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All-Trans Retinoic Acid Promotes Osteogenic Differentiation and Bone Consolidation in a Rat Distraction Osteogenesis Model

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Abstract

Distraction osteogenesis (DO) is used to treat specific disorders associated with growth abnormalities and/or loss of bone stock secondary to trauma or disease. However, a high rate of complications and discomfort hamper its further application in clinical practice. Here, we investigated the effects of all-trans retinoic acid (ATRA) on osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells (rBMSCs) and bone consolidation in a rat DO model. Different doses of ATRA were used to treat rBMSCs. Cell viability and osteogenic differentiation were assessed using CCK-8 and alkaline phosphatase staining, respectively. The mRNA expression of osteogenic differentiation-genes (including ALP, Runx2, OCN, OPN, OSX, and BMP2) and angiogenic genes (including VEGF, HIF-1, FLK-2, ANG-2, and ANG-4) were determined by quantitative real-time PCR analysis. Further, we locally injected ATRA or PBS into the gap in the rat DO model every 3 days until termination. X-rays, micro-computed tomography (Micro-CT), mechanical testing, and immunohistochemistry stains were used to evaluate the quality of the regenerates. ATRA promoted osteogenic differentiation of rBMSCs. Moreover, ATRA elevated the mRNA expression levels of osteogenic differentiation-genes and angiogenic genes. In the rat model, new bone properties of bone volume/total tissue volume and mechanical strength were significantly higher in the ATRA-treatment group. Micro-CT examination showed more mineralized bone after the ATRA-treatment, and immunohistochemistry demonstrated more new bone formation after ATRA-treatment than that in the PBS group. In conclusion, as a readily available and very cost effective bio-source, ATRA may be a novel therapeutic method to enhance bone consolidation in the clinical setting.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (NSFC Nos. 81572122, 81772338) and the Interdisciplinary Program of Shanghai Jiao Tong University (Grant No. YG2017ZD05).

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Authors and Affiliations

  1. Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai, 200233, China

    Zhenjun Weng, Chunyang Wang, Cheng Zhang, Jia Xu, Yimin Chai, Yachao Jia, Pei Han & Gen Wen

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  1. Zhenjun Weng
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  8. Gen Wen
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Correspondence to Jia Xu or Yimin Chai.

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Zhenjun Weng, Chunyang Wang, Cheng Zhang, Jia Xu, Yimin Chai, Yachao Jia, Pei Han, and Gen Wen declare that they have no conflict of interest.

Ethical Approval

This study was specifically approved by the Animal Experimentation Ethics Committee of the Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, and the animal experiments were therefore performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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Weng, Z., Wang, C., Zhang, C. et al. All-Trans Retinoic Acid Promotes Osteogenic Differentiation and Bone Consolidation in a Rat Distraction Osteogenesis Model. Calcif Tissue Int 104, 320–330 (2019). https://doi.org/10.1007/s00223-018-0501-6

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  • DOI: https://doi.org/10.1007/s00223-018-0501-6

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