title: CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling.
abstract: We identified the neuroprotein collapsing response mediator protein-4 (CRMP4) as a noncanonical osteogenic factor that regulates the differentiation of mouse bone marrow skeletal stem cells (bone marrow stromal stem cells [mBMSCs]) into osteoblastic cells. CRMP4 is the only member of the CRMP1-CRMP5 family to be expressed by mBMSCs and in osteoprogenitors of both adult mouse and human bones. In vitro gain-of-function and loss-of-function of CRMP4 in murine stromal cells revealed its inhibitory effect on osteoblast differentiation. In addition, Crmp4-deficient mice (Crmp4-/-) displayed a 40% increase in bone mass, increased mineral apposition rate, and bone formation rate, compared to wild-type controls. Increased bone mass in Crmp4-/-mice was associated with enhanced BMP2 signaling and BMP2-induced osteoblast differentiation in Crmp4-/-osteoblasts (OBs). Furthermore, Crmp4-/-OBs exhibited enhanced activation of RhoA/focal adhesion kinase (FAK) signaling that led to cytoskeletal changes with increased cell spreading. In addition, Crmp4-/-OBs exhibited increased cell proliferation that was mediated via inhibiting cyclin-dependent kinase inhibitor 1B, p27Kip1and upregulating cyclin D1 expression which are targets of RhoA signaling pathway. Our findings identify CRMP4 as a novel negative regulator of osteoblast differentiation. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark.|Department of Biological Sciences, College of Science, King Faisal University, Hofuf, Saudi Arabia.|Faculty of Science, Helwan University, Cairo, Egypt.
authors.forename: Basem M
authors.initials: BM
authors.lastname: Abdallah
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark.
authors.forename: Florence
authors.initials: F
authors.lastname: Figeac
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Larsen
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Ditzel
authors.affiliation: Department of Neurology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Keshari
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark.
authors.forename: Adiba
authors.initials: A
authors.lastname: Isa
authors.affiliation: Department of Cellular and Molecular Medicine, DanStem (Danish Stem Cell Center), Panum Institute, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Abbas
authors.initials: A
authors.lastname: Jafari
authors.affiliation: Department of Clinical Cell Biology, Vejle/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Andersen
authors.affiliation: Department of Clinical Cell Biology, Vejle/Lillebaelt Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Delaisse
authors.affiliation: Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Goshima
authors.affiliation: Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
authors.affiliation: Molecular Endocrinology Laboratory (KMEB), Department of Endocrinology, Odense University Hospital & University of Southern Denmark, Odense, Denmark.|Department of Cellular and Molecular Medicine, DanStem (Danish Stem Cell Center), Panum Institute, University of Copenhagen, Copenhagen, Denmark.|Stem Cell Unit, Department of Anatomy, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis; D015398:Signal Transduction / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; C493961:Cdkn1b protein, mouse; D009124:Muscle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: BONE REMODELING; CRMP4; DPYSL3; OSTEOBLAST; OSTEOPOROSIS