PLCγ1 inhibition-driven autophagy of IL-1β-treated chondrocyte confers cartilage protection against osteoarthritis, involving AMPK, Erk and Akt.
PLCγ1 inhibition-driven autophagy of IL-1β-treated chondrocyte confers cartilage protection against osteoarthritis, involving AMPK, Erk and Akt.
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磷脂酶Cγ1（PLCγ1）抑制驱动的白细胞介素 - 1β（IL - 1β）处理的软骨细胞自噬赋予软骨抵抗骨关节炎的保护作用，涉及腺苷酸活化蛋白激酶（AMPK）、细胞外调节蛋白激酶（Erk）和蛋白激酶B（Akt）。
DOI：
10.1111/jcmm.16245
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发表时间：
2021-03
影响因子：
5.3
通讯作者：
Xia C
中科院分区：
文献类型：
--
作者：
Chen X;Wang Y;Qu N;Zhang B;Xia C
先前的研究发现，磷脂酰脂酶C (PLC) γ - 1参与软骨细胞的某些事件。本研究旨在探讨plc γ - 1是否以及如何调节自噬在骨关节炎（OA）进展中发挥作用。用IL‐1β预处理大鼠正常或人OA软骨细胞，模拟或维持OA病理状态。通过Western blotting、免疫沉淀、qPCR、免疫荧光和二甲基亚甲基蓝检测、ELISA和透射电镜技术，我们发现plc γ γ1抑制剂U73122提高了Collagen II、Aggrecan和GAG水平，同时增加了LC3B‐II/I比值，降低了P62表达水平，而自噬抑制剂氯喹则部分减弱了其作用。同时，U73122将Beclin1从Beclin1‐IP3R‐Bcl‐2复合物中分离出来，阻断mTOR/ULK1轴，参与了plc - γ1、AMPK、Erk和Akt之间的串音。此外，通过血红素和伊红、红红素O/Fast绿和免疫组化染色，我们观察到关节内注射Ad - shlc - γ1‐1/2显著提高胶原和Aggrecan水平，并伴有LC3B升高和P62水平降低。因此，在体内和体外，plc γ - 1抑制驱动的自噬通过促进OA软骨细胞中ECM的合成，涉及plc γ - 1、AMPK、Erk和Akt之间的串扰，从而赋予软骨抗OA的保护作用。
Previous studies identified the involvement of phosphoinositide‐specific phospholipase C (PLC) γ1 in some events of chondrocytes. This study aims to investigate whether and how PLCγ1 modulates autophagy to execute its role in osteoarthritis (OA) progression. Rat normal or human OA chondrocytes were pretreated with IL‐1β for mimicking or sustaining OA pathological condition. Using Western blotting, immunoprecipitation, qPCR, immunofluorescence and Dimethylmethylene blue assays, and ELISA and transmission electron microscope techniques, we found that PLCγ1 inhibitor U73122 enhanced Collagen II, Aggrecan and GAG levels, accompanied with increased LC3B‐II/I ratio and decreased P62 expression level, whereas autophagy inhibitor Chloroquine partially diminished its effect. Meanwhile, U73122 dissociated Beclin1 from Beclin1‐IP3R‐Bcl‐2 complex and blocked mTOR/ULK1 axis, in which the crosstalk between PLCγ1, AMPK, Erk and Akt were involved. Additionally, by haematoxylin and eosin, Safranin O/Fast green, and immunohistochemistry staining, we observed that intra‐articular injection of Ad‐shPLCγ1‐1/2 significantly enhanced Collagen and Aggrecan levels, accompanied with increased LC3B and decreased P62 levels in a rat OA model induced by anterior cruciate ligament transection and medial meniscus resection. Consequently, PLCγ1 inhibition‐driven autophagy conferred cartilage protection against OA through promoting ECM synthesis in OA chondrocytes in vivo and in vitro, involving the crosstalk between PLCγ1, AMPK, Erk and Akt.
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影响因子：
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