Roles of β-catenin signaling in phenotypic expression and proliferation of articular cartilage superficial zone cells.
Roles of β-catenin signaling in phenotypic expression and proliferation of articular cartilage superficial zone cells.
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DOI：
10.1038/labinvest.2011.144
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发表时间：
2011-12
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关节软骨表浅区（SFZ）具有独特的结构和生物力学特征，被认为能促进关节软骨的自我更新，对关节的长期功能有重要意义，但其调控机制尚不清楚。以往的研究表明，Wnt/β-catenin信号通路在SFZ中持续活跃，提示其可能是SFZ功能所必需的。因此，我们检查了Wnt/β-连环蛋白信号传导是否调节SFZ细胞的增殖和表型表达。使用转基因小鼠，我们发现Wnt/β-catenin信号的急性激活增加了SFZ厚度，蛋白聚糖4（Prg 4，也称为润滑素）表达和慢细胞周期细胞的数量，而β-catenin的条件性消融则导致相反的结果。我们开发了一种新的方法来分离SFZ细胞丰富的人口从新生小鼠的骺关节软骨，并发现SFZ细胞在文化中表现出成纤维细胞的细胞结构和更高的Prg 4和Ets相关基因（Erg）的表达和较低的聚集蛋白聚糖的表达相比，软骨细胞培养。基因阵列分析表明，SFZ细胞与底层关节软骨细胞相比具有不同的基因表达谱。Wnt 3a处理强烈刺激SFZ细胞增殖并维持Prg 4和Erg的强表达，而β-连环蛋白的消融强烈损害增殖和表型表达。当这些细胞被移植到无胸腺小鼠体内时，它们形成了表达Prg 4和聚集蛋白聚糖的软骨块，证明了它们的自主表型能力。β-连环蛋白的消融导致Prg 4基因表达的快速丧失和聚集蛋白聚糖和胶原10表达的强烈增加，后者是肥大软骨细胞的特征。总之，这些数据揭示了Wnt/β-连环蛋白信号传导是SFZ细胞表型和增殖的关键调节因子，并且可能对关节软骨长期功能同样重要。
The superficial zone (SFZ) of articular cartilage has unique structural and biomechanical features, is thought to promote self-renewal of articular cartilage and is thus important for joint long-term function, but the mechanisms regulating its properties remain unclear. Previous studies revealed that Wnt/β-catenin signaling is continuously active in SFZ indicating that it may be essential for SFZ function. Thus, we examined whether Wnt/β-catenin signaling regulates proliferation and phenotypic expression in SFZ cells. Using transgenic mice we found that acute activation of Wnt/β-catenin signaling increases SFZ thickness, Proteoglycan 4 (Prg4, also called lubricin) expression and the number of slow-cell cycle cells, while conditional ablation of β-catenin causes the opposite. We developed a novel method to isolate SFZ cell-rich populations from the epiphyseal articular cartilage of neonatal mice, and found that the SFZ cells in culture exhibit a fibroblastic cytoarchitecture and higher Prg4 and Ets-related gene (Erg) expression and lower aggrecan expression compared to chondrocyte cultures. Gene array analyses indicated that SFZ cells have distinct gene expression profiles compared to underlying articular chondrocytes. Treatment of Wnt3a strongly stimulated SFZ cell proliferation and maintained strong expression of Prg4 and Erg, while ablation of β-catenin strongly impaired proliferation and phenotypic expression. When the cells were transplanted into athymic mice, they formed Prg4- and aggrecan-expressing cartilaginous masses attesting to their autonomous phenotypic capacity. Ablation of β-catenin caused a rapid loss of Prg4 gene expression and strong increases in expression of aggrecan and collagen 10, the latter being a trait of hypertrophic chondrocytes. Together, the data reveal that Wnt/β-catenin signaling is a key regulator of SFZ cell phenotype and proliferation and may be as important for articular cartilage long-term function.
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