CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling

Basem M. Abdallah*, Florence Figeac, Kenneth H. Larsen, Nicholas Ditzel, Pankaj Keshari, Adiba Isa, Abbas Jafari, Thomas L. Andersen, Jean Marie Delaisse, Yoshio Goshima, Toshio Ohshima, Moustapha Kassem

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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, p27Kip1 and upregulating cyclin D1 expression which are targets of RhoA signaling pathway. Our findings identify CRMP4 as a novel negative regulator of osteoblast differentiation.

Original languageEnglish
JournalJournal of Bone and Mineral Research
Volume32
Issue number5
Pages (from-to)913-926
ISSN0884-0431
DOIs
Publication statusPublished - May 2017

Keywords

  • BONE REMODELING
  • CRMP4
  • DPYSL3
  • OSTEOBLAST
  • OSTEOPOROSIS
  • Focal Adhesion Kinase 1/genetics
  • Stromal Cells/cytology
  • Muscle Proteins/genetics
  • rho GTP-Binding Proteins/genetics
  • Mice, Knockout
  • Signal Transduction/physiology
  • Osteoblasts/cytology
  • Animals
  • Cyclin-Dependent Kinase Inhibitor p27/genetics
  • Cell Proliferation/genetics
  • Mice
  • Osteogenesis
  • Bone Morphogenetic Protein 2/genetics

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