Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model.
Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model.
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DOI：
10.1038/boneres.2014.15
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发表时间：
2014
期刊：
影响因子：
12.7
通讯作者：
Qin, Ling
中科院分区：
文献类型：
--
作者：
Zhang, Xianrong;Zhu, Ji;Liu, Fei;Li, Yumei;Chandra, Abhishek;Levin, L. Scott;Beier, Frank;Enomoto-Iwamoto, Motomi;Qin, Ling
骨关节炎（OA）是一种退行性关节疾病，是老年人疼痛和残疾的主要原因。我们之前已经发现表皮生长因子受体（EGFR）信号是骨骺软骨发育过程中软骨基质降解的重要调节因子。为了研究其在OA进展中的功能，我们在两个EGFR活性降低的小鼠模型中进行了手术破坏内侧半月板（DMM）以诱导OA，一个是基因修饰（EgfrWa5/+小鼠），另一个是药物抑制（吉非替尼治疗）。术后3个月的组织学分析和评分显示，两种小鼠模型的软骨破坏增加，OA进展加快。TUNEL染色显示EGFR信号传导保护软骨细胞免受oa诱导的凋亡，这在原代软骨细胞培养中得到进一步证实。免疫组织化学显示，在这些小鼠模型中，聚集蛋白降解增加，这与DMM手术后关节软骨中ADAMTS5和基质金属蛋白酶13 （MMP13）的含量升高相一致，后者是负责聚集蛋白降解的主要蛋白酶。此外，缺氧诱导因子2α (HIF2α)，一个在OA期间刺激MMP13表达的关键分解代谢转录因子，也在EGFR信号减少的小鼠中上调。综上所述，我们的研究结果表明EGFR通过调节软骨细胞存活和软骨降解在OA进展过程中发挥了主要的保护作用。
Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (EgfrWa5/+ mice) and the other one with pharmacological inhibition (gefitinib treatment). Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α (HIF2α), a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.
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