METTL3-mediated m6A modification of IGFBP7-OT promotes osteoarthritis progression by regulating the DNMT1/DNMT3a-IGFBP7 axis

Osteoarthritis (OA) is the most common degenerative disorder, affecting approximately half of the elderly population. In this study, we find that the expressions of long noncoding RNA (lncRNA) IGFBP7-OT and its maternal gene, IGFBP7, are upregulated and positively correlated in osteoarthritic cartilage. Overexpression of IGFBP7-OT significantly inhibits chondrocyte viability, promotes chondrocyte apoptosis, and reduces extracellular matrix components, whereas IGFBP7-OT knockdown has the opposite effects. IGFBP7-OT overexpression promotes cartilage degeneration and markedly aggravates the monosodium iodoacetate-induced OA phenotype in vivo. Further mechanistic research reveals that IGFBP7-OT promotes OA progres-sion by upregulating IGFBP7 expression. Specifically, IGFBP7-OT suppresses the occupancy of DNMT1 and DNMT3a on the IGFBP7 promoter, thereby inhibiting methylation of the IGFBP7 promoter. The upregulation of IGFBP7-OT in OA is partially controlled by METTL3-mediated N6-methyladenosine (m6A) modification. Collectively, our findings reveal that m6A modification of IGFBP7-OT promotes OA progression by regulating the DNMT1/DNMT3a-IGFBP7 axis and provide a potential therapeutical target for OA treatment.

Automated summary

In this study, it was found that the upregulation of long noncoding RNA (lncRNA) IGFBP7-OT and its maternal gene, IGFBP7, in osteoarthritic cartilage were positively correlated. Overexpression of IGFBP7-OT inhibited chondrocyte viability, promoted chondrocyte apoptosis, and reduced extracellular matrix components, while knockdown of IGFBP7-OT had the opposite effects. IGFBP7-OT overexpression promoted cartilage degeneration and aggravated the monosodium iodoacetate-induced osteoarthritis phenotype in vivo. Mechanistic research revealed that IGFBP7-OT promoted osteoarthritis progression by upregulating IGFBP7 expression through inhibiting methylation of the IGFBP7 promoter by suppressing the occupancy of DNMT1 and DNMT3a. The upregulation of IGFBP7-OT in osteoarthritis was partially controlled by METTL3-mediated N6-methyladenosine (m6A) modification.