微小 RNA-34a-5p 在骨关节炎中促进关节破坏。
MicroRNA-34a-5p Promotes Joint Destruction During Osteoarthritis.
机构信息
Krembil Research Institute, University Health Network, and, University of Toronto, Toronto, Ontario, Canada.
Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
出版信息
Arthritis Rheumatol. 2021 Mar;73(3):426-439. doi: 10.1002/art.41552. Epub 2021 Feb 8.
OBJECTIVE
MicroRNA-34a-5p (miR-34a-5p) expression is elevated in the synovial fluid of patients with late-stage knee osteoarthritis (OA); however, its exact role and therapeutic potential in OA remain to be fully elucidated. This study was undertaken to examine the role of miR-34a-5p in OA pathogenesis.
METHODS
Expression of miR-34a-5p was determined in joint tissues and human plasma (n = 71). Experiments using miR-34a-5p mimic or antisense oligonucleotide (ASO) treatment were performed in human OA chondrocytes, fibroblast-like synoviocytes (FLS) (n = 7-9), and mouse OA models, including destabilization of the medial meniscus (DMM; n = 22) and the accelerated, more severe model of mice fed a high-fat diet and subjected to DMM (n = 11). Wild-type (WT) mice (n = 9) and miR-34a-knockout (KO) mice (n = 11) were subjected to DMM. Results were expressed as the mean ± SEM and analyzed by t-test or analysis of variance, with appropriate post hoc tests. P values less than 0.05 were considered significant. RNA sequencing was performed on WT and KO mouse chondrocytes.
RESULTS
Expression of miR-34a-5p was significantly increased in the plasma, cartilage, and synovium of patients with late-stage OA and in the cartilage and synovium of mice subjected to DMM. Plasma miR-34a-5p expression was significantly increased in obese patients with late-stage OA, and in the plasma and knee joints of mice fed a high-fat diet. In human OA chondrocytes and FLS, miR-34a-5p mimic increased key OA pathology markers, while miR-34a-5p ASO improved cellular gene expression. Intraarticular miR-34a-5p mimic injection induced an OA-like phenotype. Conversely, miR-34a-5p ASO injection imparted cartilage-protective effects in the DMM and high-fat diet/DMM models. The miR-34a-KO mice exhibited protection against DMM-induced cartilage damage. RNA sequencing of WT and KO chondrocytes revealed a putative miR-34a-5p signaling network.
CONCLUSION
Our findings provide comprehensive evidence of the role and therapeutic potential of miR-34a-5p in OA.
目的
在晚期膝骨关节炎（OA）患者的滑液中，miR-34a-5p 的表达升高；然而，其在 OA 中的确切作用和治疗潜力仍有待充分阐明。本研究旨在探讨 miR-34a-5p 在 OA 发病机制中的作用。
方法
在关节组织和人血浆中（n=71）测定 miR-34a-5p 的表达。在人 OA 软骨细胞、成纤维样滑膜细胞（FLS）（n=7-9）以及包括内侧半月板不稳定（DMM；n=22）和高脂肪饮食喂养并接受 DMM 的加速、更严重的小鼠模型中进行 miR-34a-5p 模拟物或反义寡核苷酸（ASO）治疗实验。对野生型（WT）小鼠（n=9）和 miR-34a 敲除（KO）小鼠（n=11）进行 DMM。结果表示为均值±SEM，并通过 t 检验或方差分析进行分析，并进行适当的事后检验。P 值小于 0.05 被认为具有统计学意义。对 WT 和 KO 小鼠软骨细胞进行 RNA 测序。
结果
晚期 OA 患者的血浆、软骨和滑膜以及 DMM 小鼠的软骨和滑膜中 miR-34a-5p 的表达显著增加。肥胖晚期 OA 患者的血浆 miR-34a-5p 表达以及高脂肪饮食喂养的小鼠的血浆和膝关节中，miR-34a-5p 的表达均显著增加。在人 OA 软骨细胞和成纤维样滑膜细胞中，miR-34a-5p 模拟物增加了关键的 OA 病理标志物，而 miR-34a-5p ASO 改善了细胞基因表达。关节内 miR-34a-5p 模拟物注射诱导 OA 样表型。相反，miR-34a-5p ASO 注射在 DMM 和高脂肪饮食/DMM 模型中具有软骨保护作用。miR-34a-KO 小鼠对 DMM 诱导的软骨损伤具有保护作用。WT 和 KO 软骨细胞的 RNA 测序揭示了一个潜在的 miR-34a-5p 信号网络。
结论
我们的研究结果为 miR-34a-5p 在 OA 中的作用和治疗潜力提供了全面的证据。
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