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  2. Panaxatriol exerts anti-senescence effects and alleviates osteoarthritis and cartilage repair fibrosis by targeting UFL1

Panaxatriol exerts anti-senescence effects and alleviates osteoarthritis and cartilage repair fibrosis by targeting UFL1

  • J Adv Res. 2024 Oct 21:S2090-1232(24)00470-3. doi: 10.1016/j.jare.2024.10.016.
Biao Kuang 1 Nana Geng 1 Miao Yi 1 Qiqi Zeng 1 Mengtian Fan 1 Menglin Xian 1 Lin Deng 1 Cheng Chen 2 Yiming Pan 1 Liang Kuang 3 Fengtao Luo 3 Yangli Xie 3 Chao Liu 4 Zhongliang Deng 5 Mao Nie 6 Yu Du 7 Fengjin Guo 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Ultrasound in Medicine and Engineering, School of Basic Medical Sciences, Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
  • 2 Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
  • 3 Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair (CBMR), State Key Laboratory of Trauma and Chemical Poisoning, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China.
  • 4 Department of Biomedical Engineering, College of Engineering, Guangdong Provincial Key Laboratory of Advanced Biomaterials, Southern University of Science and Technology, Shenzhen, China.
  • 5 Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
  • 6 Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China. Electronic address: 302218@cqmu.edu.cn.
  • 7 Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China. Electronic address: duyu@hospital.cqmu.edu.cn.
  • 8 State Key Laboratory of Ultrasound in Medicine and Engineering, School of Basic Medical Sciences, Department of Orthopedics, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China. Electronic address: guo.fengjin@cqmu.edu.cn.
Abstract

Introduction: Osteoarthritis (OA), the most common degenerative joint disease, can eventually lead to disability. However, no safe or effective intervention is currently available. Therefore, there is an urgent need to develop effective drugs that reduce cartilage damage and treat OA.

Objectives: This study aimed to ascertain the potential of panaxatriol, a natural small molecule, as a therapeutic drug for alleviating the progression of OA.

Methods: An in vitro culture of human cartilage explants and C28/I2 human chondrocytes and an in vivo surgically induced OA mouse model were used to evaluate the chondroprotective effect of panaxatriol. The Drug Affinity Responsive Target Stability assay, CRISPR-Cas9 assay, Whole-transcriptome RNA Sequencing analysis and agonist or antagonist assays were used to identify the target and potential signaling pathways of panaxatriol. Poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) was used to construct the sustained-release system of panaxatriol.

Results: Panaxatriol protected against OA by regulating chondrocyte metabolism. Ubiquitin-fold modifier 1-specific E3 Ligase 1 (UFL1) was identified as a novel target of panaxatriol. Whole transcriptome RNA Sequencing showed that UFL1 was closely related to cell senescence. Panaxatriol inhibited chondrocyte senescence through UFL1/forkhead box O1 (FOXO1)/P21 and UFL1/NF-κB/SASPs signaling pathways. It also could inhibit fibrocartilage formation during cartilage repair via the UFL1/FOXO1/Collagen 1 signaling pathway. Finally, we constructed a sustained-release system for panaxatriol based on PLGA-PEG, which reduced the number of intra-articular injections, thereby alleviating joint swelling and injury.

Conclusions: Panaxatriol exerts anti-senescence effects and has the potential to delay OA progression and reduce cartilage repair fibrosis by targeting UFL1.

Keywords

Cell senescence; Fibrosis; Osteoarthritis; PLGA; Panaxatriol; UFL1.

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