Stimulation of α7-nAChRs coordinates autophagy and apoptosis signaling in experimental knee osteoarthritis.
Stimulation of α7-nAChRs coordinates autophagy and apoptosis signaling in experimental knee osteoarthritis.
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DOI：
10.1038/s41419-021-03726-4
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发表时间：
2021-05-05
影响因子：
9
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Liu Y;Xu S;Zhang H;Qian K;Huang J;Gu X;Li Y;Fan Y;Hu J
骨关节炎（OA）是老年人最常见的慢性关节疾病。越来越多的证据表明，软骨细胞自噬和凋亡之间的平衡在OA软骨降解中起着关键作用。因此，靶向细胞凋亡和自噬平衡的药物是OA治疗的潜在治疗方法。在之前的研究中，我们发现α7烟碱乙酰胆碱受体（α7- nachrs）的激活可以缓解碘乙酸钠（MIA）诱导的关节退化和骨关节炎疼痛。为了探讨α7-nAChRs在膝关节骨性关节炎中自噬和凋亡信号传导中的潜在功能，我们比较了正常人和OA患者膝关节软骨组织中α7-nAChRs的表达。我们发现OA患者膝关节软骨组织α7- nachr降低，自噬与凋亡失衡。接下来，我们观察到α7-nAChRs缺乏并不影响OA发展过程中的软骨降解，但却逆转了尼古丁对机械性异常痛、软骨降解和mia诱导的自噬向凋亡转换的有益作用。与体内研究不同，我们发现α7-nAChRs敲除（KO）小鼠的原代软骨细胞在正常情况下LC3水平下降，对mia诱导的细胞凋亡更敏感。最后，我们发现α7-nAChRs的缺乏增加了MIA治疗后mTOR的磷酸化，这在OA患者的组织中也可以观察到。因此，我们的研究结果不仅证实了尼古丁通过刺激α7-nAChRs/mTOR信号通路减轻了nia诱导的疼痛行为和软骨降解，而且发现了α7-nAChRs在调节细胞凋亡和自噬之间的平衡中的潜在作用。
Osteoarthritis (OA) is the most common chronic joint disease in the elderly population. Growing evidence indicates that a balance between autophagy and apoptosis in chondrocytes plays a key role in OA’s cartilage degradation. Thus, drugs targeting the balance between apoptosis and autophagy are potential therapeutic approaches for OA treatment. In previous studies, we found that the activation of α7 nicotinic acetylcholine receptors (α7-nAChRs) alleviated monosodium iodoacetate (MIA)-induced joint degradation and osteoarthritis pain. To explore the potential functions of α7-nAChRs in autophagy and apoptosis signaling in knee OA, we compared the expression of α7-nAChRs in human knee articular cartilage tissues from normal humans and OA patients. We found that knee joint cartilage tissues of OA patients showed decreased α7-nAChRs and an imbalance between autophagy and apoptosis. Next, we observed that α7-nAChRs deficiency did not affect cartilage degradation in OA development but reversed the beneficial effects of nicotine on mechanical allodynia, cartilage degradation, and an MIA-induced switch from autophagy to apoptosis. Unlike in vivo studies, we found that primary chondrocytes from α7-nAChRs knockout (KO) mice showed decreased LC3 levels under normal conditions and were more sensitive toward MIA-induced apoptosis. Finally, we found that α7-nAChRs deficiency increased the phosphorylation of mTOR after MIA treatment, which can also be observed in OA patients’ tissues. Thus, our findings not only confirmed that nicotine alleviated MIA-induced pain behavior and cartilage degradation via stimulating the α7-nAChRs/mTOR signal pathway but found the potential role of α7-nAChRs in mediating the balance between apoptosis and autophagy.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1158/1541-7786.mcr-13-0541
发表时间：
2014-01
期刊：
Molecular cancer research : MCR
影响因子：
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通讯作者：
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