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      Insulin-like Growth Factor 2 (IGF-2) Potentiates BMP-9-Induced Osteogenic Differentiation and Bone Formation

      research-article
      1 , 2 , 3 , 2 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 4 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 2 , 3 , 3 , 5 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 2 , 2 , 2 , 2 , 2 , 6 , 2 , 7 , 2 , 2 , 3 , 2 , 2 , 2 , 2 , 3 , 1 , 2 , 3
      Journal of Bone and Mineral Research
      Wiley Subscription Services, Inc., A Wiley Company
      BMP-9, bone formation, fracture healing, IGF-2, osteoblastic differentiation

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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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          Identification of c-MYC as a target of the APC pathway.

          The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
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            A simplified system for generating recombinant adenoviruses.

            Recombinant adenoviruses provide a versatile system for gene expression studies and therapeutic applications. We report herein a strategy that simplifies the generation and production of such viruses. A recombinant adenoviral plasmid is generated with a minimum of enzymatic manipulations, using homologous recombination in bacteria rather than in eukaryotic cells. After transfections of such plasmids into a mammalian packaging cell line, viral production is conveniently followed with the aid of green fluorescent protein, encoded by a gene incorporated into the viral backbone. Homogeneous viruses can be obtained from this procedure without plaque purification. This system should expedite the process of generating and testing recombinant adenoviruses for a variety of purposes.
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              Role of insulin-like growth factors in embryonic and postnatal growth.

              A developmental analysis of growth kinetics in mouse embryos carrying null mutations of the genes encoding insulin-like growth factor I (IGF-I), IGF-II, and the type 1 IGF receptor (IGF1R), alone or in combination, defined the onset of mutational effects leading to growth deficiency and indicated that between embryonic days 11.0 and 12.5, IGF1R serves only the in vivo mitogenic signaling of IGF-II. From E13.5 onward, IGF1R interacts with both IGF-I and IGF-II, while IGF-II recognizes an additional unknown receptor (XR). In contrast with the embryo proper, placental growth is served exclusively by an IGF-II-XR interaction. Additional genetic data suggested that the type 2IGF/mannose 6-phosphate receptor is an unlikely candidate for XR. Postnatal growth curves indicated that surviving Igf-1(-/-) mutants, which are infertile and exhibit delayed bone development, continue to grow with a retarded rate after birth in comparison with wild-type littermates and become 30% of normal weight as adults.
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                Author and article information

                Journal
                J Bone Miner Res
                jbmr
                Journal of Bone and Mineral Research
                Wiley Subscription Services, Inc., A Wiley Company
                0884-0431
                1523-4681
                November 2010
                17 May 2010
                : 25
                : 11
                : 2447-2459
                Affiliations
                [1 ]simpleDepartment of Orthopaedic Surgery, Second Affiliated Hospital, Chongqing Medical University Chongqing, People's Republic of China
                [2 ]simpleMolecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center Chicago, IL, USA
                [3 ]simpleKey Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and the Affiliated Hospitals, Chongqing Medical University Chongqing, People's Republic of China
                [4 ]simpleDepartment of Orthopaedic Surgery, West China Hospital, Sichuan University Chengdu, Sichuan, People's Republic of China
                [5 ]simpleDepartment of Radiology, The University of Chicago Chicago, ILUSA
                [6 ]simpleSchool of Bioengineering, Chongqing University Chongqig, People's Republic of China
                [7 ]simpleDepartment of Geriatrics, Xinhua Hospital of Shanghai Jiatong University Shanghai, People's Republic of China
                Author notes
                Address correspondence to: Tong-Chuan He, MD, PhD, Molecular Oncology Laboratory, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3079, Chicago, IL 60637, USA. E-mail: tche@ 123456surgery.bsd.uchicago.edu or Department of Orthopaedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, People's Republic of China. E-mail: deng7586@ 123456gmail.com

                Additional Supporting Information may be found in the online version of the article.

                Article
                10.1002/jbmr.133
                3179288
                20499340
                91a71f39-3e22-4b51-b3ff-b01046ff0ce1
                Copyright © 2010 American Society for Bone and Mineral Research

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Categories
                Original Article

                Human biology
                fracture healing,igf-2,bone formation,osteoblastic differentiation,bmp-9
                Human biology
                fracture healing, igf-2, bone formation, osteoblastic differentiation, bmp-9

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