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Melatonin Rescues the Ti Particle-Impaired Osteogenic Potential of Bone Marrow Mesenchymal Stem Cells via the SIRT1/SOD2 Signaling Pathway

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Abstract

Wear particles released by joint implants are a major cause of osteolysis around the prosthesis by negatively affecting bone reconstruction. Bone marrow mesenchymal stem cells (BMMSCs) stimulated by wear particles showed an impaired osteogenic potential. Melatonin has been shown beneficial effects on intracellular antioxidant functions and bone formation; however, whether it could restore the osteogenic potential of BMMSCs inhibited by wear particles was unknown. This study aimed to evaluate the protective effect of melatonin on the osteogenic capacity of BMMSCs exposed to titanium (Ti) wear particles and to investigated the underlying mechanisms involving intracellular antioxidant properties. When BMMSCs were exposed to Ti particles in vitro, melatonin treatment successfully improved the matrix mineralization and expression of osteogenic markers in BMMSCs, while decreasing the levels of intracellular reactive oxygen species (ROS) and mitochondrial superoxide. The protective effect of melatonin on osteolysis was validated in a Ti particle-exposed murine calvarial model. Meanwhile, silent information regulator type 1 (SIRT1) and intracellular antioxidant enzymes were significantly up-regulated, particularly superoxide dismutase 2 (SOD2), in melatonin-treated BMMSCs. Furthermore, inhibition of SIRT1 by EX527 completely counteracted the protective effect of melatonin on Ti particle-treated BMMSCs, evidenced by the reduced expression of SOD2, increased ROS and superoxide, and decreased osteogenic differentiation. These results demonstrated that melatonin restored the osteogenic potential and improved the antioxidant properties of BMMSCs through the SIRT1 signaling pathway. Our findings suggest that melatonin is a promising candidate for treating osteolysis induced by wear particles.

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Acknowledgements

We acknowledge financial support from the National Natural Science Foundation of China (31771063, 81871789); the Natural Science Foundation of Jiangsu Province (BK20180052); Research and Development of Biomedical Materials and Substitution of Tissue and Organ Repair under National Key R&D Program (2016YFC1101505).

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Authors and Affiliations

  1. Department of Orthopaedics, The First Affiliated Hospital of Soochow University, No. 188 Shizi Street, 215006, Suzhou, Jiangsu, China

    Yazhong Zhang, Xu Zhu, Genlin Wang, Liang Chen, Huilin Yang, Fan He & Jun Lin

  2. Medical College, Orthopaedic Institute, Soochow University, No. 708 Renmin Road, 215007, Suzhou, Jiangsu, China

    Yazhong Zhang, Xu Zhu, Huilin Yang & Fan He

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  1. Yazhong Zhang
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  2. Xu Zhu
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  3. Genlin Wang
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  5. Huilin Yang
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  6. Fan He
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  7. Jun Lin
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Contributions

Yazhong Zhang and Fan He designed the research study; Yazhong Zhang, Xu Zhu, and Genlin Wang performed the experiments; Yazhong Zhang, Liang Chen, and Huilin Yang analyzed the data; Yazhong Zhang, Fan He, and Jun Lin wrote the paper. All authors approve of the final version to be published.

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Correspondence to Fan He or Jun Lin.

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Yazhong Zhang, Xu Zhu, Genlin Wang, Liang Chen, Huilin Yang, Fan He and Jun Lin declare that they have no conflicts of interest.

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All aspects of this research were conducted in accordance with the Chinese Guidelines for Animal Welfare and Experimental Protocols. All animal experiments were performed under the approval of the Ethics Committee of the First Affiliated Hospital of Soochow University.

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Zhang, Y., Zhu, X., Wang, G. et al. Melatonin Rescues the Ti Particle-Impaired Osteogenic Potential of Bone Marrow Mesenchymal Stem Cells via the SIRT1/SOD2 Signaling Pathway. Calcif Tissue Int 107, 474–488 (2020). https://doi.org/10.1007/s00223-020-00741-z

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