Essential role of beta-catenin in postnatal bone acquisition.
Essential role of beta-catenin in postnatal bone acquisition.
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发表时间：
2005
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通讯作者：
S. Holmen;Cassandra R. Zylstra;A. Mukherjee;R. Sigler;M. Faugere;M. Bouxsein;L. Deng;T. Clemens
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作者：
S. Holmen;Cassandra R. Zylstra;A. Mukherjee;R. Sigler;M. Faugere;M. Bouxsein;L. Deng;T. Clemens
Wnt辅助受体LRP 5的突变改变了人类的骨量，但Wnt在骨骼中的作用机制尚不清楚。为了研究经典Wnt信号通路在成骨中的作用，我们产生了成骨细胞中缺乏β-连环蛋白或腺瘤性结肠息肉病（Apc）基因的小鼠。β-连环蛋白的缺失导致严重的骨质减少，破骨细胞显著增加，而条件性Apc突变体中β-连环蛋白的组成性激活导致骨沉积显著增加和破骨细胞消失。在体外，缺乏β-连环蛋白基因的成骨细胞表现出成熟和矿化受损，破骨细胞分化因子（由核因子-κ B配体（RANKL）激活的受体）表达升高，RANKL诱饵受体（骨保护素）表达减少。相比之下，APC缺陷型成骨细胞正常成熟，但RANKL表达减少，骨保护素表达增加。这些发现表明，成骨细胞中的Wnt/β-连环蛋白信号通过控制成骨细胞和破骨细胞的分化和活性来协调出生后的骨获取。
Mutations in the Wnt co-receptor LRP5 alter bone mass in humans, but the mechanisms responsible for Wnts actions in bone are unclear. To investigate the role of the classical Wnt signaling pathway in osteogenesis, we generated mice lacking the beta-catenin or adenomatous polyposis coli (Apc) genes in osteoblasts. Loss of beta-catenin produced severe osteopenia with striking increases in osteoclasts, whereas constitutive activation of beta-catenin in the conditional Apc mutants resulted in dramatically increased bone deposition and a disappearance of osteoclasts. In vitro, osteoblasts lacking the beta-catenin gene exhibited impaired maturation and mineralization with elevated expression of the osteoclast differentiation factor, receptor activated by nuclear factor-kappaB ligand (RANKL), and diminished expression of the RANKL decoy receptor, osteoprotegerin. By contrast, Apc-deficient osteoblasts matured normally but demonstrated decreased expression of RANKL and increased osteoprotegerin. These findings suggest that Wnt/beta-catenin signaling in osteoblasts coordinates postnatal bone acquisition by controlling the differentiation and activity of both osteoblasts and osteoclasts.