Kuang Biao, Geng Nana, Yi Miao, Zeng Qiqi, Fan Mengtian, Xian Menglin, Deng Lin, Chen Cheng, Pan Yiming, Kuang Liang, Luo Fengtao, Xie Yangli, Liu Chao, Deng Zhongliang, Nie Mao, Du Yu, Guo Fengjin
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.
Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
J Adv Res. 2024 Oct 21. doi: 10.1016/j.jare.2024.10.016.
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.
This study aimed to ascertain the potential of panaxatriol, a natural small molecule, as a therapeutic drug for alleviating the progression of OA.
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.
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.
Panaxatriol exerts anti-senescence effects and has the potential to delay OA progression and reduce cartilage repair fibrosis by targeting UFL1.
骨关节炎（OA）是最常见的退行性关节疾病，最终可导致残疾。然而，目前尚无安全有效的干预措施。因此，迫切需要开发有效的药物来减少软骨损伤并治疗OA。
本研究旨在确定天然小分子人参三醇作为治疗药物缓解OA进展的潜力。
采用人软骨外植体和C28/I2人软骨细胞的体外培养以及手术诱导的OA小鼠体内模型来评估人参三醇的软骨保护作用。使用药物亲和响应靶点稳定性分析、CRISPR-Cas9分析、全转录组RNA测序分析以及激动剂或拮抗剂分析来鉴定人参三醇的靶点和潜在信号通路。聚乳酸-乙醇酸共聚物-聚乙二醇（PLGA-PEG）用于构建人参三醇的缓释系统。
人参三醇通过调节软骨细胞代谢来预防OA。泛素折叠修饰因子1特异性E3连接酶1（UFL1）被鉴定为人参三醇的新靶点。全转录组RNA测序表明UFL1与细胞衰老密切相关。人参三醇通过UFL1/叉头框O1（FOXO1）/P21和UFL1/核因子κB/衰老相关分泌表型（SASP）信号通路抑制软骨细胞衰老。它还可通过UFL1/FOXO1/胶原蛋白1信号通路抑制软骨修复过程中的纤维软骨形成。最后，我们基于PLGA-PEG构建了人参三醇的缓释系统，减少了关节内注射次数，从而减轻了关节肿胀和损伤。
人参三醇具有抗衰老作用，通过靶向UFL1有可能延缓OA进展并减少软骨修复纤维化。
