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

doi:10.1016/j.isci.2023.107838

ALKBH5-mediated m⁶A demethylation of HS3ST3B1-IT1 prevents osteoarthritis progression

iScience. 2023 Sep 7;26(10):107838. doi: 10.1016/j.isci.2023.107838. eCollection 2023 Oct 20.

Authors

Yuting Tang^{1

2}, Yang Liu³, Xiaoshu Zhu¹, Yanlin Chen¹, Xinluan Jiang¹, Siyang Ding¹, Que Zheng¹, Ming Zhang¹, Jiashu Yang¹, Yunfei Ma¹, Mengying Xing¹, Zongyu Zhang⁴, Huimin Ding⁵, Yucui Jin^{1

2}, Changyan Ma^{1

2}

Affiliations

¹ Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China.
² Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, Nanjing, P.R. China.
³ Department of Orthopedics, Nanjing First Hospital, Nanjing, P.R. China.
⁴ Department of Orthopedics, the Traditional Chinese Medical Hospital of Lianyungang, Lianyungang, P.R. China.
⁵ Department of Orthopedics, BenQ Medical Center, the Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, P.R. China.

Abstract

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.

Keywords: Biological sciences; Molecular biology; Molecular mechanism of gene regulation; Orthopedics.