2. Academic Validation
  3. Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx

Mechanical overloading induces GPX4-regulated chondrocyte ferroptosis in osteoarthritis via Piezo1 channel facilitated calcium influx

  • J Adv Res. 2022 Nov:41:63-75. doi: 10.1016/j.jare.2022.01.004.
Shaoyi Wang 1,  Weiwei Li 2,  Pengfei Zhang 3,  Zihao Wang 4,  Xiaoyuan Ma 5,  Chuanju Liu 6,  Krasimir Vasilev 7,  Lei Zhang 8,  Xiaocong Zhou 9,  Liang Liu 10,  John Hayball 11,  Shuli Dong 12,  Yuhua Li 5,  Yuan Gao 5,  Lei Cheng 13,  Yunpeng Zhao 14
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China; Qilu Hospital of Shandong University Spine and Spinal Cord Disease Research Center-ICMRS Collaborating Center for Orthopaedic translational Research, Shandong University, Jinan, Shandong 250012, PR China; Institute of Stomatology, Shandong University, Jinan, Shandong, 250012, PR China; NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
  • 2 Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
  • 3 Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China; Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
  • 4 Qilu Hospital of Shandong University Spine and Spinal Cord Disease Research Center-ICMRS Collaborating Center for Orthopaedic translational Research, Shandong University, Jinan, Shandong 250012, PR China; Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, PR China.
  • 5 Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
  • 6 Department of Orthopaedic Surgery, New York University School of Medicine, New York University Medical Center, New York City, NY, USA.
  • 7 Future Industries Institute, University of South Australia, Mawson Lakes Campus, Mawson Lakes 5095, Australia; School of Engineering, University of South Australia, Mawson Lakes Campus, Mawson Lakes 5095, Australia.
  • 8 Department of Orthopaedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250012, PR China.
  • 9 Health Management Centre. The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250012, PR China.
  • 10 Experimental Therapeutics Laboratory, University of South Australia Cancer Research Institute, Adelaide SA 5000, Australia.
  • 11 Experimental Therapeutics Laboratory, University of South Australia Cancer Research Institute, Adelaide SA 5000, Australia; Robinson Research Institute and Adelaide Medical School, University of Adelaide, Adelaide SA 5005, Australia.
  • 12 Key Laboratory of Colloid and Interface Chemistry (Shandong University), Ministry of Education, Jinan 250100, PR China.
  • 13 Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China; Qilu Hospital of Shandong University Spine and Spinal Cord Disease Research Center-ICMRS Collaborating Center for Orthopaedic translational Research, Shandong University, Jinan, Shandong 250012, PR China. Electronic address: [email protected].
  • 14 Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China. Electronic address: [email protected].
PMID: 36328754 DOI: 10.1016/j.jare.2022.01.004
Abstract

Introductions: Excessive mechanical stress is closely associated with cell death in various conditions. Exposure of chondrocytes to excessive mechanical loading leads to a catabolic response as well as exaggerated cell death. Ferroptosis is a recently identified form of cell death during cell aging and degeneration. However, it's potential association with mechanical stress remains to be illustrated.

Objectives: To identify whether excessive mechanical stress can cause Ferroptosis. To explore the role of mechanical overloading in chondrocyte Ferroptosis.

Methods: Chondrocytes were collected from loading and unloading zones of cartilage in patients with osteoarthritis (OA), and the Ferroptosis phenotype was analyzed through transmission electron microscope and microarray. Moreover, the relationship between Ferroptosis and OA was analyzed by GPX4-conditional knockout (Col2a1-CreERT: GPX4flox/flox) mice OA model and chondrocytes cultured with high strain mechanical stress. Furthermore, the role of Piezo1 ion channel in chondrocyte Ferroptosis and OA development was explored by using its inhibitor (GsMTx4) and agonist (Yoda1). Additionally, chondrocyte was cultured in calcium-free medium with mechanical stress, and Ferroptosis phenotype was tested.

Results: Human cartilage and mouse chondrocyte experiments revealed that mechanical overloading can induce GPX4-associated Ferroptosis. Conditional knockout of GPX4 in cartilage aggravated experimental OA process, while additional treatment with Ferroptosis suppressor protein (FSP-1) and coenzyme Q10 (CoQ10) abated OA development in GPX4-CKO mice. In mouse OA model and chondrocyte experiments, inhibition of Piezo1 channel activity increased GPX4 expression, attenuated Ferroptosis phenotype and reduced the severity of osteoarthritis. Additionally, high strain mechanical stress induced Ferroptosis damage in chondrocyte was largely abolished by blocking calcium influx through calcium-free medium.

Conclusions: Our findings show that mechanical overloading induces Ferroptosis through Piezo1 activation and subsequent calcium influx in chondrocytes, which might provide a potential target for OA treatment.

Keywords

Chondrocytes; Ferroptosis; Mechanical stress; Osteoarthritis; Piezo1.

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