Antisense Oligonucleotide-Based Therapy on miR-181a-5p Alleviates Cartilage Degradation of Temporomandibular Joint Osteoarthritis via Promoting SIRT1.
Antisense Oligonucleotide-Based Therapy on miR-181a-5p Alleviates Cartilage Degradation of Temporomandibular Joint Osteoarthritis via Promoting SIRT1.
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DOI：
10.3389/fphar.2022.898334
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发表时间：
2022
影响因子：
5.6
通讯作者：
Fang, Jie
中科院分区：
文献类型：
--
作者：
Qi, Hexu;Zhao, Zhenxing;Xu, Lin;Zhang, Yue;Li, Yifei;Xiao, Li;Li, Yu;Zhao, Zhihe;Fang, Jie
颞下颌关节骨关节炎（TMJOA）是髁突软骨退行性变和异常的软骨下骨病理性改建引起的疼痛和关节功能障碍，软骨退行性变被认为是不可逆的。在实践中很少有治疗方法。核苷酸作为下一代药物已经显示出相当大的潜力，并且它们已经应用于几种骨关节炎模型。因此，需要建立有效的TMJOA基因治疗方案。在目前的研究中，单侧前牙反（UAC）手术被用来模拟机械应力诱导的TMJOA小鼠。在受损关节中观察到髁突软骨退化和软骨下骨破坏，并且软骨细胞中miR-181 a-5 p升高。关节腔内注射miR-181 a-5 p反义寡核苷酸（阿索）可减轻软骨损伤，缓解UAC诱导的TMJOA进展，但不能恢复受损的软骨下骨。在机制上，miR-181 a-5 p明显直接靶向Sirt 1的3'非翻译区，导致沉默信息调节因子1表达的抑制，并通过提高p53依赖性信号传导促进细胞凋亡，表明miR-181 a-5 p阿索促进软骨细胞存活。本研究表明，基于ASO的基因治疗可能是一种有效的TMJOA治疗。
Temporomandibular joint osteoarthritis (TMJOA) condylar cartilage degeneration and abnormal subchondral bone pathological remodeling induce pain and joint dysfunction, and cartilage degeneration is considered irreversible. Very few therapeutic approaches are administrated in practice. Nucleotides have demonstrated considerable potential as a next-generation medication, and they have been applied in several models of osteoarthritis. There is a need to establish an effective protocol for TMJOA gene therapy. In the current study unilateral anterior crossbite (UAC) surgery was used to simulate mechanical stress-induced TMJOA in mice. Degeneration of condylar cartilage and destruction of subchondral bone were observed in damaged joints, and miR-181a-5p was elevated in chondrocytes. Intra-articular injection of miR-181a-5p antisense oligonucleotide (ASO) could reduce the cartilage damage and alleviate UAC-induced TMJOA progression, but it did not restore injured subchondral bone. Mechanically, miR-181a-5p evidently targeted the 3’ untranslated region of Sirt1 directly, resulting in inhibition of silent information regulator 1 expression and promoting apoptosis by elevating p53-dependent signaling, indicating that miR181a-5p ASO promoted chondrocyte survival. The present study suggests that ASO-based gene therapy may be an effective TMJOA treatment.
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影响因子：
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作者：
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