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Updated: Aug 6, 2026
Software-Assisted Quantitative Measurement of Osteoarthritic Subchondral Bone Thickness
Published on: March 18, 2022
Downregulation of FTO aggravates osteoarthritis with obesity by erasing m6A methylation of PDP2
Xu-Ying Sun1, Jing-Yue Su2,3, Xin Chen2,3
1Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Background:
Osteoarthritis (OA) is currently the most common age-related degenerative joint disease, but there remains a lack of disease-modifying therapy for OA treatment. This study aimed to elucidate the critical roles and underlying mechanism of the fat mass and obesity associated gene (FTO) in OA pathogenesis induced by high fat diet (HFD) and HFD coupled with destabilized medial meniscus (DMM) surgery, and to ascertain the synergistic action of the two in OA pathogenesis.
Methods:
Mouse models were established using solely HFD feeding and combined HFD feeding and DMM surgery. Primary mouse chondrocytes were treated with palmitic acid (PA) and interleukin-1β (IL-1β) to simulate lipotoxicity and inflammation. FTO expression was modulated via genetic, adenoviral, or pharmacological methods. Downstream pyruvate dehydrogenase phosphatases 2 (PDP2) and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) were similarly manipulated by siRNA or overexpression plasmids; adenovirus-mediated knockdown/overexpression of Pdp2 was applied in vivo. Mechanistic studies included RNA sequencing (RNA-Seq) and methylated RNA immunoprecipitation sequencing (MeRIP-Seq).
Results:
The results revealed reduced FTO expression in the cartilage of both obese OA patients and mouse models. Genetically, adenovirus-induced or pharmacologically-induced FTO inhibition exacerbated OA progression in HFD-fed and HFD+DMM mice. Mechanistically, Fto knockdown downregulated the PDP2 level in an m6A-dependent manner via YTHDF2. Pdp2 knockdown exacerbated OA progression in HFD-fed and HFD+DMM mice, whereas PDP2 overexpression markedly alleviated cartilage degeneration. Moreover, YTHDF2 overexpression reversed the role of Fto knockdown in lipid deposition and cartilage degeneration.
Conclusions:
Our study identifies that downregulation of FTO exerts a pivotal effect on OA with obesity. FTO drives disease progression by regulating PDP2 activity, and YTHDF2 mediates the m6A modification of FTO to PDP2. Targeting the FTO/YTHDF2/PDP2 axis offers promising therapeutic potential for OA treatment.
Insights
Downregulation of the fat mass and obesity associated gene (FTO) worsens osteoarthritis (OA) in obesity. Targeting the FTO/YTHDF2/PDP2 pathway may offer new OA treatments.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Osteoarthritis (OA) is a prevalent age-related degenerative joint disease lacking disease-modifying treatments.
- Obesity and high-fat diets are significant risk factors contributing to OA pathogenesis.
- The role of the fat mass and obesity associated gene (FTO) in OA, particularly in obesity-induced models, requires elucidation.
Purpose of the Study:
- To investigate the role and mechanism of FTO in OA pathogenesis induced by high-fat diet (HFD) and destabilized medial meniscus (DMM) surgery.
- To explore the synergistic effects of HFD and DMM surgery on OA development.
- To identify potential therapeutic targets within the FTO regulatory pathway.
Main Methods:
- Establishment of mouse models using HFD feeding and/or DMM surgery.
- In vitro studies using primary mouse chondrocytes treated with palmitic acid (PA) and interleukin-1β (IL-1β).
- Manipulation of FTO, pyruvate dehydrogenase phosphatases 2 (PDP2), and YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) expression using genetic, adenoviral, and pharmacological methods.
- Mechanistic investigations including RNA sequencing (RNA-Seq) and methylated RNA immunoprecipitation sequencing (MeRIP-Seq).
Main Results:
- Reduced FTO expression was observed in obese OA patients and mouse models.
- FTO inhibition exacerbated OA progression in HFD and HFD+DMM mice.
- FTO knockdown downregulated PDP2 in an m6A-dependent manner via YTHDF2.
- PDP2 knockdown worsened OA, while PDP2 overexpression alleviated cartilage degeneration.
- YTHDF2 overexpression reversed the effects of FTO knockdown on lipid deposition and cartilage degeneration.
Conclusions:
- Downregulation of FTO plays a critical role in obesity-associated OA.
- FTO promotes OA progression by regulating PDP2 activity.
- The YTHDF2 protein mediates FTO's m6A modification of PDP2.
- The FTO/YTHDF2/PDP2 axis represents a promising therapeutic target for OA treatment.
