Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation

Authors

  • Liang Chen,

    1. Department of Orthopaedic Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
    2. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    3. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Wei Jiang,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Jiayi Huang,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Bai-Cheng He,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Guo-Wei Zuo,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Wenli Zhang,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Department of Orthopaedic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
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  • Qing Luo,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Qiong Shi,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Bing-Qiang Zhang,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Eric R Wagner,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Jinyong Luo,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Min Tang,

    1. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Christian Wietholt,

    1. Department of Radiology, The University of Chicago, Chicago, ILUSA
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  • Xiaoji Luo,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Yang Bi,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Yuxi Su,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Bo Liu,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Stephanie H Kim,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Connie J He,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Yawen Hu,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Jikun Shen,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Farbod Rastegar,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Enyi Huang,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. School of Bioengineering, Chongqing University, Chongqig, People's Republic of China
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  • Yanhong Gao,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Department of Geriatrics, Xinhua Hospital of Shanghai Jiatong University, Shanghai, People's Republic of China
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  • Jian-Li Gao,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Jian-Zhong Zhou,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
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  • Russell R Reid,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Hue H Luu,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Rex C Haydon,

    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
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  • Tong-Chuan He,

    Corresponding author
    1. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    2. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
    • Tong-Chuan He, Molecular Oncology Laboratory, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA.

      Zhong-Liang Deng, Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, People's Republic of China.

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  • Zhong-Liang Deng

    Corresponding author
    1. Department of Orthopaedic Surgery, Second Affiliated Hospital, Chongqing Medical University, Chongqing, People's Republic of China
    2. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA
    3. Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University, Chongqing, People's Republic of China
    • Tong-Chuan He, Molecular Oncology Laboratory, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA.

      Zhong-Liang Deng, Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, People's Republic of China.

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Abstract

Efficient osteogenic differentiation and bone formation from mesenchymal stem cells (MSCs) should have clinical applications in treating nonunion fracture healing. MSCs are adherent bone marrow stromal cells that can self-renew and differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. We have identified bone morphogenetic protein 9 (BMP-9) as one of the most osteogenic BMPs. Here we investigate the effect of insulin-like growth factor 2 (IGF-2) on BMP-9-induced bone formation. We have found that endogenous IGF-2 expression is low in MSCs. Expression of IGF-2 can potentiate BMP-9-induced early osteogenic marker alkaline phosphatase (ALP) activity and the expression of later markers. IGF-2 has been shown to augment BMP-9-induced ectopic bone formation in the stem cell implantation assay. In perinatal limb explant culture assay, IGF-2 enhances BMP-9-induced endochondral ossification, whereas IGF-2 itself can promote the expansion of the hypertropic chondrocyte zone of the cultured limb explants. Expression of the IGF antagonists IGFBP3 and IGFBP4 leads to inhibition of the IGF-2 effect on BMP-9-induced ALP activity and matrix mineralization. Mechanistically, IGF-2 is further shown to enhance the BMP-9-induced BMPR-Smad reporter activity and Smad1/5/8 nuclear translocation. PI3-kinase (PI3K) inhibitor LY294002 abolishes the IGF-2 potentiation effect on BMP-9-mediated osteogenic signaling and can directly inhibit BMP-9 activity. These results demonstrate that BMP-9 crosstalks with IGF-2 through PI3K/AKT signaling pathway during osteogenic differentiation of MSCs. Taken together, our findings suggest that a combination of BMP-9 and IGF-2 may be explored as an effective bone-regeneration agent to treat large segmental bony defects, nonunion fracture, and/or osteoporotic fracture. © 2010 American Society for Bone and Mineral Research.

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