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Updated: Aug 4, 2025
Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
Published on: March 18, 2022
FTO-mediated m6A demethylation of pri-miR-3591 alleviates osteoarthritis progression
Wengang Liu1, Tao Jiang1, Wei Zheng2
1Department of Orthopedics, Guangdong Provincial Second Hospital of Traditional Chinese Medicine, Guangzhou, 510095, China.
Objectives:
Increasing evidence have demonstrated the N6-methyladenosine (m6A) plays critical roles in osteoarthritis (OA) progression, but the role of m6A in OA has not been completely illuminated. Herein, we investigated the function and underlying mechanism of m6A demethylase fat mass and obesity-associated protein (FTO) in OA progression.
Materials And Methods:
The FTO expression was detected in mice OA cartilage tissues and lipopolysaccharide (LPS)-stimulated chondrocytes. Gain-of-function assays was used to evaluate the role of FTO in OA cartilage injury in vitro and in vivo. The miRNA-sequencing, RNA-binding protein immunoprecipitation (RIP), luciferase reporter assay, and in vitro pri-miRNA processing assays were conducted to confirm that FTO modulated the pri-miR-3591 process in an m6A-dependent manner and then the binding sites of miR-3591-5p with PRKAA2.
Results:
FTO was outstandingly downregulated in LPS-stimulated chondrocytes and OA cartilage tissues. FTO overexpression enhanced the proliferation, suppressed apoptosis, and decreased degradation of extracellular matrix in LPS-induced chondrocytes, whereas FTO knockdown contributed to the opposite effects. In vivo animal experiments showed that FTO overexpression markedly alleviated OA mice cartilage injury. Mechanically, FTO-mediated m6A demethylation of pri-miR-3591 leaded to a maturation block of miR-3591-5p, which relieved the inhibitory effect of miR-3591-5p on PRKAA2 and then promoted the increase of PRKAA2, thereby alleviating OA cartilage damage.
Conclusions:
Our results attested that FTO alleviated the OA cartilage damage by mediating FTO/miR-3591-5p/PRKAA2 axis, which provided fresh insights into the therapeutic strategies for OA.
Insights
Fat mass and obesity-associated protein (FTO) alleviates osteoarthritis (OA) cartilage damage by regulating the FTO/miR-3591-5p/PRKAA2 pathway. This finding offers new therapeutic strategies for OA progression.
Area of Science:
- Biochemistry
- Molecular Biology
- Orthopedics
Background:
- N6-methyladenosine (m6A) modification is increasingly recognized for its role in osteoarthritis (OA) pathogenesis.
- The specific functions and mechanisms of m6A regulators, such as the fat mass and obesity-associated protein (FTO), in OA remain incompletely understood.
Purpose of the Study:
- To investigate the role and underlying molecular mechanisms of FTO in the progression of osteoarthritis.
- To explore the potential of targeting the FTO pathway for OA therapeutic strategies.
Main Methods:
- Detection of FTO expression in OA cartilage and lipopolysaccharide (LPS)-stimulated chondrocytes.
- In vitro and in vivo gain-of-function assays to assess FTO's impact on OA cartilage injury.
- miRNA-sequencing, RIP, luciferase reporter assays, and pri-miRNA processing assays to elucidate the FTO/miR-3591-5p/PRKAA2 interaction.
Main Results:
- FTO expression was significantly downregulated in OA cartilage and LPS-stimulated chondrocytes.
- FTO overexpression promoted chondrocyte proliferation, inhibited apoptosis, and reduced extracellular matrix degradation, alleviating OA cartilage injury in vivo.
- Mechanistically, FTO demethylated pri-miR-3591, blocking miR-3591-5p maturation, thereby relieving its suppression of PRKAA2 and promoting PRKAA2 expression.
Conclusions:
- FTO plays a protective role in OA by mediating the FTO/miR-3591-5p/PRKAA2 axis.
- This pathway represents a novel therapeutic target for mitigating OA cartilage damage.
- The findings provide new insights into the molecular mechanisms underlying OA and potential treatment strategies.
