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Discovery of Taurocholic Acid Sodium Hydrate as a Novel Repurposing Drug for Intervertebral Disc Degeneration by Targeting MAPK3

Authors :
Ping Li
Zesen Chen
Keyu Meng
Yanlin Chen
Jiajia Xu
Xin Xiang
Xiuhua Wu
Zhiping Huang
Ruijun Lai
Peng Li
Zhongming Lai
Xiang Ao
Zhongyuan Liu
Kaifan Yang
Xiaochun Bai
Zhongmin Zhang
Source :
Orthopaedic Surgery, Vol 16, Iss 1, Pp 183-195 (2024)
Publication Year :
2024
Publisher :
Wiley, 2024.

Abstract

Objective Nowadays, more than 90% of people over 50 years suffer from intervertebral disc degeneration (IDD), but there are exist no ideal drugs. The aim of this study is to identify a new drug for IDD. Methods An approved small molecular drug library including 2040 small molecular compounds was used here. We found that taurocholic acid sodium hydrate (NAT) could induce chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs). Then, an in vivo mouse model of IDD was established and the coccygeal discs transcriptome analysis and surface plasmon resonance analysis (SPR) integrated with liquid chromatography–tandem mass spectrometry assay (LC‐MS) were performed in this study to study the therapy effect and target proteins of NAT for IDD. Micro‐CT was used to evaluate the cancellous bone. The expression of osteogenic (OCN, RNX2), chondrogenic (COL2A1, SOX9), and the target related (ERK1/2, p‐ERK1/2) proteins were detected. The alkaline phosphatase staining was performed to estimate osteogenic differentiation. Blood routine and blood biochemistry indexes were analyzed for the safety of NAT. Results The results showed that NAT could induce chondrogenesis and osteogenesis in MSCs. Further experiments confirmed NAT could ameliorate the secondary osteoporosis and delay the development of IDD in mice. Transcriptome analysis identified 128 common genes and eight Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for NAT. SPR‐LC–MS assay detected 57 target proteins for NAT, including MAPK3 (mitogen‐activated protein kinase 3), also known as ERK1 (extracellular regulated protein kinase 1). Further verification experiment confirmed that NAT significantly reduced the expression of ERK1/2 phosphorylation. Conclusion NAT would induce chondrogenesis and osteogenesis of MSCs, ameliorate the secondary osteoporosis and delay the progression of IDD in mice by targeting MAPK3.Furthermore, MAPK3, especially the phosphorylation of MAPK3, would be a potential therapeutic target for IDD treatment.

Details

Language :
English
ISSN :
17577861 and 17577853
Volume :
16
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Orthopaedic Surgery
Publication Type :
Academic Journal
Accession number :
edsdoj.8132a1f55f46c29d3443927fc35031
Document Type :
article
Full Text :
https://doi.org/10.1111/os.13909