CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling

TY - JOUR

T1 - CRMP4 Inhibits Bone Formation by Negatively Regulating BMP and RhoA Signaling

AU - Abdallah, Basem M.

AU - Figeac, Florence

AU - Larsen, Kenneth H.

AU - Ditzel, Nicholas

AU - Keshari, Pankaj

AU - Isa, Adiba

AU - Jafari Kermani, Abbas

AU - Andersen, Thomas L

AU - Delaisse, Jean-Marie

AU - Goshima, Yoshio

AU - Ohshima, Toshio

AU - Kassem, Moustapha

N1 - M1 - Copyright (C) 2017 U.S. National Library of Medicine. MEDLINE AN 2018089741(Journal; Article; (JOURNAL ARTICLE))

PY - 2017/5

Y1 - 2017/5

N2 - 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.

AB - 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.

KW - bone remodeling

KW - crmp4

KW - dpysl3

KW - osteoblast

KW - osteoporosis

U2 - 10.1002/jbmr.3069

DO - 10.1002/jbmr.3069

M3 - Journal article

C2 - 28019696

SN - 0884-0431

VL - 32

SP - 913

EP - 926

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 5

ER -