期刊
OSTEOARTHRITIS AND CARTILAGE
卷 29, 期 4, 页码 579-591出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.joca.2021.01.002
关键词
LRRK2; Mitochondria-dependent apoptosis; Mitophagy; Intervertebral disc degeneration
资金
- Zhejiang Public Service Technology Research Program/Social Development, China [LGF21H060011, LGF18H060008, LGF20H060013]
- Zhejiang Provincial Natural Science Foundation of China [LY17H060010, LY18H060012]
- National Natural Foundation of China, China [81871806, 81972094]
- Zhejiang Provincial Project for Medical and Health Science and Technology, China [2017KY463]
- Wenzhou Science and Technology Bureau Foundation, China [ZY2019014, Y2020059]
The study demonstrated the crucial role of LRRK2 in intervertebral disc degeneration (IDD) and revealed that its knockdown inhibits oxidative stress-induced apoptosis through promoting mitophagy, suggesting that inhibition of LRRK2 may be a promising therapeutic strategy for IDD.
Objective: To elucidate the role of LRRK2 in intervertebral disc degeneration (IDD) as well as its mitophagy regulation mechanism. Methods: The expression of LRRK2 in human degenerative nucleus pulposus tissues as well as in oxidative stress-induced rat nucleus pulposus cells (NPCs) was detected by western blot. LRRK2 was knocked down in NPCs by lentivirus (LV)-shLRRK2 transfection; apoptosis and mitophagy were assessed by western blot, TUNEL assay, immunofluorescence staining and mitophagy detection assay in LRRK2deficient NPCs under oxidative stress. After knockdown of Parkin in NPCs with siRNA transfection, apoptosis and mitophagy were further assessed. In puncture-induced rat IDD model, X-ray, MRI, hematoxylin-eosin (HE) and Safranin O-Fast green (SO) staining were performed to evaluate the therapeutic effects of LV-shLRRK2 on IDD. Results: We found that the expression of LRRK2 was increased in degenerative NPCs both in vivo and in vitro. LRRK2 deficiency significantly suppressed oxidative stress-induced mitochondria-dependent apoptosis in NPCs; meanwhile, mitophagy was promoted. However, these effects were abolished by the mitophagy inhibitor, suggesting the effect of LRRK2 on apoptosis in NPCs is mitophagy-dependent. Furthermore, Parkin knockdown study showed that LRRK2 deficiency activated mitophagy by recruiting Parkin. In vivo study demonstrated that LRRK2 inhibition ameliorated IDD in rats. Conclusions: The results revealed that LRRK2 is involved in the pathogenesis of IDD, while knockdown of LRRK2 inhibits oxidative stress-induced apoptosis through mitophagy. Thus, inhibition of LRRK2 may be a promising therapeutic strategy for IDD. (c) 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据