State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China.
Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
J Dent Res. 2023 Dec;102(13):1498-1506. doi: 10.1177/00220345231198448. Epub 2023 Oct 10.
Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease with the cessation of matrix anabolism and aggravation of inflammation, which results in severe pain and impaired joint function. However, the mechanisms are not well understood. Circular RNAs (circRNAs) are reported to have various biological functions and participate in the development, diagnosis, prognosis, and treatment of different diseases. This study aimed to investigate the roles and mechanisms of circ-slain2 in TMJOA. We first established TMJOA mouse models and found circ-slain2 was lowly expressed in the cartilage of TMJOA through sequencing data. We observed that circ-slain2 is predominantly localized in the cytoplasm and downregulated in mouse condylar chondrocytes (mCCs) treated with tumor necrosis factor α (TNFα) and interferon γ (IFNγ). Micro-computed tomography and histological examination showed that intra-articular injection of circ-slain2 overexpressing adeno-associated virus could alleviate cartilage catabolism and synovial inflammation to relieve TMJOA in vivo. In addition, elevated circ-slain2 also showed anticatabolic and anti-inflammatory effects on IFNγ- and TNFα-stimulated mouse condylar chondrocytes (mCCs). Functional enrichment analysis indicated that protein processing in endoplasmic reticulum (ER) was associated with TMJOA, and further functional experiments confirmed that circ-slain2 could suppress ER stress in OA mCCs. RNA binding protein immunoprecipitation assay revealed an overt interaction between activating transcription factor 6 (ATF6) and circ-slain2. Inhibition of the expression of both ATF6 and circ-slain2 resulted in dilation of the ER and enhanced the expression of ER stress markers, whose ER stress level was higher than inhibition of ATF6 but lower than knockdown of circ-slain2 expression. Collectively, our research demonstrated that circ-slain2 could regulate ATF6 to relieve ER stress, reducing temporomandibular joint cartilage degradation and synovial inflammation. These findings provide prospects for developing novel osteoarthritis therapies based on circ-slain2 by focusing on reducing the inflammation of synovium and the imbalance between matrix synthesis and degradation.
颞下颌关节骨关节炎（TMJOA）是一种退行性疾病，其特征是基质合成停止和炎症加重，导致严重疼痛和关节功能受损。然而，其机制尚不清楚。环状 RNA（circRNA）具有多种生物学功能，并参与不同疾病的发展、诊断、预后和治疗。本研究旨在探讨 circ-slain2 在 TMJOA 中的作用和机制。我们首先建立了 TMJOA 小鼠模型，并通过测序数据发现 TMJOA 软骨中 circ-slain2 表达水平降低。我们观察到 circ-slain2 主要定位于细胞质中，并在 TNFα 和 IFNγ 处理的鼠髁突软骨细胞（mCC）中下调。微计算机断层扫描和组织学检查显示，关节内注射过表达 circ-slain2 的腺相关病毒可以缓解软骨分解代谢和滑膜炎症，从而缓解体内 TMJOA。此外，提高 circ-slain2 对 IFNγ 和 TNFα 刺激的 mCC 也表现出抗分解代谢和抗炎作用。功能富集分析表明内质网（ER）中的蛋白加工与 TMJOA 相关，进一步的功能实验证实 circ-slain2 可以抑制 OA mCC 中的 ER 应激。RNA 结合蛋白免疫沉淀实验表明 ATF6 和 circ-slain2 之间存在明显的相互作用。抑制 ATF6 和 circ-slain2 的表达均导致 ER 扩张，并增强 ER 应激标志物的表达，其 ER 应激水平高于抑制 ATF6，但低于敲低 circ-slain2 表达。综上所述，我们的研究表明 circ-slain2 可以通过调节 ATF6 来缓解 ER 应激，减少颞下颌关节软骨降解和滑膜炎症。这些发现为开发基于 circ-slain2 的新型骨关节炎治疗方法提供了前景，其重点是减少滑膜炎症和基质合成与降解之间的失衡。
