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Monotropein Protects Mesenchymal Stem Cells from Lipopolysaccharide-Induced Impairments and Promotes Fracture Healing in an Ovariectomized Mouse Model

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Abstract

Monotropein is one of the active ingredients in Morinda Officinalis, which has been used for the treatment in multiple bone and joint diseases. This study aimed to observe the in vitro effects of Monotropein on osteogenic differentiation of lipopolysaccharide treated bone marrow mesenchymal stem cells (bMSCs), and the in vivo effects of local application of Monotropein on bone fracture healing in ovariectomized mice. Lipopolysaccharide was used to set up the inflammatory model in bMSCs, which were treated by Monotropein. Molecular docking analysis was performed to evaluate the potential interaction between Monotropein and p65. Transverse fractures of middle tibias were established in ovariectomized mice, and Monotropein was locally applied to the fracture site using injectable hydrogel. Monotropein enhanced the ability of primary bMSCs in chondro-osteogenic differentiation. Furthermore, Monotropein rescued lipopolysaccharide-induced osteogenic differentiation impairment and inhibited lipopolysaccharide-induced p65 phosphorylation in primary bMSCs. Docking analysis showed that the binding activity of Monotropein and p65/14-3-3 complex is stronger than the selective inhibitor of NF-κB (p65), DP-005. Local application of Monotropein partially rescued the decreased bone mass and biomechanical properties of callus or healed tibias in ovariectomized mice. The expressions of Runx2, Osterix and Collagen I in the 2-week callus were partially restored in Monotropein-treated ovariectomized mice. Taking together, local application of Monotropein promoted fracture healing in ovariectomized mice. Inhibition of p65 phosphorylation and enhancement in osteogenesis of mesenchymal stem cells could be partial of the effective mechanisms.

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Funding

This work was partially supported by the National Natural Science Foundation of China (Grant Numbers 81929004, 81973876 and 82274555).

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Author notes

  1. Shitian Zhao and Liqiang Guo have contributed equally to this work.

Authors and Affiliations

  1. Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai, 200032, China

    Shitian Zhao, Liqiang Guo, Yongjian Zhao, Kanghui Sun, Hong Zhang, Yueli Sun, Dongfeng Zhao, Xiaohui Hu, Ziyu Huang, Sheng Lu, Yongjun Wang & Bing Shu

  2. Spine Institute, Shanghai Academy of Traditional Chinese Medicine, Shanghai, 200032, China

    Shitian Zhao, Liqiang Guo, Yongjian Zhao, Kanghui Sun, Hong Zhang, Yueli Sun, Dongfeng Zhao, Xiaohui Hu, Ziyu Huang, Sheng Lu, Yongjun Wang & Bing Shu

  3. Key Laboratory, Ministry of Education of China, Shanghai, 200032, China

    Shitian Zhao, Liqiang Guo, Yongjian Zhao, Jing Wang, Kanghui Sun, Hong Zhang, Yueli Sun, Dongfeng Zhao, Xiaohui Hu, Ziyu Huang, Sheng Lu, Yongjun Wang & Bing Shu

  4. Caolu Community Health Service Center, Shanghai, 200120, China

    Wei Cui

  5. Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Xinhua Liu

  6. Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China

    Weian Zhang

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  1. Shitian Zhao
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Contributions

BS, WZ and XL designed the study. Experimental work and data collection were performed by SZ, LG, WC, YZ, YS, KS, HZ, DZ, XH and ZH. JW and SL were responsible for statistical analysis of the data. The first draft of the manuscript was written by BS, SZ and LG. WZ, XL and YW revised the manuscript critically. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xinhua Liu, Weian Zhang or Bing Shu.

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Conflict of interest

Shitian Zhao, Liqiang Guo, Wei Cui, Yongjian Zhao, Jing Wang, Kanghui Sun, Hong Zhang, Yueli Sun, Dongfeng Zhao, Xiaohui Hu, Ziyu Huang, Sheng Lu, Yongjun Wang, Xinhua Liu, Weian Zhang, and Bing Shu declares that there is no conflict of interest regarding the publication of this article.

Human and Animal Rights and Informed Consent

The experimental protocols were performed with the approval of the Laboratory Animal Management and Use (Animal Welfare) Committee of Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (LHERAW-19051), and all the international, national and institutional guidelines for the care and use of animals were followed.

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Zhao, S., Guo, L., Cui, W. et al. Monotropein Protects Mesenchymal Stem Cells from Lipopolysaccharide-Induced Impairments and Promotes Fracture Healing in an Ovariectomized Mouse Model. Calcif Tissue Int 113, 558–570 (2023). https://doi.org/10.1007/s00223-023-01130-y

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