NDR2 is critical for the osteoclastogenesis by regulating ULK1-mediated mitophagy.

IF 6.3 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

JCI insight Pub Date : 2024-11-19 DOI:10.1172/jci.insight.180409

Xiangxi Kong, Zhi Shan, Yihao Zhao, Siyue Tao, Jingyun Chen, Zhongyin Ji, Jiayan Jin, Junhui Liu, Wenlong Lin, Xiaojian Wang, Jian Wang, Fengdong Zhao, Bao Huang, Jian Chen

{"title":"NDR2 is critical for the osteoclastogenesis by regulating ULK1-mediated mitophagy.","authors":"Xiangxi Kong, Zhi Shan, Yihao Zhao, Siyue Tao, Jingyun Chen, Zhongyin Ji, Jiayan Jin, Junhui Liu, Wenlong Lin, Xiaojian Wang, Jian Wang, Fengdong Zhao, Bao Huang, Jian Chen","doi":"10.1172/jci.insight.180409","DOIUrl":null,"url":null,"abstract":"<p><p>Bone homeostasis primarily stems from the balance between osteoblasts and osteoclasts, wherein an augmented number or heightened activity of osteoclasts is a prevalent etiological factor in the development of bone loss. Nuclear Dbf2-related kinase (NDR2), also known as STK38L, is a member of the Hippo family with serine/threonine kinase activity. We unveiled an upregulation of NDR2 expression during osteoclast differentiation. Manipulation of NDR2 levels through knockdown or overexpression facilitated or hindered osteoclast differentiation respectively, indicating a negative feedback role for NDR2 in the osteoclastogenesis. Myeloid NDR2-dificient mice (Lysm+NDR2f/f) showed lower bone mass and further exacerbated ovariectomy-induced or aging-related bone loss. Mechanically, NDR2 enhanced autophagy and mitophagy through mediating ULK1 instability. In addition, ULK1 inhibitor (ULK1-IN2) ameliorated NDR2 cKO-induced bone loss. Finally, we clarified a significant inverse association between NDR2 expression and the occurrence of osteoporosis in patients. In a word, NDR2-ULK1-mitophagy axis was a potential innovative therapeutic target for the prevention and management of bone loss.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3000,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JCI insight","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1172/jci.insight.180409","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Bone homeostasis primarily stems from the balance between osteoblasts and osteoclasts, wherein an augmented number or heightened activity of osteoclasts is a prevalent etiological factor in the development of bone loss. Nuclear Dbf2-related kinase (NDR2), also known as STK38L, is a member of the Hippo family with serine/threonine kinase activity. We unveiled an upregulation of NDR2 expression during osteoclast differentiation. Manipulation of NDR2 levels through knockdown or overexpression facilitated or hindered osteoclast differentiation respectively, indicating a negative feedback role for NDR2 in the osteoclastogenesis. Myeloid NDR2-dificient mice (Lysm+NDR2f/f) showed lower bone mass and further exacerbated ovariectomy-induced or aging-related bone loss. Mechanically, NDR2 enhanced autophagy and mitophagy through mediating ULK1 instability. In addition, ULK1 inhibitor (ULK1-IN2) ameliorated NDR2 cKO-induced bone loss. Finally, we clarified a significant inverse association between NDR2 expression and the occurrence of osteoporosis in patients. In a word, NDR2-ULK1-mitophagy axis was a potential innovative therapeutic target for the prevention and management of bone loss.

查看原文本刊更多论文

NDR2 通过调节 ULK1 介导的有丝分裂，对破骨细胞的形成至关重要。

骨稳态主要源于成骨细胞和破骨细胞之间的平衡，破骨细胞数量增加或活性增强是导致骨质流失的主要病因。核Dbf2相关激酶（NDR2）又称STK38L，是具有丝氨酸/苏氨酸激酶活性的Hippo家族成员。我们发现在破骨细胞分化过程中，NDR2的表达会上调。通过敲除或过表达NDR2分别促进或阻碍破骨细胞分化，表明NDR2在破骨细胞生成过程中起负反馈作用。骨髓NDR2缺失小鼠（Lysm+NDR2f/f）的骨量较低，并进一步加剧了卵巢切除术诱导的或与衰老相关的骨质流失。从机制上讲，NDR2 通过介导 ULK1 的不稳定性增强了自噬和有丝分裂。此外，ULK1抑制剂（ULK1-IN2）可改善NDR2 cKO诱导的骨质流失。最后，我们明确了NDR2的表达与患者骨质疏松症的发生之间存在显著的反向关联。总之，NDR2-ULK1-肉食轴是预防和控制骨质流失的潜在创新治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

JCI insight Medicine-General Medicine

CiteScore

13.70

自引率

1.20%

发文量

543

审稿时长

6 weeks

期刊介绍： JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.