MicroRNA-34a-5p Promotes Joint Destruction During Osteoarthritis.
Adult
Aged
Animals
Cartilage, Articular
/ metabolism
Chondrocytes
/ drug effects
Diet, High-Fat
Disease Models, Animal
Female
Humans
Male
Menisci, Tibial
/ surgery
Mice
Mice, Knockout
MicroRNAs
/ metabolism
Middle Aged
Oligonucleotides, Antisense
/ pharmacology
Osteoarthritis
/ genetics
Osteoarthritis, Knee
/ genetics
Reverse Transcriptase Polymerase Chain Reaction
Synovial Membrane
/ metabolism
Synoviocytes
/ drug effects
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
20
09
2019
accepted:
29
09
2020
pubmed:
10
10
2020
medline:
23
3
2021
entrez:
9
10
2020
Statut:
ppublish
Résumé
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. 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. 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. Our findings provide comprehensive evidence of the role and therapeutic potential of miR-34a-5p in OA.
Identifiants
pubmed: 33034147
doi: 10.1002/art.41552
pmc: PMC7986901
doi:
Substances chimiques
MIRN34 microRNA, human
0
MIRN34a microRNA, mouse
0
MicroRNAs
0
Oligonucleotides, Antisense
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
426-439Subventions
Organisme : Canadian Institute of Health Research Operating grant
Informations de copyright
© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
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