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

    Research output: Contribution to journalArticle

    5 Citations (Scopus)

    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
    Pages (from-to)913-926
    Number of pages14
    JournalJournal of Bone and Mineral Research
    Volume32
    Issue number5
    DOIs
    Publication statusPublished - 2017 May 1

    Fingerprint

    Osteoblasts
    Osteogenesis
    Stem Cells
    Proteins
    Mesenchymal Stromal Cells
    Bone and Bones
    Bone Marrow
    Cyclin-Dependent Kinase Inhibitor p27
    Focal Adhesion Protein-Tyrosine Kinases
    Cyclin D1
    Stromal Cells
    Minerals
    Cell Proliferation

    Keywords

    • BONE REMODELING
    • CRMP4
    • DPYSL3
    • OSTEOBLAST
    • OSTEOPOROSIS

    ASJC Scopus subject areas

    • Endocrinology, Diabetes and Metabolism
    • Orthopedics and Sports Medicine

    Cite this

    Abdallah, B. M., Figeac, F., Larsen, K. H., Ditzel, N., Keshari, P., Isa, A., ... Kassem, M. (2017). CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling. Journal of Bone and Mineral Research, 32(5), 913-926. https://doi.org/10.1002/jbmr.3069

    CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling. / Abdallah, Basem M.; Figeac, Florence; Larsen, Kenneth H.; Ditzel, Nicholas; Keshari, Pankaj; Isa, Adiba; Jafari, Abbas; Andersen, Thomas L.; Delaisse, Jean Marie; Goshima, Yoshio; Ohshima, Toshio; Kassem, Moustapha.

    In: Journal of Bone and Mineral Research, Vol. 32, No. 5, 01.05.2017, p. 913-926.

    Research output: Contribution to journalArticle

    Abdallah, BM, Figeac, F, Larsen, KH, Ditzel, N, Keshari, P, Isa, A, Jafari, A, Andersen, TL, Delaisse, JM, Goshima, Y, Ohshima, T & Kassem, M 2017, 'CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling', Journal of Bone and Mineral Research, vol. 32, no. 5, pp. 913-926. https://doi.org/10.1002/jbmr.3069
    Abdallah BM, Figeac F, Larsen KH, Ditzel N, Keshari P, Isa A et al. CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling. Journal of Bone and Mineral Research. 2017 May 1;32(5):913-926. https://doi.org/10.1002/jbmr.3069
    Abdallah, Basem M. ; Figeac, Florence ; Larsen, Kenneth H. ; Ditzel, Nicholas ; Keshari, Pankaj ; Isa, Adiba ; Jafari, Abbas ; Andersen, Thomas L. ; Delaisse, Jean Marie ; Goshima, Yoshio ; Ohshima, Toshio ; Kassem, Moustapha. / CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling. In: Journal of Bone and Mineral Research. 2017 ; Vol. 32, No. 5. pp. 913-926.
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    AU - Keshari, Pankaj

    AU - Isa, Adiba

    AU - Jafari, Abbas

    AU - Andersen, Thomas L.

    AU - Delaisse, Jean Marie

    AU - Goshima, Yoshio

    AU - Ohshima, Toshio

    AU - Kassem, Moustapha

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