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

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    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

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    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., Jafari, A., Andersen, T. L., Delaisse, J. M., Goshima, Y., Ohshima, T., & 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