1. Academic Validation
  2. ROS/MMP-9 mediated CS degradation in BMSC inhibits citric acid metabolism participating in the dual regulation of bone remodelling

ROS/MMP-9 mediated CS degradation in BMSC inhibits citric acid metabolism participating in the dual regulation of bone remodelling

  • Cell Death Discov. 2024 Feb 14;10(1):77. doi: 10.1038/s41420-024-01835-5.
Wacili Da 1 Wen Jiang 2 Lin Tao 3
Affiliations

Affiliations

  • 1 Department of Orthopedics Surgery, Orthopedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China.
  • 2 Department of Orthopedics, First Hospital of China Medical University, Shenyang, Liaoning, China. jiangwende2020@163.com.
  • 3 Department of Orthopedics, First Hospital of China Medical University, Shenyang, Liaoning, China. taolin@cmu.edu.cn.
Abstract

It is necessary to figure out the abnormal energy metabolites at the cellular level of postmenopausal osteoporosis (PMOP) bone microenvironment. In this study, we constructed PMOP model by ovariectomy and identified 9 differential metabolites compared with control femur by energy metabolomic. The enrichment analysis of differential metabolites revealed that tricarboxylic acid cycle, glucagon pathway and purinergic signaling pathway were the main abnormal metabolic processes. Citric acid was identified as the key metabolite by constructing compound reaction-enzyme-gene network. The functional annotation of citric acid targets identified by network pharmacological tools indicated that matrix metalloproteinase 9 (MMP-9) may be involved in regulating citric acid metabolism in the osteogenic differentiation of bone marrow mesenchymal stem cell (BMSC). Molecular docking shows that the interaction forces between MMP-9 and citric acid synthase (CS) is -638, and there are multiple groups of residues used to form hydrogen bonds. Exogenous H2O2 promotes the expression of MMP-9 in BMSC to further degrade CS resulting in a decrease in mitochondrial citric acid synthesis, which leads to the disorder of bone remodeling by two underlying mechanisms ((1) the decreased histone acetylation inhibits the osteogenic differentiation potential of BMSC; (2) the decreased bone mineralization by citric acid deposition). MMP-9-specific inhibitor (MMP-9-IN-1) could significantly improve the amount of CS in BMSC to promote cellular citric acid synthesis, and further enhance bone remodeling. These findings suggest inhibiting the degradation of CS by MMP-9 to promote the net production of citric acid in osteogenic differentiation of BMSC may be a new direction of PMOP research.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-135232
    99.71%, MMP-9 抑制剂
    MMP