ALKBH5-mediated m6A demethylation of HS3ST3B1-IT1 prevents osteoarthritis progression
Yuting Tang,
Yang Liu,
Xiaoshu Zhu,
Yanlin Chen,
Xinluan Jiang,
Siyang Ding,
Que Zheng,
Ming Zhang,
Jiashu Yang,
Yunfei Ma,
Mengying Xing,
Zongyu Zhang,
Huimin Ding,
Yucui Jin,
Changyan Ma
Affiliations
Yuting Tang
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China
Yang Liu
Department of Orthopedics, Nanjing First Hospital, Nanjing, P.R. China
Xiaoshu Zhu
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China
Yanlin Chen
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China
Xinluan Jiang
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China
Siyang Ding
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China
Que Zheng
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China
Ming Zhang
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China
Jiashu Yang
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China
Yunfei Ma
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China
Mengying Xing
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China
Zongyu Zhang
Department of Orthopedics, the Traditional Chinese Medical Hospital of Lianyungang, Lianyungang, P.R. China; Corresponding author
Huimin Ding
Department of Orthopedics, BenQ Medical Center, the Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, P.R. China; Corresponding author
Yucui Jin
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China; Corresponding author
Changyan Ma
Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China; Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China; Corresponding author
Summary: HS3ST3B1-IT1 was identified as a downregulated long noncoding RNA in osteoarthritic cartilage. However, its roles and mechanisms in the pathogenesis of osteoarthritis (OA) are unclear. In this study, we demonstrated that the expressions of HS3ST3B1-IT1 and its maternal gene HS3ST3B1 were downregulated and positively correlated in osteoarthritic cartilage. Overexpression of HS3ST3B1-IT1 significantly increased chondrocyte viability, inhibited chondrocyte apoptosis, and upregulated extracellular matrix (ECM) proteins, whereas HS3ST3B1-IT1 knockdown had the opposite effects. In addition, HS3ST3B1-IT1 significantly ameliorated monosodium-iodoacetate-induced OA in vivo. Mechanistically, HS3ST3B1-IT1 upregulated HS3ST3B1 expression by blocking its ubiquitination-mediated degradation. Knockdown of HS3ST3B1 reversed the effects of HS3ST3B1-IT1 on chondrocyte viability, apoptosis, and ECM metabolism. AlkB homolog 5 (ALKBH5)-mediated N6-methyladenosine (m6A) demethylation stabilized HS3ST3B1-IT1 RNA. Together, our data revealed that ALKBH5-mediated upregulation of HS3ST3B1-IT1 suppressed OA progression by elevating HS3ST3B1 expression, suggesting that HS3ST3B1-IT1/HS3ST3B1 may serve as potential therapeutic targets for OA treatment.
