N-cadherin and cadherin 11 modulate postnatal bone growth and osteoblast differentiation by distinct mechanisms
N-cadherin and cadherin 11 modulate postnatal bone growth and osteoblast differentiation by distinct mechanisms
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DOI：
10.1242/jcs.067777
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发表时间：
2010-08-01
影响因子：
4
通讯作者：
Civitelli, Roberto
中科院分区：
文献类型：
--
作者：
Di Benedetto, Adriana;Watkins, Marcus;Civitelli, Roberto
我们之前的研究表明，n -钙粘蛋白（Cdh2）的显性阴性截断形式的靶向表达延迟了小鼠峰值骨量的获得并延缓了成骨细胞的分化；而另一种成骨细胞钙粘蛋白cadherin 11 （Cdh11）的缺失只会导致适度的骨质减少。为了确定这两种钙粘蛋白在成年骨骼中的具体作用，我们培养了成骨细胞/骨细胞特异性Cdh2消融（cKO）和双Cdh2（+/-）的小鼠；Cdh11（-/-）种系突变小鼠。年龄相关性骨质减少和较小的骨干伴骨强度下降是cKO骨的特征。相比之下，Cdh2(+/-)；与单一Cdh11缺失小鼠相比，Cdh11（-/-）小鼠表现出骨小梁骨量严重减少、体内成骨率下降、骨干缩小和骨强度受损。cKO和Cdh2患者骨髓未成熟前体细胞和骨祖细胞数量均减少（+/-）；Cdh11（-/-）小鼠，提示n -钙粘蛋白通过成骨细胞参与基质细胞前体池的维持。虽然Cdh11对出生后骨骼生长是必不可少的，但它更有利于成骨而不是脂肪生成。任何一种钙粘蛋白的缺失都会降低β -连环蛋白的丰度和β -连环蛋白依赖基因的表达，而n-钙粘蛋白的缺失比钙粘蛋白11的缺失更严重地破坏细胞-细胞粘附。因此，Cdh2和Cdh11是出生后骨骼生长和骨量维持的关键调节因子，在成骨谱系中具有重叠但不同的功能。
We have previously 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; whereas deletion of cadherin 11 (Cdh11), another osteoblast cadherin, leads to only modest osteopenia. To determine the specific roles of these two cadherins in the adult skeleton, we generated mice with an osteoblast/osteocyte specific Cdh2 ablation (cKO) and double Cdh2(+/-); Cdh11(-/-) germline mutant mice. Age-dependent osteopenia and smaller diaphyses with decreased bone strength characterize cKO bones. By contrast, Cdh2(+/-);Cdh11(-/-) exhibit severely reduced trabecular bone mass, decreased in vivo bone formation rate, smaller diaphyses and impaired bone strength relative to single Cdh11 null mice. The number of bone marrow immature precursors and osteoprogenitor cells is reduced in both cKO and Cdh2(+/-);Cdh11(-/-) mice, suggesting that N-cadherin is involved in maintenance of the stromal cell precursor pool via the osteoblast. Although Cdh11 is dispensable for postnatal skeletal growth, it favors osteogenesis over adipogenesis. Deletion of either cadherin reduces beta-catenin abundance and beta-catenin-dependent gene expression, whereas N-cadherin loss disrupts cell-cell adhesion more severely than loss of cadherin 11. Thus, Cdh2 and Cdh11 are crucial regulators of postnatal skeletal growth and bone mass maintenance, serving overlapping, yet distinct, functions in the osteogenic lineage.