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      Bone Morphogenetic Protein (BMP) signaling in development and human diseases

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          Abstract

          Bone Morphogenetic Proteins (BMPs) are a group of signaling molecules that belongs to the Transforming Growth Factor-β (TGF-β) superfamily of proteins. Initially discovered for their ability to induce bone formation, BMPs are now known to play crucial roles in all organ systems. BMPs are important in embryogenesis and development, and also in maintenance of adult tissue homeostasis. Mouse knockout models of various components of the BMP signaling pathway result in embryonic lethality or marked defects, highlighting the essential functions of BMPs. In this review, we first outline the basic aspects of BMP signaling and then focus on genetically manipulated mouse knockout models that have helped elucidate the role of BMPs in development. A significant portion of this review is devoted to the prominent human pathologies associated with dysregulated BMP signaling.

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          New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure.

          Yu-Hua Tseng, Efi Kokkotou, Tim Schulz … (2008)
          Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue, which is specialized in energy expenditure and can counteract obesity. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood. Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (BMPs) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 (PR-domain-containing 16; ref. 4) and PGC-1alpha (peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (UCP1) and adipogenic transcription factors PPARgamma and CCAAT/enhancer-binding proteins (C/EBPs), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (MAP) kinase-(also known as Mapk14) and PGC-1-dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout embryos show a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-mediated expression of BMP7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and a reduction in weight gain. These data reveal an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential new therapeutic approach for the treatment of obesity.
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            Novel regulators of bone formation: molecular clones and activities.

            J Wozney, R Kriz, R Hewick … (1988)
            Protein extracts derived from bone can initiate the process that begins with cartilage formation and ends in de novo bone formation. The critical components of this extract, termed bone morphogenetic protein (BMP), that direct cartilage and bone formation as well as the constitutive elements supplied by the animal during this process have long remained unclear. Amino acid sequence has been derived from a highly purified preparation of BMP from bovine bone. Now, human complementary DNA clones corresponding to three polypeptides present in this BMP preparation have been isolated, and expression of the recombinant human proteins have been obtained. Each of the three (BMP-1, BMP-2A, and BMP-3) appears to be independently capable of inducing the formation of cartilage in vivo. Two of the encoded proteins (BMP-2A and BMP-3) are new members of the TGF-beta supergene family, while the third, BMP-1, appears to be a novel regulatory molecule.
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              Bmp4 is required for the generation of primordial germ cells in the mouse embryo.

              K Lawson, N. Dunn, B A J Roelen … (1999)
              In many organisms the allocation of primordial germ cells (PGCs) is determined by the inheritance of maternal factors deposited in the egg. However, in mammals, inductive cell interactions are required around gastrulation to establish the germ line. Here, we show that Bmp4 homozygous null embryos contain no PGCs. They also lack an allantois, an extraembryonic mesodermal tissue derived, like the PGCs, from precursors in the proximal epiblast. Heterozygotes have fewer PGCs than normal, due to a reduction in the size of the founding population and not to an effect on its subsequent expansion. Analysis of beta-galactosidase activity in Bmp4(lacZneo) embryos reveals that prior to gastrulation, Bmp4 is expressed in the extraembryonic ectoderm. Later, Bmp4 is expressed in the extraembryonic mesoderm, but not in PGCs. Chimera analysis indicates that it is the Bmp4 expression in the extraembryonic ectoderm that regulates the formation of allantois and primordial germ cell precursors, and the size of the founding population of PGCs. The initiation of the germ line in the mouse therefore depends on a secreted signal from the previously segregated, extraembryonic, trophectoderm lineage.
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                Author and article information

                Contributors
                Lewis L. Shi
                Journal
                Journal ID (nlm-ta): Genes Dis
                Journal ID (iso-abbrev): Genes Dis
                Title: Genes & Diseases
                Publisher: Chongqing Medical University
                ISSN (Print): 2352-4820
                ISSN (Electronic): 2352-3042
                Publication date PMC-release: 27 July 2014
                Publication date Collection: September 2014
                Publication date (Electronic): 27 July 2014
                Volume: 1
                Issue: 1
                Pages: 87-105
                Affiliations
                [a ]The University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
                [b ]Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
                [c ]Departments of Orthopaedic Surgery, Medicine, and Gynecology, the Affiliated Hospitals of Chongqing Medical University, Chongqing 400016, China
                [d ]School of Bioengineering, Chongqing University, Chongqing, China
                Author notes
                [∗ ] Corresponding author. Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3079, Chicago IL 60637, USA. Tel.: +1 773 834 2461; fax: +1 773 702 4384. lewisshi@ 123456uchicago.edu lshi@ 123456bsd.uchicago.edu
                Article
                Publisher ID: S2352-3042(14)00010-5
                DOI: 10.1016/j.gendis.2014.07.005
                PMC ID: 4232216
                PubMed ID: 25401122
                SO-VID: 210ece08-5e27-4cc7-8e41-1c5b45a30d1c
                Copyright © Copyright © 2014, Chongqing Medical University. Production and hosting by Elsevier B.V. All rights reserved.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                Date received : 11 July 2014
                Date accepted : 15 July 2014
                Categories
                Subject: Article

                Keywords: bmp signaling,development,genetics,mouse knockout,pathogenesis,signal transduction
                Data availability:
                Keywords: bmp signaling, development, genetics, mouse knockout, pathogenesis, signal transduction

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