Title

Contribution of microRNA-27b-3p to synovial fibrotic responses in knee osteoarthritis

Document Type

Article

Publication Date

7-6-2022

Publication Title

Arthritis Rheumatol

Abstract

OBJECTIVES: Synovial fibrosis contributes to osteoarthritis (OA) pathology but the underlying mechanisms remain unknown. We have observed increased microRNA (miR)-27b-3p levels in synovial fluid of late-stage radiographic knee OA patients. Here, we determined the contribution of miR-27b-3p to synovial fibrosis.

METHODS: Synovium sections obtained from Kellgren-Lawrence-graded knee OA patients and a mouse model of knee OA (destabilization of medial meniscus; DMM) were stained for miR-27b-3p using in situ hybridization. Effects of intra-articular injections of miR-27b-3p mimic into naïve mouse knee joints, and miR-27b-3p inhibitor in the DMM model were also examined. MiR-27b-3p mimic or inhibitor transfection experiments were performed on human OA fibroblast-like synoviocytes (FLS) using RT-qPCR array, RNA sequencing, RT-qPCR, Western blotting, immunofluorescence and migration assays.

RESULTS: MiR-27b-3p expression increased in the synovium of knee OA patients and after DMM surgery in mice. Intra-articular injections of miR-27b-3p mimic injected in mouse knee joints induced a synovial fibrosis-like phenotype with increased synovitis scores and increased COL1A1 and α-SMA expression. In the DMM model, miR-27b-3p inhibitor decreased α-SMA with unchanged COL1A1 expression and synovitis scores. MiR-27b-3p mimic treatment of human OA FLS induced pro-fibrotic responses including increased migration and expression of key extracellular matrix (ECM) genes, while inhibitor transfection had opposite effects. RNA-sequencing identified a PPARG/ADAMTS8 signaling axis regulated by miR-27b-3p in OA FLS. MiR-27b-3p mimic-transfected OA FLS treated with the PPARG agonist rosiglitazone or ADAMTS8-siRNA exhibited altered expression of select ECM genes.

CONCLUSIONS: This study demonstrates a key role of miR-27b-3p in ECM regulation associated with synovial fibrosis during OA.

PubMed ID

35791923

ePublication

ePub ahead of print

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