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TGF-β1-induced Migration of Bone Mesenchymal Stem Cells Couples Bone Resorption and Formation

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      SUMMARY

      Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Disturbances of this process are associated with skeletal diseases, such as Camurati-Engelmann disease (CED). We show using in vitro and animal models that active TGF-β1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells (BMSCs) to the bone resorptive sites and that this process is mediated through SMAD signaling pathway. Analysis of a mouse model carrying a CED-derived TGF-β1 mutation, which exhibits the typical progressive diaphyseal dysplasia with tibial fractures, we found high levels of active TGF-β1 in the bone marrow. Treatment with a TGF-β type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. Thus, as TGF-β1 functions to couple bone resorption and formation, modulation of TGF-β1 activity could be an effective treatment for the bone remodeling diseases.

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      Most cited references 60

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        Marrow stromal cells as stem cells for nonhematopoietic tissues.

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        Marrow stromal cells can be isolated from other cells in marrow by their tendency to adhere to tissue culture plastic. The cells have many of the characteristics of stem cells for tissues that can roughly be defined as mesenchymal, because they can be differentiated in culture into osteoblasts, chondrocytes, adipocytes, and even myoblasts. Therefore, marrow stromal cells present an intriguing model for examining the differentiation of stem cells. Also, they have several characteristics that make them potentially useful for cell and gene therapy.
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          The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.
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            Author and article information

            Affiliations
            [1 ] Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
            [2 ] Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
            [3 ] The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, Xinjiang 832008, China
            [4 ] Department of Pathology, School of Medicine, Shihezi University, Shihezi, Xinjiang 832002, China
            [5 ] Departments of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
            [6 ] Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
            Author notes
            Corresponding author: Xu Cao, 1670 University Blvd., VH G003, Birmingham, AL 35294-0019, Telephone: (205) 934-0162, Fax: (205) 934-1775, E-mail: cao@ 123456uab.edu
            [7]

            These authors contributed equally to this work.

            Journal
            9502015
            8791
            Nat Med
            Nature medicine
            1078-8956
            1546-170X
            6 May 2009
            5 July 2009
            July 2009
            1 January 2010
            : 15
            : 7
            : 757-765
            2727637
            19584867
            10.1038/nm.1979
            nihpa115641
            Funding
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
            Award ID: R01 DK057501-08 ||DK
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
            Award ID: R01 AR053973-02 ||AR
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            Medicine

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