably by regulating osteoprogenitors number and differentiation through stabilization of cell-cell adhesion and/or signaling modulation.