METTL3-mediated m6A modification of IGFBP7-OT promotes osteoarthritis progression by regulating the DNMT1/DNMT3a-IGFBP7 axis
Yuting Tang,
Fangling Hong,
Siyang Ding,
Jiashu Yang,
Ming Zhang,
Yunfei Ma,
Que Zheng,
Dawei Yang,
Yucui Jin,
Changyan Ma
Affiliations
Yuting Tang
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China
Fangling Hong
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China
Siyang Ding
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China
Jiashu Yang
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China
Ming Zhang
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China
Yunfei Ma
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China
Que Zheng
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China
Dawei Yang
Department of Orthopaedic Surgery, Nanjing First Hospital, Nanjing, P.R. China
Yucui Jin
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China; Corresponding author
Changyan Ma
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, Nanjing 211166, P.R. China; Corresponding author
Summary: 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 progression 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.
