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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.

Author information

1
Arthritis Program, University Health Network, Toronto, Ontario, Canada.
2
Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto , Ontario, Canada.
3
Division of Rheumatology, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada.
4
Department of Surgery, University of Toronto, Ontario, Canada.
5
McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Alberta, Canada.
6
Institute of Health Policy, Management & Evaluation, Dalla Lana School of Public Health, University of Toronto, Ontario, Canada.
7
Arthritis Program, University Health Network, Toronto, Ontario, Canada mkapoor@uhnresearch.ca.
8
Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.

Abstract

OBJECTIVES:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

Our data demonstrate, for the first time, that LNA-miR-181a-5p ASO exhibit cartilage-protective effects in FJ and knee OA.

KEYWORDS:

chondrocytes; microRNA; osteoarthritis; treatment

Comment in

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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