AUTHOR=Kong Ruina , Ji Lianmei , Pang Yafei , Zhao Dongbao , Gao Jie 

TITLE=Exosomes from osteoarthritic fibroblast-like synoviocytes promote cartilage ferroptosis and damage via delivering microRNA-19b-3p to target SLC7A11 in osteoarthritis

JOURNAL=Frontiers in Immunology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1181156

DOI=10.3389/fimmu.2023.1181156

ISSN=1664-3224

ABSTRACT=Objective: Our previous studies revealed that normal synovial exosomes promoted chondrogenesis, and microRNA (miR)-19b-3p independently related to osteoarthritis (OA) risk. Subsequently, this study intended to further explore the effect of OA fibroblast-like synoviocytes (OA-FLS) exosomal miR-19b-3p on OA ferroptosis and its potential mechanisms.
Methods: IL-1β-stimulated chondrocytes and medial meniscus surgery were used to construct OA cellular model and the OA rat model, respectively. OA-FLS exosomes with/without miR-19b-3p modification were added to IL-1β-stimulated chondrocytes and OA rat models, followed by direct miR-19b-3p mimics/inhibitors transfection with/without SLC7A11 overexpression plasmids. MiR-19b-3p, ferroptosis-related markers (MDA, GSH/GSSG, Fe2+, GPX4, SLC7A11, and ACSL4), mitochondrial membrane potential (MMP), and ROS levels were detected.
Results: An enhanced ferroptosis reflected by dysregulated ferroptosis-related markers, reduced MMP, and increased ROS were observed in cartilage tissues from OA patients versus controls, in IL-1β-stimulated chondrocytes versus normal ones, and OA rat models versus sham, so did miR-19b-3p. OA-FLS exosomes promoted MDA, Fe2+, ACSL4, and ROS but reduced cell viability, GSH/GSSG, GPX4, SLC7A11, and MMP in IL-1β-stimulated chondrocytes, whose effect was enhanced by miR-19b-3p mimics and attenuated by miR-19b-3p inhibitors. MiR-19b-3p negatively regulated SLC7A11 and directly bound to SLC7A11 via Luciferase-reporter-gene assay. Furthermore, SLC7A11 overexpression weakened miR-19b-3p mimics’ effect on ferroptosis-related markers, MMP, or ROS in IL-1β-stimulated chondrocytes. OA-FLS exosomes also induced cartilage damage and ferroptosis in OA rats, whose influence was tempered by miR-19b-3p inhibitors.
Conclusion: OA-FLS exosomal miR-19b-3p enhances cartilage ferroptosis and damage by sponging SLC7A11 in OA, indicating a potential linkage among synovium, cartilage, and ferroptosis during the OA process.