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Knockdown of Ggps1 in chondrocyte expedites fracture healing by accelerating the progression of endochondral ossification in mice

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Abstract

Bone fracture healing is achieved through the proliferation and differentiation of stem cells, while bone marrow stem cells (BMSCs) contribute to endochondral ossification. During fracture healing, mesenchymal progenitor cells first form a cartilaginous blastema that becomes vascularized to recruit precursor cells of osteoblasts through the bone morphogenetic protein 2 (Bmp2)/Smad-dependent Runx2 pathway. Statins deplete geranylgeranyl diphosphate (GGPP), which participates in the regulation of BMSCs differentiation, through the inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, leading to impaired protein geranylgeranylation, which strongly impacts the bone synthesis induced by Bmp2. Accordingly, we would like to investigate the role of geranylgeranyl diphosphate synthase 1 (Ggps1) in bone fracture via endochondral ossification in mice. We used a Cre-loxP system, namely the tamoxifen-inducible Collagen 2-CreERT2 Ggps1 fl/fl, to eliminate specifically the Ggps1 activity in chondrocytes of 8–10-week-old mice. We found that the endochondral bone formation, calcification and vasculogenesis of the bony callus were accelerated in fractures in Ggps1−/−mice. Together, the results of this study confirm that the specific deletion of Ggps1, using the Collagen 2-CreERT2 mice, will accelerate the fracture healing process by activating the Bmp2/Smad-dependent Runx2 pathway. In addition, we managed to improve the fracture healing process by inhibiting the Ggps1 activity and its related products with statin drugs.

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Acknowledgements

This work was supported by the project of the National Natural Science Foundation of China (81271945) and the National Natural Science Foundation of China (81420108021).

Author contributions

BD, CL, HT, and QJ conceived and designed the study. XS, CW, QL, and YG collected the data. KZ and JW performed the experiments. DC, YZ, and ZX analyzed the data. BD and QL wrote the paper. CL and QJ reviewed and edited the manuscript. None of the authors have conflict of interest.

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    Authors and Affiliations

    1. Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, School of Medicine, Nanjing University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People’s Republic of China

      Bingyang Dai, Xiaoxiao Song, Yuxiang Ge, Kaijia Zhang, Chao Wang & Qing Jiang

    2. Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing, 210093, Jiangsu, People’s Republic of China

      Bingyang Dai, Xiaoxiao Song, Yuxiang Ge, Kaijia Zhang, Chao Wang, Huajian Teng & Qing Jiang

    3. Department of Sports Medicine and Adult Reconstructive Surgery, Drum Tower Hospital, Clinical College of Nanjing Medical University, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, People’s Republic of China

      Qiangqiang Li & Qing Jiang

    4. MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center (MARC) and the School of Medicine, Nanjing University, Nanjing, 210093, People’s Republic of China

      Chaojun Li

    5. The School of Medicine, Nanjing University, Nanjing, 210093, People’s Republic of China

      Jing Wu & Yifeng Zhang

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    1. Bingyang Dai
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    Correspondence to Huajian Teng, Chaojun Li or Qing Jiang.

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    B. Dai and Q. Li contributed equally to this work.

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    Dai, B., Li, Q., Song, X. et al. Knockdown of Ggps1 in chondrocyte expedites fracture healing by accelerating the progression of endochondral ossification in mice. J Bone Miner Metab 36, 133–147 (2018). https://doi.org/10.1007/s00774-017-0824-9

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