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  3. Single cell RNA-seq analysis identifies ferroptotic chondrocyte cluster and reveals TRPV1 as an anti-ferroptotic target in osteoarthritis

Single cell RNA-seq analysis identifies ferroptotic chondrocyte cluster and reveals TRPV1 as an anti-ferroptotic target in osteoarthritis

  • EBioMedicine. 2022 Sep 19;84:104258. doi: 10.1016/j.ebiom.2022.104258.
Zhongyang Lv 1,  Jie Han 2,  Jiawei Li 1,  Hu Guo 1,  Yuxiang Fei 1,  Ziying Sun 1,  Jian Dong 1,  Maochun Wang 1,  Chunmei Fan 2,  Weitong Li 3,  Ya Xie 3,  Wei Sun 4,  Jiaqi Chen 1,  Yuan Liu 1,  Fufei Chen 1,  Zizheng Liu 1,  Anlong Liu 1,  Rui Wu 1,  Xingquan Xu 1,  Wenjin Yan 1,  Qing Jiang 1,  Shiro Ikegawa 5,  Xiao Chen 6,  Dongquan Shi 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, PR China.
  • 2 Dr. Li Dak Sum-Yip Yio Chin Center for Stem Cells and Regenerative Medicine and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, PR China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310000, PR China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou 310000, PR China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou 310000, PR China.
  • 3 Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, Jiangsu, PR China.
  • 4 Department of orthopedics, The Affiliated Jiangyin Hospital of Southeast University Medical College, Wuxi, Jiangsu 214400, PR China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, PR China; Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science (IMS, RIKEN), Tokyo 108-8639, Japan.
  • 6 Dr. Li Dak Sum-Yip Yio Chin Center for Stem Cells and Regenerative Medicine and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, PR China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310000, PR China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou 310000, PR China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou 310000, PR China. Electronic address: chenxiao-610@zju.edu.cn.
  • 7 State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, PR China. Electronic address: shidongquan@nju.edu.cn.
PMID: 36137413 DOI: 10.1016/j.ebiom.2022.104258
Abstract

Background: Osteoarthritis (OA) is the most common degenerative joint disease primarily characterized by cartilage destruction. The aim of this study was to investigate the role, molecular characteristics and potential therapeutic target of chondrocyte Ferroptosis in the pathogenesis of OA.

Methods: The expression of ferroptotic hallmarks (iron and lipid peroxidation accumulation, glutathione deletion) were analyzed in paired intact and damaged cartilages from OA patients. Single cell RNA Sequencing (scRNA-seq) analysis was performed on 17,638 chondrocytes to verify the presence, investigate the molecular signatures and unveil the potential therapeutic target of ferroptotic chondrocyte cluster in human OA cartilages. Destabilization of medial meniscus (DMM)-induced OA model and tert-butyl hydroperoxide (TBHP)-treated primary mouse chondrocytes and human cartilage explants were used to evaluate the protective effect of pharmacologically activated transient receptor potential vanilloid 1 (TRPV1). The downstream molecular mechanisms of TRPV1 was further investigated in Glutathione Peroxidase 4 (Gpx4) heterozygous genetic deletion mice (Gpx4+/-).

Findings: The concentrations of iron and lipid peroxidation and the expression of ferroptotic drivers in the damaged areas of human OA cartilages were significantly higher than those in the intact cartilage. scRNA-seq analysis revealed a chondrocyte cluster characterized by preferentially expressed ferroptotic hallmarks and genes, namely ferroptotic chondrocyte cluster. Comprehensive gene set variation analysis revealed TRPV1 as an anti-ferroptotic target in human OA cartilage. Pharmacological activation of TRPV1 significantly abrogated cartilage degeneration by protecting chondrocytes from Ferroptosis. Mechanistically, TRPV1 promoted the expression of GPX4, and its anti-ferroptotic role was largely mitigated in the OA model of Gpx4+/- mice.

Interpretation: TRPV1 activation protects chondrocytes from Ferroptosis and ameliorates OA progression by upregulating GPX4.

Funding: National Key R&D Program of China (2018YFC1105904), Key Program of NSFC (81730067), National Science Foundation of China (81772335, 81941009, 81802196), Natural Science Foundation of Jiangsu Province, China (BK20180127), Jiangsu Provincial Key Medical Talent Foundation, Six Talent Peaks Project of Jiangsu Province (WSW-079).

Keywords

Ferroptosis; GPX4; Osteoarthritis; Single cell RNA sequencing; TRPV1.

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