Inhibition of aberrant Hif1α activation delays intervertebral disc degeneration in adult mice

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

doi:10.1038/s41413-021-00165-x

Bone Research (Jan 2022)

Inhibition of aberrant Hif1α activation delays intervertebral disc degeneration in adult mice

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

Affiliations

Zuqiang Wang: 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
Hangang Chen: 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
Qiaoyan Tan: 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
Junlan Huang: 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
Siru Zhou: 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
Fengtao Luo: 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
Dali Zhang: 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
Jing Yang: 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
Can Li: 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
Bo Chen: 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
Xianding Sun: 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
Liang Kuang: 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
Wanling Jiang: 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
Zhenhong Ni: 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
Quan Wang: 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
Shuai Chen: 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
Xiaolan Du: 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
Di Chen: Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
Chuxia Deng: Faculty of Health Sciences, University of Macau
Liangjun Yin: Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University
Lin Chen: 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
Yangli Xie: 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

DOI: https://doi.org/10.1038/s41413-021-00165-x
Journal volume & issue: Vol. 10, no. 1
pp. 1 – 16

Abstract

Read online

Abstract 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.

Published in Bone Research

ISSN: 2095-4700 (Print); 2095-6231 (Online)
Publisher: Nature Publishing Group
Country of publisher: United Kingdom
LCC subjects: Science: Biology (General); Science: Physiology
Website: http://www.nature.com/boneres/

About the journal