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      TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation

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          Abstract

          Transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP) signaling is involved in a vast majority of cellular processes and is fundamentally important throughout life. TGF-β/BMPs have widely recognized roles in bone formation during mammalian development and exhibit versatile regulatory functions in the body. Signaling transduction by TGF-β/BMPs is specifically through both canonical Smad-dependent pathways (TGF-β/BMP ligands, receptors and Smads) and non-canonical Smad-independent signaling pathway ( e.g. p38 mitogen-activated protein kinase pathway, MAPK). Following TGF-β/BMP induction, both the Smad and p38 MAPK pathways converge at the Runx2 gene to control mesenchymal precursor cell differentiation. The coordinated activity of Runx2 and TGF-β/BMP-activated Smads is critical for formation of the skeleton. Recent advances in molecular and genetic studies using gene targeting in mice enable a better understanding of TGF-β/BMP signaling in bone and in the signaling networks underlying osteoblast differentiation and bone formation. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in bone from studies of genetic mouse models and human diseases caused by the disruption of TGF-β/BMP signaling. This review also highlights the different modes of cross-talk between TGF-β/BMP signaling and the signaling pathways of MAPK, Wnt, Hedgehog, Notch, and FGF in osteoblast differentiation and bone formation.

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          Most cited references 152

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          BMP type I receptor inhibition reduces heterotopic [corrected] ossification.

          Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues and is without known effective treatments. Affected individuals harbor conserved mutations in the ACVR1 gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2). Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref. 6), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.
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            BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk.

            Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGF-beta) superfamily, bind to two different serine/threonine kinase receptors, and mediate their signals through Smad-dependent and Smad-independent pathways. Receptor regulated-Smad (R-Smad) proteins specific for the BMP pathways interact with various proteins, including transcription factor Runx, and transmit specific signals in target cells. The recent development of DNA microarray techniques has allowed us to identify many BMP target genes. BMP signaling is modulated by various molecules, including inhibitory Smads (I-Smads). Moreover, recent findings have revealed that BMP pathways interact with other signaling pathways, and such signaling cross-talk plays pivotal roles in growth and differentiation of target cells.
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              Runx2 is a common target of transforming growth factor beta1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12.

              When C2C12 pluripotent mesenchymal precursor cells are treated with transforming growth factor beta1 (TGF-beta1), terminal differentiation into myotubes is blocked. Treatment with bone morphogenetic protein 2 (BMP-2) not only blocks myogenic differentiation of C2C12 cells but also induces osteoblast differentiation. The molecular mechanisms governing the ability of TGF-beta1 and BMP-2 to both induce ligand-specific responses and inhibit myogenic differentiation are not known. We identified Runx2/PEBP2alphaA/Cbfa1, a global regulator of osteogenesis, as a major TGF-beta1-responsive element binding protein induced by TGF-beta1 and BMP-2 in C2C12 cells. Consistent with the observation that Runx2 can be induced by either TGF-beta1 or BMP-2, the exogenous expression of Runx2 mediated some of the effects of TGF-beta1 and BMP-2 but not osteoblast-specific gene expression. Runx2 mimicked common effects of TGF-beta1 and BMP-2 by inducing expression of matrix gene products (for example, collagen and fibronectin), suppressing MyoD expression, and inhibiting myotube formation of C2C12 cells. For osteoblast differentiation, an additional effector, BMP-specific Smad protein, was required. Our results indicate that Runx2 is a major target gene shared by TGF-beta and BMP signaling pathways and that the coordinated action of Runx2 and BMP-activated Smads leads to the induction of osteoblast-specific gene expression in C2C12 cells.
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                Author and article information

                Journal
                Int J Biol Sci
                ijbs
                International Journal of Biological Sciences
                Ivyspring International Publisher (Sydney )
                1449-2288
                2012
                21 January 2012
                : 8
                : 2
                : 272-288
                Affiliations
                1. Institute of Genetics, Life Science College, Zhejiang University, 388 Yuhang Road, Hangzhou 310058, China
                2. Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892, USA.
                3. Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Blvd, Birmingham AL, 35294-2182, USA.
                Author notes
                ✉ Corresponding author: Yi-Ping Li, Department of Pathology, University of Alabama at Birmingham, SHEL 810, 1825 University Blvd, Birmingham AL 35294-2182, USA . Tel: 205-975-2606, Fax: 205-975-4919, E-mail: ypli@ 123456uab.edu . Chuxia Deng, Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892, USA. Tel: 301-402-7225, Fax: 301-480-113, E-mail: Chuxiad@ 123456bdg10.niddk.nih.gov

                Conflict of Interests: The authors have declared that no conflict of interest exists.

                Article
                ijbsv08p0272
                10.7150/ijbs.2929
                3269610
                22298955
                © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
                Categories
                Review

                Life sciences

                runx2, tgf signaling, bone, smad, osteoblasts, bmp signaling

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