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.

中文翻译：

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Panaxatriol 通过靶向 UFL1 发挥抗衰老作用并缓解骨关节炎和软骨修复纤维化

 介绍

骨关节炎 （OA） 是最常见的退行性关节疾病，最终会导致残疾。然而，目前尚无安全有效的干预措施。因此，迫切需要开发减少软骨损伤和治疗 OA 的有效药物。

 目标

本研究旨在确定天然小分子 panaxatriol 作为缓解 OA 进展的治疗药物的潜力。

 方法

人软骨外植体和 C28/I2 人软骨细胞的体外培养和体内手术诱导的 OA 小鼠模型用于评价人三醇的软骨保护作用。采用药物亲和反应靶点稳定性测定、CRISPR-Cas9 测定、全转录组 RNA 测序分析和激动剂或拮抗剂测定来确定人三醇的靶点和潜在信号通路。聚乳酸-羟基乙酸共聚乙二醇 （PLGA-PEG） 用于构建人三醇缓释系统。

 结果

Panaxatriol 通过调节软骨细胞代谢来预防 OA。泛素折叠修饰物 1 特异性 E3 连接酶 1 （UFL1） 被确定为人三醇的新靶点。全转录组 RNA 测序显示，UFL1 与细胞衰老密切相关。Panaxatriol 通过 UFL1/forkhead box O1 （FOXO1）/P21 和 UFL1/NF-κB/SASPs 信号通路抑制软骨细胞衰老。它还可以通过 UFL1/FOXO1/Collagen 1 信号通路在软骨修复过程中抑制纤维软骨的形成。最后，我们构建了基于 PLGA-PEG 的人三醇缓释系统，减少了关节内注射的次数，从而减轻了关节肿胀和损伤。

 结论

Panaxatriol 发挥抗衰老作用，并有可能通过靶向 UFL1 来延缓 OA 进展和减少软骨修复纤维化。