@article{b9dfdd3c6dfb4e4fbbe959c77a80212c,
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, 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.",
keywords = "BONE REMODELING, CRMP4, DPYSL3, OSTEOBLAST, OSTEOPOROSIS",
author = "Abdallah, {Basem M.} and Florence Figeac and Larsen, {Kenneth H.} and Nicholas Ditzel and Pankaj Keshari and Adiba Isa and Abbas Jafari and Andersen, {Thomas L.} and Delaisse, {Jean Marie} and Yoshio Goshima and Toshio Ohshima and Moustapha Kassem",
note = "Funding Information: This work was funded by Danish council for independent research (Det Frie Forskningsr{\aa}d, DFF – 4004-00045), Novo Nordisk Foundation (Exploratory Pre Seed Grants, NNF13OC0004192 and NNF15OC0016284), and University of Southern Denmark (grant SDU 647-108). The generation of Crmp4 –/– mice was performed with Grant-in-aid for Scientific Research on Priority Areas No. 178082006 to YG. We are grateful to Bianca J{\o}rgensen, Tina L. Nielsen, Lone Christiansen, Birgit MacDonald, and Kaja Laursen for excellent technical assistance. We thank Dr. A.K.A. Ali for some technical assistance. Authors{\textquoteright} roles: BMA and MK conceived the project. BMA, FF, KL, ND, PK, AI, AJ, and TLA performed the in vitro and in vivo experiments. BMA, FF, ND, and TLA collected and analyzed data. BMA designed and supervised the study and wrote the manuscript. JD, YG, TO, and MK analyzed data, revised and approved the manuscript. Publisher Copyright: {\textcopyright} 2016 American Society for Bone and Mineral Research",
year = "2017",
month = may,
doi = "10.1002/jbmr.3069",
language = "English",
volume = "32",
pages = "913--926",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "5",
}