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Effect of SDF-1/Cxcr4 Signaling Antagonist AMD3100 on Bone Mineralization in Distraction Osteogenesis

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Abstract

Distraction osteogenesis (DO) is a widely applied technique in orthopedics surgery, which involves rapid stem cell migration, homing, and differentiation. Interactions between the chemokine receptor Cxcr4 and its ligand, stromal derived factor-1 (SDF-1), regulate hematopoietic stem cell trafficking to the ischemic area and induce their subsequent differentiation. Here, we examined SDF-1 expression and further investigated the role of SDF-1/Cxcr4 signaling antagonist AMD3100 during bone regeneration in rat DO model. The results showed that expression levels of SDF-1 and osteogenic genes were higher in DO zones than in the fracture zones, and SDF-1 expression level was the highest at the termination of the distraction phase. Radiological, mechanical, and histological analyses demonstrated that the local administration of AMD3100 (400 μM) to DO rats significantly inhibited new bone formation. In the rat bone marrow mesenchymal stem cells culture, comparing to the group treated with osteogenic induction medium, AMD3100 supplement led to a considerable decrease in the expression of alkaline phosphatase and early osteogenic marker genes. However, the amount of calcium deposits in rat MSCs did not differ between the groups. Therefore, our study demonstrated that the DO process induced higher expression of SDF-1, which collated to rapid induction of callus formation. Local application of SDF-1/Cxcr4 signaling antagonist AMD3100 significantly inhibited bone mineralization and osteogenesis in DO, which may represent a potential therapeutic approach to the enhancement of bone consolidation in patients undergoing DO.

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Acknowledgements

The work was partially supported by grants from National Natural Science Foundation of China (NSFC Nos. 81371946, 81374568), Hong Kong Government Research Grant Council, General Research Fund (CUHK470813 and 14119115), and a project grant from China Shenzhen City Science and Technology Bureau (JGJHZ20140419120051680 and JCYJ20150630165236960) to Gang Li. This study was also partly supported by SMART program, Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong.

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    Authors and Affiliations

    1. Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China

      Jia Xu, Qinglin Kang & Yimin Chai

    2. Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Room 904, 9/F, Shatin, Hong Kong Sar, People’s Republic of China

      Yuanfeng Chen, Yang Liu, Jinfang Zhang, Kiwai Ho & Gang Li

    3. Institute of Orthopedic Diseases and Department of Orthopedics, the First Affiliated Hospital, Jinan University, Guangzhou, People’s Republic of China

      Yuanfeng Chen

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    Correspondence to Yimin Chai or Gang Li.

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    Jia Xu, Yuanfeng Chen, Yang Liu, Jinfang Zhang, Qinglin Kang, Kiwai Ho, Yimin Chai, and Gang Li declare that they have no conflict of interest.

    Human and Animal Rights and Informed Consent

    All animal experiments were carried out under the animal license issued by the Hong Kong SAR Government and the approval of the Animal Experimentation Ethics Committee of the Chinese University of Hong Kong (Ref No. 14-052-MIS).

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    Jia Xu and Yuanfeng Chen contributed equally as first authors.

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    Xu, J., Chen, Y., Liu, Y. et al. Effect of SDF-1/Cxcr4 Signaling Antagonist AMD3100 on Bone Mineralization in Distraction Osteogenesis. Calcif Tissue Int 100, 641–652 (2017). https://doi.org/10.1007/s00223-017-0249-4

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