Chondroprotection of PPAR alpha activation by WY14643 via autophagy involving Akt and ERK in LPS-treated mouse chondrocytes and osteoarthritis model
Chondroprotection of PPAR alpha activation by WY14643 via autophagy involving Akt and ERK in LPS-treated mouse chondrocytes and osteoarthritis model
复制标题
在 LPS 处理的小鼠软骨细胞和骨关节炎模型中，WY14643 通过涉及 Akt 和 ERK 的自噬对 PPAR α 激活进行软骨保护
DOI：
10.1111/jcmm.14184
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发表时间：
2019
影响因子：
5.3
通讯作者：
Xia Chun
中科院分区：
文献类型：
--
作者：
Zhou Yang;Chen Xiaolei;Qu Ning;Zhang Bing;Xia Chun
自噬维持细胞内环境的稳定。增强软骨细胞的自噬功能可以阻止关节软骨中骨关节炎的进展。过氧化物酶体增殖物激活受体α(PPARα)的激活也可以保护关节软骨细胞免受OA软骨的降解。然而，激活的PPARα的保护作用是否与诱导软骨细胞自噬有关尚不确定。在这项研究中，我们用Western blotting方法研究了PPARα激动剂WY14643对自噬生物标志物LC3B和P62的蛋白表达水平以及自噬生物标志物LC3B和P62蛋白表达水平的影响。此外，在内毒素处理的软骨细胞中检测到Akt和ERK的磷酸化。此外，关节内注射WY14643对内侧半月板失稳建立的小鼠OA模型的关节软骨的影响使用国际骨关节炎研究学会(OARSI)组织病理学评估系统进行评估，并采用免疫组织化学方法检测Aggrecan、ADAMTS5、LC3B和p62蛋白水平。结果表明，WY14643激活PPARα可促进体内和体外培养的骨性关节炎软骨细胞蛋白多糖的合成，并伴随着蛋白多糖磷酸化水平的升高。因此，自噬可能有助于WY14643激活PPARα对软骨的保护作用，提示WY14643激活PPARα可能是治疗OA的一种潜在途径。
Autophagy maintains cellular homoeostasis. The enhancement of autophagy in chondrocytes could prevent osteoarthritis (OA) progression in articular cartilage. Peroxisome proliferator‐activated receptor α (PPARα) activation may also protect articular chondrocytes against cartilage degradation in OA. However, whether the protective effect of activated PPARα is associated with autophagy induction in chondrocytes is not determined. In this study, we investigated the effect of PPARα activation by its agonist, WY14643, on the protein expression level of Aggrecan and ADAMTS5, and the protein expression level of autophagy biomarkers, including LC3B and P62, using Western blotting analysis in isolated mouse chondrocytes pre‐treated with lipopolysaccharides (LPS, mimicking OA chondrocytes) with or without the autophagy inhibitor chloroquine diphosphate salt. Furthermore, Akt and ERK phosphorylation was detected in LPS‐treated chondrocytes in response to WY14643. In addition, the effect of intra‐articularly injected WY14643 on articular cartilage in a mouse OA model established by the destabilization of the medial meniscus was assessed using the Osteoarthritis Research Society International (OARSI) histopathology assessment system, along with the detection of Aggrecan, ADAMTS5, LC3B and P62 protein levels using immunohistochemistry assay. The results indicated that PPARα activation by WY14643 promoted proteoglycan synthesis by autophagy enhancement in OA chondrocytes in vivo and in vitro concomitant with the elevation of Akt and ERK phosphorylation. Therefore, autophagy could contribute to the chondroprotection of PPARα activation by WY14643, with the implication that PPARα activation by WY14643 may be a potential approach for OA therapy.