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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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          Matrix elasticity directs stem cell lineage specification.

          Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. During the initial week in culture, reprogramming of these lineages is possible with addition of soluble induction factors, but after several weeks in culture, the cells commit to the lineage specified by matrix elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types. Inhibition of nonmuscle myosin II blocks all elasticity-directed lineage specification-without strongly perturbing many other aspects of cell function and shape. The results have significant implications for understanding physical effects of the in vivo microenvironment and also for therapeutic uses of stem cells.
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            Marrow stromal cells as stem cells for nonhematopoietic tissues.

             L D Prockop (1997)
            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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              Bone resorption by osteoclasts.

              Osteoporosis, a disease endemic in Western society, typically reflects an imbalance in skeletal turnover so that bone resorption exceeds bone formation. Bone resorption is the unique function of the osteoclast, and anti-osteoporosis therapy to date has targeted this cell. The osteoclast is a specialized macrophage polykaryon whose differentiation is principally regulated by macrophage colony-stimulating factor, RANK ligand, and osteoprotegerin. Reflecting integrin-mediated signals, the osteoclast develops a specialized cytoskeleton that permits it to establish an isolated microenvironment between itself and bone, wherein matrix degradation occurs by a process involving proton transport. Osteopetrotic mutants have provided a wealth of information about the genes that regulate the differentiation of osteoclasts and their capacity to resorb bone.
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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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