microRNA-181a-5p antisense oligonucleotides attenuate osteoarthritis in facet and knee joints

医学 骨关节炎 面(心理学) 小RNA 膝关节 生物信息学 寡核苷酸 外科 病理 基因 遗传学 生物 五大性格特征 社会心理学 人格 替代医学 心理学
作者
Akihiro Nakamura,Y. Raja Rampersaud,Sayaka Nakamura,Anirudh Sharma,Fanxing Zeng,Evgeny Rossomacha,Shabana Amanda Ali,Roman Krawetz,Nigil Haroon,Anthony V. Perruccio,Nizar N. Mahomed,Rajiv Gandhi,Jason S. Rockel,Mohit Kapoor
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:78 (1): 111-121 被引量:100
标识
DOI:10.1136/annrheumdis-2018-213629
摘要

We recently identified microRNA-181a-5p (miR-181a-5p) as a critical mediator involved in the destruction of lumbar facet joint (FJ) cartilage. In this study, we tested if locked nucleic acid (LNA) miR-181a-5p antisense oligonucleotides (ASO) could be used as a therapeutic to limit articular cartilage degeneration.We used a variety of experimental models consisting of both human samples and animal models of FJ and knee osteoarthritis (OA) to test the effects of LNA-miR-181a-5p ASO on articular cartilage degeneration. Histopathological analysis including immunohistochemistry and in situ hybridisation were used to detect key OA catabolic markers and microRNA, respectively. Apoptotic/cell death markers were evaluated by flow cytometry. qPCR and immunoblotting were applied to quantify gene and protein expression.miR-181a-5p expression was increased in human FJ OA and knee OA cartilage as well as injury-induced FJ OA (rat) and trauma-induced knee OA (mouse) cartilage compared with control cartilage, correlating with classical OA catabolic markers in human, rat and mouse cartilage. We demonstrated that LNA-miR-181a-5p ASO in rat and mouse chondrocytes reduced the expression of cartilage catabolic and chondrocyte apoptotic/cell death markers in vitro. Treatment of OA-induced rat FJ or mouse knee joints with intra-articular injections of in vivo grade LNA-miR-181a-5p ASO attenuated cartilage destruction, and the expression of catabolic, hypertrophic, apoptotic/cell death and type II collagen breakdown markers. Finally, treatment of LNA-miR-181a-5p ASO in cultures of human knee OA chondrocytes (in vitro) and cartilage explants (ex vivo) further demonstrated its cartilage protective effects.Our data demonstrate, for the first time, that LNA-miR-181a-5p ASO exhibit cartilage-protective effects in FJ and knee OA.
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