Downregulation of FTO aggravates osteoarthritis with obesity by erasing m6A methylation of PDP2.

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.