PTEN inhibitor VO-OHpic protects endplate chondrocytes against apoptosis and calcification via activating Nrf-2 signaling pathway.
PTEN inhibitor VO-OHpic protects endplate chondrocytes against apoptosis and calcification via activating Nrf-2 signaling pathway.
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DOI：
10.18632/aging.204612
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发表时间：
2023-03-24
期刊：
影响因子：
5.2
通讯作者：
Wang, Wenchao
中科院分区：
文献类型：
--
作者：
Cui, Xingang;Liu, Xiaoyang;Kong, Peng;Du, Ting;Li, Tao;Yang, Guihe;Zhang, Weimin;Jing, Xingzhi;Wang, Wenchao
软骨终板（CEP）的退变和钙化是椎间盘退变（IDD）发病的重要原因。然而，CEP变性的潜在机制仍然难以捉摸，更不用说根据治疗策略来预防CEP变性了。磷酸酶和张力蛋白同源物（Phosphatase and tensin homolog，PTEN）是一种促进细胞凋亡的抑癌基因，近年来的研究表明，在退变的椎间盘组织中，PTEN表达过强。然而，是否直接抑制PTEN减弱CEP变性和IDD的发展仍然在很大程度上未知。在本研究中，我们的体内实验表明，VO-OHpic可以减轻IDD进展和CEP钙化。VO-OHpic通过激活Nrf-2/HO-1通路抑制氧化应激诱导的软骨细胞凋亡和退变，从而促进parkin介导的线粒体自噬过程，抑制软骨细胞铁凋亡，减轻氧化还原失衡，最终改善细胞存活。Nrf-2 siRNA转染显著逆转VO-OHpic对终板软骨细胞的保护作用。总之，我们的研究表明，用VO-OHpic抑制PTEN可减弱CEP钙化和IDD进展。VO-OHpic通过激活Nrf-2/HO-1介导的线粒体自噬过程和抑制铁凋亡来保护终板软骨细胞免受凋亡和退变。提示VO-OHpic可能是一种潜在的有效的IDD防治药物。
Cartilage endplate (CEP) degeneration and calcification is an important contributor to the onset and pathogenesis of intervertebral disc degeneration (IDD). However, the underlying mechanisms of CEP degeneration remain elusive, let alone according treatment strategies to prevent CEP degeneration. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that promotes cell apoptosis, and recent studies indicated that PTEN is overexpressed in degenerated intervertebral disc. However, whether direct inhibition of PTEN attenuates CEP degeneration and IDD development remains largely unknown. In the present study, our in vivo experiments demonstrated that VO-OHpic could attenuate IDD progression and CEP calcification. We also found that VO-OHpic inhibited oxidative stress induced chondrocytes apoptosis and degeneration by activating Nrf-2/HO-1 pathway, thus promoted parkin mediated mitophagy process and inhibited chondrocytes ferroptosis, alleviated redox imbalance and eventually improved cell survival. Nrf-2 siRNA transfection significantly reversed the protective effect of VO-OHpic on endplate chondrocytes. In conclusion, our study demonstrated that inhibition of PTEN with VO-OHpic attenuates CEP calcification and IDD progression. Moreover, VO-OHpic protects endplate chondrocytes against apoptosis and degeneration via activating Nrf-2/HO-1 mediated mitophagy process and ferroptosis inhibition. Our results suggest that VO-OHpic may be a potential effective medicine for IDD prevention and treatment.
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影响因子：
3
作者：
Rade M;Määttä JH;Freidin MB;Airaksinen O;Karppinen J;Williams FMK
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DOI：
10.1007/s12154-010-0041-7
发表时间：
2010-10-01
期刊：
Journal of chemical biology
影响因子：
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作者：
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通讯作者：
Woscholski, Rudiger