Cartilage-specific β-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development.
Cartilage-specific β-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development.
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DOI：
10.1002/jbmr.1639
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发表时间：
2012-08
期刊：
影响因子：
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通讯作者：
O'Keefe RJ
中科院分区：
文献类型：
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作者：
Dao DY;Jonason JH;Zhang Y;Hsu W;Chen D;Hilton MJ;O'Keefe RJ
WNT/β-连环蛋白信号通路是软骨和骨发育多个阶段中软骨细胞和成骨细胞分化的关键调节因子。虽然先前已经使用在骨骼祖细胞和成骨细胞中操纵β-连环蛋白的各种遗传模型认识到β-连环蛋白信号传导在软骨内骨发育过程中的重要性，但证明β-连环蛋白在定向生长板软骨细胞中的特定作用的遗传证据不太可靠。为了鉴定软骨来源的β-连环蛋白在调节软骨和骨发育中的特定作用，我们分别使用他莫昔芬诱导的Col 2CreERT 2转基因与β-连环蛋白（外显子3）/wt或β-连环蛋白/fx floxed等位基因组合，研究了软骨细胞特异性功能获得和功能丧失遗传小鼠模型。从这些遗传模型和生化数据中，发现了三个重要的新发现。首先，软骨特异性β-连环蛋白信号传导促进软骨细胞成熟，可能涉及BMP 2介导的机制。第二，软骨特异性β-连环蛋白通过诱导软骨细胞肥大促进初级和次级骨化中心的形成，可能通过增强软骨降解部位的MMP表达，并可能通过增强IHH信号传导活性以募集血管组织。最后，软骨特异性β-连环蛋白信号传导可能通过BMP 2和IHH旁分泌信号协同作用加速软骨膜成骨细胞分化的机制促进软骨膜骨形成。本研究支持软骨源性β-CATENIN信号是软骨内骨形成过程中主要事件的中心介导因子，包括软骨细胞成熟、初级和次级骨化中心发育、血管化和软骨膜骨形成。
The WNT/β-CATENIN signaling pathway is a critical regulator of chondrocyte and osteoblast differentiation during multiple phases of cartilage and bone development. While the importance of β-CATENIN signaling during the process of endochondral bone development has been previously appreciated using a variety of genetic models that manipulate β-CATENIN in skeletal progenitors and osteoblasts, genetic evidence demonstrating a specific role for β-CATENIN in committed growth plate chondrocytes has been less robust. To identify the specific role of cartilage-derived β-CATENIN in regulating cartilage and bone development, we studied chondrocyte-specific gain- and loss-of-function genetic mouse models using the tamoxifen-inducible Col2CreERT2 transgene in combination with β-cateninfx(exon3)/wt or β-cateninfx/fx floxed alleles, respectively. From these genetic models and biochemical data, three significant and novel findings were uncovered. First, cartilage-specific β-CATENIN signaling promotes chondrocyte maturation, possibly involving a BMP2 mediated mechanism. Second, cartilage-specific β–CATENIN facilitates primary and secondary ossification center formation via the induction of chondrocyte hypertrophy, possibly through enhanced MMP expression at sites of cartilage degradation, and potentially by enhancing IHH signaling activity to recruit vascular tissues. Finally, cartilage-specific β-CATENIN signaling promotes perichondrial bone formation possibly via a mechanism in which BMP2 and IHH paracrine signals synergize to accelerate perichondrial osteoblastic differentiation. The work presented here supports the concept that the cartilage-derived β-CATENIN signal is a central mediator for major events during endochondral bone formation, including chondrocyte maturation, primary and secondary ossification center development, vascularization, and perichondrial bone formation.