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Ann Rheum Dis. 2019 Jan;78(1):111-121. doi: 10.1136/annrheumdis-2018-213629. Epub 2018 Oct 4.

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

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Arthritis Program, University Health Network, Toronto, Ontario, Canada.
Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto , Ontario, Canada.
Division of Rheumatology, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada.
Department of Surgery, University of Toronto, Ontario, Canada.
McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
Institute of Health Policy, Management & Evaluation, Dalla Lana School of Public Health, University of Toronto, Ontario, Canada.
Arthritis Program, University Health Network, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.



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.


chondrocytes; microRNA; osteoarthritis; treatment

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Conflict of interest statement

Competing interests: A US provisional patent application (62/299,305, filed 24 February 2016) and a PCT international patent application (PCT/CA2017/000019, filed 31 January 2017) have been filed in respect of therapeutic and diagnostic uses of miRNA-181a-5p.

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