Transient anabolic effects accompany epidermal growth factor receptor signal activation in articular cartilage in vivo.
Transient anabolic effects accompany epidermal growth factor receptor signal activation in articular cartilage in vivo.
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DOI：
10.1186/ar4233
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发表时间：
2013
影响因子：
4.9
通讯作者：
Dealy CN
中科院分区：
文献类型：
--
作者：
Shepard JB;Jeong JW;Maihle NJ;O'Brien S;Dealy CN
来自表皮生长因子受体（EGFR）的信号通常被认为在关节软骨中提供分解代谢活性，因此被认为在骨关节炎进展中具有因果作用。本研究的目的是确定关节软骨内源性 EGFR 信号激活的体内作用。使用 CreLoxP（Mig-6-flox；Prx1Cre）重组产生了有条件、肢体靶向删除内源性细胞内 EGFR 抑制剂 Mig-6 的转基因小鼠。使用组织学、组织化学染色和免疫组织化学来确认关节软骨和关节中 EGFR 信号传导的激活，并分析 Mig-6 缺失对关节软骨形态、增殖、祖细胞标记物表达、软骨细胞肥大和关节软骨基质降解的表型影响。 Mig-6 条件敲除 (Mig-6-cko) 小鼠的关节软骨在 6 周龄和 12 周龄时明显比正常关节软骨厚。 Mig-6-cko 关节软骨含有一群 EGFR 信号被激活的软骨细胞，其增殖能力是正常 Mig-6-flox 关节软骨细胞的三到四倍。这些细胞表达高水平的主要软骨形成调节因子 Sox9，以及高水平的假定祖细胞标记物，包括浅层区蛋白 (SZP)、生长和分化因子 5 (GDF-5) 和 Notch1。活化的 β-连环蛋白和转化生长因子 β (TGF-β) 介质磷酸化 Smad2/3 (pSmad2/3) 的表达水平也很高。关节软骨中 EGFR 激活的合成代谢效应之后是分解代谢事件，包括通过聚集蛋白聚糖裂解片段的积累确定的基质降解，以及通过类型 × 胶原表达确定的肥大的发生。到了 16 周龄时，Mig-6-cko 膝盖的关节软骨不再增厚并且开始退化。这些结果证明了关节软骨中 EGFR 信号激活的意想不到的合成代谢作用，并提出了这样的假设：这些作用可能促进关节软骨内内源 EGFR 应答细胞群的扩张和/或活性。
Signals from the epidermal growth factor receptor (EGFR) have typically been considered to provide catabolic activities in articular cartilage, and accordingly have been suggested to have a causal role in osteoarthritis progression. The aim of this study was to determine in vivo roles for endogenous EGFR signal activation in articular cartilage. Transgenic mice with conditional, limb-targeted deletion of the endogenous intracellular EGFR inhibitor Mig-6 were generated using CreLoxP (Mig-6-flox; Prx1Cre) recombination. Histology, histochemical staining and immunohistochemistry were used to confirm activation of EGFR signaling in the articular cartilage and joints, and to analyze phenotypic consequences of Mig-6 loss on articular cartilage morphology, proliferation, expression of progenitor cell markers, presence of chondrocyte hypertrophy and degradation of articular cartilage matrix. The articular cartilage of Mig-6-conditional knockout (Mig-6-cko) mice was dramatically and significantly thicker than normal articular cartilage at 6 and 12 weeks of age. Mig-6-cko articular cartilage contained a population of chondrocytes in which EGFR signaling was activated, and which were three to four times more proliferative than normal Mig-6-flox articular chondrocytes. These cells expressed high levels of the master chondrogenic regulatory factor Sox9, as well as high levels of putative progenitor cell markers including superficial zone protein (SZP), growth and differentiation factor-5 (GDF-5) and Notch1. Expression levels were also high for activated β-catenin and the transforming growth factor beta (TGF-β) mediators phospho-Smad2/3 (pSmad2/3). Anabolic effects of EGFR activation in articular cartilage were followed by catabolic events, including matrix degradation, as determined by accumulation of aggrecan cleavage fragments, and onset of hypertrophy as determined by type × collagen expression. By 16 weeks of age, the articular cartilage of Mig-6-cko knees was no longer thickened and was degenerating. These results demonstrate unexpected anabolic effects of EGFR signal activation in articular cartilage, and suggest the hypothesis that these effects may promote the expansion and/or activity of an endogenous EGFR-responsive cell population within the articular cartilage.
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