Bidirectional signaling through EphrinA2-EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis

Naoko Irie, Yasunari Takada, Yoshihiko Watanabe, Yumi Matsuzaki, Chie Naruse, Masahide Asano, Yoichiro Iwakura, Toshio Suda, Koichi Matsuo

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Bone is remodeled constantly throughout life by bone-resorbing osteoclasts and bone-forming osteoblasts. To maintain bone volume and quality, differentiation of osteoclasts and osteoblasts is tightly regulated through communication between and within these two cell lineages. Previously we reported that cell-cell interaction mediated by ephrinB2 ligand on osteoclasts and EphB4 receptor on osteoblasts generates bidirectional anti-osteoclastogenic and pro-osteoblastogenic signals into respective cells and presumably facilitates transition from bone resorption to bone formation. Here we show that bidirectional ephrinA2-EphA2 signaling regulates bone remodeling at the initiation phase. EphrinA2 expression was rapidly induced by receptor activator of NF-κB ligand in osteoclast precursors; this was dependent on the transcription factor c-Fos but independent of the c-Fos target gene product NFATc1. Receptor EphA2 was expressed in osteoclast precursors and osteoblasts. Overexpression experiments revealed that both ephrinA2 and EphA2 in osteoclast precursors enhanced differentiation of multinucleated osteoclasts and that phospholipase Cγ2 may mediate ephrinA2 reverse signaling. Moreover, ephrinA2 on osteoclasts was cleaved by metalloproteinases, and ephrinA2 released in the culture medium enhanced osteoclastogenesis. Interestingly, differentiation of osteoblasts lacking EphA2 was enhanced along with alkaline phosphatase, Runx2, and Osterix expression, indicating that EphA2 on osteoblasts generates anti-osteoblastogenic signals presumably by up-regulating RhoA activity. Therefore, ephrinA2-EphA2 interaction facilitates the initiation phase of bone remodeling by enhancing osteoclast differentiation and suppressing osteoblast differentiation.

Original languageEnglish
Pages (from-to)14637-14644
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number21
DOIs
Publication statusPublished - 2009 May 22

Fingerprint

Osteoclasts
Osteogenesis
Osteoblasts
Bone
Bone and Bones
Bone Remodeling
EphB4 Receptor
EphA2 Receptor
Ligands
fos Genes
Phospholipases
Metalloproteases
Cell Lineage
Bone Resorption
Cell Communication
Alkaline Phosphatase
Culture Media
Transcription Factors
Genes
Communication

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Bidirectional signaling through EphrinA2-EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis. / Irie, Naoko; Takada, Yasunari; Watanabe, Yoshihiko; Matsuzaki, Yumi; Naruse, Chie; Asano, Masahide; Iwakura, Yoichiro; Suda, Toshio; Matsuo, Koichi.

In: Journal of Biological Chemistry, Vol. 284, No. 21, 22.05.2009, p. 14637-14644.

Research output: Contribution to journalArticle

Irie, N, Takada, Y, Watanabe, Y, Matsuzaki, Y, Naruse, C, Asano, M, Iwakura, Y, Suda, T & Matsuo, K 2009, 'Bidirectional signaling through EphrinA2-EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis', Journal of Biological Chemistry, vol. 284, no. 21, pp. 14637-14644. https://doi.org/10.1074/jbc.M807598200
Irie, Naoko ; Takada, Yasunari ; Watanabe, Yoshihiko ; Matsuzaki, Yumi ; Naruse, Chie ; Asano, Masahide ; Iwakura, Yoichiro ; Suda, Toshio ; Matsuo, Koichi. / Bidirectional signaling through EphrinA2-EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 21. pp. 14637-14644.
@article{ad13c1d55ad04a798b0088e5130bc4f7,
title = "Bidirectional signaling through EphrinA2-EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis",
abstract = "Bone is remodeled constantly throughout life by bone-resorbing osteoclasts and bone-forming osteoblasts. To maintain bone volume and quality, differentiation of osteoclasts and osteoblasts is tightly regulated through communication between and within these two cell lineages. Previously we reported that cell-cell interaction mediated by ephrinB2 ligand on osteoclasts and EphB4 receptor on osteoblasts generates bidirectional anti-osteoclastogenic and pro-osteoblastogenic signals into respective cells and presumably facilitates transition from bone resorption to bone formation. Here we show that bidirectional ephrinA2-EphA2 signaling regulates bone remodeling at the initiation phase. EphrinA2 expression was rapidly induced by receptor activator of NF-κB ligand in osteoclast precursors; this was dependent on the transcription factor c-Fos but independent of the c-Fos target gene product NFATc1. Receptor EphA2 was expressed in osteoclast precursors and osteoblasts. Overexpression experiments revealed that both ephrinA2 and EphA2 in osteoclast precursors enhanced differentiation of multinucleated osteoclasts and that phospholipase Cγ2 may mediate ephrinA2 reverse signaling. Moreover, ephrinA2 on osteoclasts was cleaved by metalloproteinases, and ephrinA2 released in the culture medium enhanced osteoclastogenesis. Interestingly, differentiation of osteoblasts lacking EphA2 was enhanced along with alkaline phosphatase, Runx2, and Osterix expression, indicating that EphA2 on osteoblasts generates anti-osteoblastogenic signals presumably by up-regulating RhoA activity. Therefore, ephrinA2-EphA2 interaction facilitates the initiation phase of bone remodeling by enhancing osteoclast differentiation and suppressing osteoblast differentiation.",
author = "Naoko Irie and Yasunari Takada and Yoshihiko Watanabe and Yumi Matsuzaki and Chie Naruse and Masahide Asano and Yoichiro Iwakura and Toshio Suda and Koichi Matsuo",
year = "2009",
month = "5",
day = "22",
doi = "10.1074/jbc.M807598200",
language = "English",
volume = "284",
pages = "14637--14644",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "21",

}

TY - JOUR

T1 - Bidirectional signaling through EphrinA2-EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis

AU - Irie, Naoko

AU - Takada, Yasunari

AU - Watanabe, Yoshihiko

AU - Matsuzaki, Yumi

AU - Naruse, Chie

AU - Asano, Masahide

AU - Iwakura, Yoichiro

AU - Suda, Toshio

AU - Matsuo, Koichi

PY - 2009/5/22

Y1 - 2009/5/22

N2 - Bone is remodeled constantly throughout life by bone-resorbing osteoclasts and bone-forming osteoblasts. To maintain bone volume and quality, differentiation of osteoclasts and osteoblasts is tightly regulated through communication between and within these two cell lineages. Previously we reported that cell-cell interaction mediated by ephrinB2 ligand on osteoclasts and EphB4 receptor on osteoblasts generates bidirectional anti-osteoclastogenic and pro-osteoblastogenic signals into respective cells and presumably facilitates transition from bone resorption to bone formation. Here we show that bidirectional ephrinA2-EphA2 signaling regulates bone remodeling at the initiation phase. EphrinA2 expression was rapidly induced by receptor activator of NF-κB ligand in osteoclast precursors; this was dependent on the transcription factor c-Fos but independent of the c-Fos target gene product NFATc1. Receptor EphA2 was expressed in osteoclast precursors and osteoblasts. Overexpression experiments revealed that both ephrinA2 and EphA2 in osteoclast precursors enhanced differentiation of multinucleated osteoclasts and that phospholipase Cγ2 may mediate ephrinA2 reverse signaling. Moreover, ephrinA2 on osteoclasts was cleaved by metalloproteinases, and ephrinA2 released in the culture medium enhanced osteoclastogenesis. Interestingly, differentiation of osteoblasts lacking EphA2 was enhanced along with alkaline phosphatase, Runx2, and Osterix expression, indicating that EphA2 on osteoblasts generates anti-osteoblastogenic signals presumably by up-regulating RhoA activity. Therefore, ephrinA2-EphA2 interaction facilitates the initiation phase of bone remodeling by enhancing osteoclast differentiation and suppressing osteoblast differentiation.

AB - Bone is remodeled constantly throughout life by bone-resorbing osteoclasts and bone-forming osteoblasts. To maintain bone volume and quality, differentiation of osteoclasts and osteoblasts is tightly regulated through communication between and within these two cell lineages. Previously we reported that cell-cell interaction mediated by ephrinB2 ligand on osteoclasts and EphB4 receptor on osteoblasts generates bidirectional anti-osteoclastogenic and pro-osteoblastogenic signals into respective cells and presumably facilitates transition from bone resorption to bone formation. Here we show that bidirectional ephrinA2-EphA2 signaling regulates bone remodeling at the initiation phase. EphrinA2 expression was rapidly induced by receptor activator of NF-κB ligand in osteoclast precursors; this was dependent on the transcription factor c-Fos but independent of the c-Fos target gene product NFATc1. Receptor EphA2 was expressed in osteoclast precursors and osteoblasts. Overexpression experiments revealed that both ephrinA2 and EphA2 in osteoclast precursors enhanced differentiation of multinucleated osteoclasts and that phospholipase Cγ2 may mediate ephrinA2 reverse signaling. Moreover, ephrinA2 on osteoclasts was cleaved by metalloproteinases, and ephrinA2 released in the culture medium enhanced osteoclastogenesis. Interestingly, differentiation of osteoblasts lacking EphA2 was enhanced along with alkaline phosphatase, Runx2, and Osterix expression, indicating that EphA2 on osteoblasts generates anti-osteoblastogenic signals presumably by up-regulating RhoA activity. Therefore, ephrinA2-EphA2 interaction facilitates the initiation phase of bone remodeling by enhancing osteoclast differentiation and suppressing osteoblast differentiation.

UR - http://www.scopus.com/inward/record.url?scp=67649811207&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649811207&partnerID=8YFLogxK

U2 - 10.1074/jbc.M807598200

DO - 10.1074/jbc.M807598200

M3 - Article

VL - 284

SP - 14637

EP - 14644

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 21

ER -