State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Affiliated Drum Tower Hospital, Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, Jiangsu, PR China.
Department of Orthopedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325200, Zhejiang, PR China.
Theranostics. 2023 Jun 12;13(10):3480-3496. doi: 10.7150/thno.85077. eCollection 2023.
Chondrocytes (CHs) in cartilage undergo several detrimental events during the development of osteoarthritis (OA). However, the mechanism underlying CHs regeneration involved in pathogenesis is largely unknown. The aim of this study was to explore the underlying mechanism of regeneration of CHs involved in the pathological condition and the potential therapeutic strategies of cartilage repair. CHs were isolated from human cartilage in different OA stages and the high-resolution cellular architecture of human osteoarthritis was examined by applying single-cell RNA sequencing. The analysis of gene differential expression and gene set enrichment was utilized to reveal the relationship of cartilage regeneration and microtubule stabilization. Microtubule destabilizer (nocodazole) and microtubule stabilizer (docetaxel) treated-human primary CHs and rats cartilage defect model were used to investing the effects and downstream signaling pathway of microtubule stabilization on cartilage regeneration. CHs subpopulations were identified on the basis of their gene markers and the data indicated an imbalance caused by an increase in the degeneration and disruption of CHs regeneration in OA samples. Interestingly, the CHs subpopulation namely CHI3L1 CHs, was characterized by the cell regenerative capacity, stem cell potency and the activated microtubule (MT) process. Furthermore, the data indicated that MT stabilization was effective in promoting cartilage regeneration in rats with cartilage injury model by inhibiting YAP activity. These findings lead to a new understanding of CHs regeneration in the OA pathophysiology context and suggest that MT stabilization is a promising therapeutic target for OA and cartilage injury.
软骨细胞（CHs）在骨关节炎（OA）的发展过程中经历了几种有害事件。然而，涉及发病机制的 CHs 再生的机制在很大程度上尚不清楚。本研究旨在探讨涉及病理状况的 CHs 再生的潜在机制和软骨修复的潜在治疗策略。从不同 OA 阶段的人软骨中分离 CHs，并通过单细胞 RNA 测序检查人骨关节炎的高分辨率细胞结构。利用基因差异表达和基因集富集分析来揭示软骨再生和微管稳定之间的关系。使用微管解稳定剂（诺考达唑）和微管稳定剂（多西紫杉醇）处理人原代 CHs 和大鼠软骨缺损模型，研究微管稳定对软骨再生的影响及其下游信号通路。基于基因标志物鉴定 CHs 亚群，数据表明 OA 样本中 CHs 再生的退化和破坏增加导致失衡。有趣的是，CHs 亚群，即 CHI3L1 CHs，其特征在于细胞再生能力、干细胞潜能和激活的微管（MT）过程。此外，数据表明，通过抑制 YAP 活性，MT 稳定在抑制软骨损伤模型大鼠的软骨再生方面是有效的。这些发现使我们对 OA 病理生理学背景下的 CHs 再生有了新的认识，并表明 MT 稳定是 OA 和软骨损伤的有前途的治疗靶点。
