Inhibition of aberrant Hif1αactivation delays intervertebral disc degeneration in adult mice  

作　　者：Zuqiang Wang Hangang Chen Qiaoyan Tan Junlan Huang Siru Zhou Fengtao Luo Dali Zhang Jing Yang Can Li Bo Chen Xianding Sun Liang Kuang Wanling Jiang Zhenhong Ni Quan Wang Shuai Chen Xiaolan Du Di Chen Chuxia Deng Liangjun Yin Lin Chen Yangli Xie 

机构地区：[1]Center of Bone Metabolism and Repair,Department of Wound Repair and Rehabilitation Medicine,State Key Laboratory of Trauma,Burns and Combined Injury,Trauma Center,Research Institute of Surgery,Daping Hospital,Army Medical University,Chongqing,China [2]Senior Department of Orthopedics,the Fourth Medical Center of PLA General Hospital,Beijing,China [3]Department of Orthopedic Surgery,The Second Affiliated Hospital,Chongqing Medical University,Chongqing,China [4]Research Center for Human Tissues and Organs Degeneration,Shenzhen Institutes of Advanced Technology,Chinese Academy of Sciences,Shenzhen,China [5]Faculty of Health Sciences,University of Macao,Macao SAR,China

出　　处：《Bone Research》2022年第1期65-80,共16页骨研究（英文版）

基　　金：supported by grants from the National Key Research and Development Program of China (2018YFA0800802);the National Natural Science Foundation of China (81830075, 81772306, 81530071, and 81991513);the Chongqing Talent Plan (CQYC202001008 and CQYC202005088)

摘　　要：The intervertebral disc(IVD) is the largest avascular tissue. Hypoxia-inducible factors(HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease(DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate(EP) and annulus fibrosus(AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol(2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.

关 键 词：HIF1Α DEGENERATION ABERRANT 

分 类 号：R681.53[医药卫生—骨科学]