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

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftJournal of Bone and Mineral Research
Vol/bind32
Udgave nummer5
Sider (fra-til)913-926
ISSN0884-0431
DOI
StatusUdgivet - maj 2017

Fingeraftryk

Osteoblasts
Osteogenesis
Proteins
Mesenchymal Stromal Cells
Cyclin D1
Stromal Cells
Minerals
Cell Proliferation

Citer dette

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. I: Journal of Bone and Mineral Research. 2017 ; Bind 32, Nr. 5. s. 913-926.
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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, 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",
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",
year = "2017",
month = "5",
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",

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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.

I: Journal of Bone and Mineral Research, Bind 32, Nr. 5, 05.2017, s. 913-926.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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, Abbas

AU - Andersen, Thomas L.

AU - Delaisse, Jean Marie

AU - Goshima, Yoshio

AU - Ohshima, Toshio

AU - Kassem, Moustapha

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

KW - Focal Adhesion Kinase 1/genetics

KW - Stromal Cells/cytology

KW - Muscle Proteins/genetics

KW - rho GTP-Binding Proteins/genetics

KW - Mice, Knockout

KW - Signal Transduction/physiology

KW - Osteoblasts/cytology

KW - Animals

KW - Cyclin-Dependent Kinase Inhibitor p27/genetics

KW - Cell Proliferation/genetics

KW - Mice

KW - Osteogenesis

KW - Bone Morphogenetic Protein 2/genetics

U2 - 10.1002/jbmr.3069

DO - 10.1002/jbmr.3069

M3 - Journal article

C2 - 28019696

AN - SCOPUS:85011681231

VL - 32

SP - 913

EP - 926

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 5

ER -