下颌髁突软骨干细胞在颞下颌关节骨关节炎中的作用及其调控机制研究

In the treatment of temporal mandibular joint osteoarthritis (TMJOA), the most critical point is to prevent or retard the cartilage degradation and to activate its regeneration under osteoarthritis (OA) status. For the past few years, using various stem cells as the seed cell for cartilage rebuilt has always been a hot research field of OA treatment. In our latest NSFC grant supported project, we for the first time successfully extracted and identified chondrogenic progenitor cells (CPCs) from rat temporal mandibular joint condyle, which cells were characterized by typical progenitor cell features. However, the mechanism how CPCs function in TMJOA hasn’t been systemically investigated yet, indeed, further studies, like using CPCs as seed cells for cartilage tissue engineering, remains a relatively unworked area. In this project, our main goal is to observe transformation of CPCs during TMJOA process using lineage-tracing technique; meanwhile we will identify important target molecules both inside the cells and in the ECMs that regulate CPCs’ homeostasis; and we will clarify specific roles of these molecules for cartilage regeneration under OA status; finally we will try to verify the feasibility of CPCs as seed cells for stem cell therapy in TMJOA using different animal models. This project could help us better understand the mechanism TMJOA in the cell and molecular levels. Moreover, it might bring us a new stem cell treatment strategy for cartilage regeneration during OA in the near future.

如何阻止关节炎（OA）状态下的关节软骨破坏并启动后续软骨修复机制是突破目前TMJOA治疗瓶颈的关键。干细胞作为种子细胞被证明能有效促进OA状态下损伤软骨的修复。我们在上一轮基金资助中成功从下颌髁突软骨中提取了具有干细胞特性的软骨干细胞（CPCs）。然而，CPCs在TMJOA中维系软骨细胞和软骨环境稳定的作用机制仍不清楚。本项目研究内容主要包括通过标记颞下颌关节CPCs进行细胞谱系追踪（Lineage Tracing），研究其在TMJOA发生、发展过程中的细胞转归；明确TMJOA中细胞内外环境中调控CPCs性状改变的关键靶点；通过对关键靶点的干预，观察其对TMJOA发生、发展的影响； 建立TMJOA动物模型对外源性CPCs修复损伤软骨进行功能性验。本项目的开展将有助于进一步阐明TMJOA发生、发展的细胞学与分子学机制，同时将为OA状态下关节软骨的修复提供一种全新的种子细胞治疗策略。

本课题对髁突软骨干细胞（FCSCs）参与颞下颌关节骨关节炎(TMJOA)进程中的细胞分子机制进行探究，发现转录因子SOX9对干细胞成软骨特性的关键调控作用。在TMJOA状态下，观察炎症通路TNF-α/Nf-κB激活对FCSCs成软骨潜能的影响，从而探索经炎症靶向抑制促进干细胞功能参与TMJOA软骨修复的潜在治疗策略。开展PVA+PCL人工颞下颌关节盘对TMJOA大动物模型损伤关节盘的功能替代实验，发现PVA+PCL人工颞下颌关节盘能够改善TMJOA微环境，有助于维持FCSCs成软骨潜能，延缓TMJOA软骨破坏进程。通过对FCSCs深入研究，我们发现维持髁突表层FCSCs干细胞潜能对髁突软骨生长发育与稳态维持具有重要生理学意义。课题组以此为理论基础，指导颞下颌关节强直患者的临床治疗，建立充分保留髁突FCSCs干细胞潜能的关节强直外科治疗新体系。

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