Search

The commonest type of eukaryotic RNA modification, N6-methyladenosine (m6A), has drawn increased scrutiny in the context of pathological functioning as well as relevance in determination of RNA stability, splicing, transportation, localization, and translation efficiency. The m6A modification plays an important role in several types of arthritis, especially osteoarthritis and rheumatoid arthritis. Recent studies have reported that m6A modification regulates arthritis pathology in cells, such as chondrocytes and synoviocytes via immune responses and inflammatory responses through functional proteins classified as writers, erasers, and readers. The aim of this review was to highlight recent advances relevant to m6A modification in the context of arthritis pathogenesis and detail underlying molecular mechanisms, regulatory functions, clinical applications, and future perspectives of m6A in arthritis with the aim of providing a foundation for future research directions., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Obesity has always been considered a significant risk factor in osteoarthritis (OA) progression, but the underlying mechanism of obesity-related inflammation in OA synovitis remains unclear. The present study found that synovial macrophages infiltrated and polarized in the obesity microenvironment and identified the essential role of M1 macrophages in impaired macrophage efferocytosis using pathology analysis of obesity-associated OA. The present study revealed that obese OA patients and Apoe -/- mice showed a more pronounced synovitis and enhanced macrophage infiltration in synovial tissue, accompanied by dominant M1 macrophage polarization. Obese OA mice had a more severe cartilage destruction and increased levels of synovial apoptotic cells (ACs) than OA mice in the control group. Enhanced M1-polarized macrophages in obese synovium decreased growth arrest-specific 6 (GAS6) secretion, resulting in impaired macrophage efferocytosis in synovial ACs. Intracellular contents released by accumulated ACs further triggered an immune response and lead to a release of inflammatory factors, such as TNF-α, IL-1β, and IL-6, which induce chondrocyte homeostasis dysfunction in obese OA patients. Intra-articular injection of GAS6 restored the phagocytic capacity of macrophages, reduced the accumulation of local ACs, and decreased the levels of TUNEL and Caspase-3 positive cells, preserving cartilage thickness and preventing the progression of obesity-associated OA. Therefore, targeting macrophage-associated efferocytosis or intra-articular injection of GAS6 is a potential therapeutic strategy for obesity-associated OA., Competing Interests: ZY, WQ, HZ, ZZ, LL, YS, HZ, JY, HP, XG, AL, DC, XB, HZ No competing interests declared, (© 2023, Yao, Qi, Zhang et al.)