EGFL7 is expressed in bone microenvironment and promotes angiogenesis via ERK, STAT3, and integrin signaling cascades

Shek Chim, V. Kuek, Siu To Chow, B. Lim, Jennifer Tickner, J. Zhao, R. Chung, Y. Su, G. Zhang, Wendy Erber, C.J. Xian, V.M. Rosen, Jiake Xu

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    Abstract

    © 2014 Wiley Periodicals, Inc. Angiogenesis plays a pivotal role in bone formation, remodeling, and fracture healing. The regulation of angiogenesis in the bone microenvironment is highly complex and orchestrated by intercellular communication between bone cells and endothelial cells. Here, we report that EGF-like domain 7 (EGFL7), a member of the epidermal growth factor (EGF) repeat protein superfamily is expressed in both the osteoclast and osteoblast lineages, and promotes endothelial cell activities. Addition of exogenous recombinant EGFL7 potentiates SVEC (simian virus 40-transformed mouse microvascular endothelial cell line) cell migration and tube-like structure formation in vitro. Moreover, recombinant EGFL7 promotes angiogenesis featuring web-like structures in ex vivo fetal mouse metatarsal angiogenesis assay. We show that recombinant EGFL7 induces phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and focal adhesion kinase (FAK) in SVEC cells. Inhibition of ERK1/2 and STAT3 signaling impairs EGFL7-induced endothelial cell migration, and angiogenesis in fetal mouse metatarsal explants. Bioinformatic analyses indicate that EGFL7 contains a conserved RGD/QGD motif and EGFL7-induced endothelial cell migration is significantly reduced in the presence of RGD peptides. Moreover, EGFL7 gene expression is significantly upregulated during growth plate injury repair. Together, these results demonstrate that EGFL7 expressed by bone cells regulates endothelial cell activities through integrin-mediated signaling. This study highlights the important role that EGFL7, like EGFL6, expressed in bone microenvironment plays in the regulation of angiogenesis in bone.
    Original languageEnglish
    Pages (from-to)82-94
    JournalJournal of Cellular Physiology
    Volume230
    Issue number1
    DOIs
    Publication statusPublished - Jan 2015

    Fingerprint

    STAT3 Transcription Factor
    Epidermal Growth Factor
    Integrins
    Bone
    Bone and Bones
    Endothelial cells
    Endothelial Cells
    Cell Movement
    Metatarsal Bones
    Mitogen-Activated Protein Kinase 3
    Mitogen-Activated Protein Kinase 1
    Focal Adhesion Protein-Tyrosine Kinases
    Phosphorylation
    Fracture Healing
    Simian virus 40
    Bone Remodeling
    Osteoblasts
    Bone Fractures
    Osteoclasts
    Bioinformatics

    Cite this

    Chim, Shek ; Kuek, V. ; Chow, Siu To ; Lim, B. ; Tickner, Jennifer ; Zhao, J. ; Chung, R. ; Su, Y. ; Zhang, G. ; Erber, Wendy ; Xian, C.J. ; Rosen, V.M. ; Xu, Jiake. / EGFL7 is expressed in bone microenvironment and promotes angiogenesis via ERK, STAT3, and integrin signaling cascades. In: Journal of Cellular Physiology. 2015 ; Vol. 230, No. 1. pp. 82-94.
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    abstract = "{\circledC} 2014 Wiley Periodicals, Inc. Angiogenesis plays a pivotal role in bone formation, remodeling, and fracture healing. The regulation of angiogenesis in the bone microenvironment is highly complex and orchestrated by intercellular communication between bone cells and endothelial cells. Here, we report that EGF-like domain 7 (EGFL7), a member of the epidermal growth factor (EGF) repeat protein superfamily is expressed in both the osteoclast and osteoblast lineages, and promotes endothelial cell activities. Addition of exogenous recombinant EGFL7 potentiates SVEC (simian virus 40-transformed mouse microvascular endothelial cell line) cell migration and tube-like structure formation in vitro. Moreover, recombinant EGFL7 promotes angiogenesis featuring web-like structures in ex vivo fetal mouse metatarsal angiogenesis assay. We show that recombinant EGFL7 induces phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and focal adhesion kinase (FAK) in SVEC cells. Inhibition of ERK1/2 and STAT3 signaling impairs EGFL7-induced endothelial cell migration, and angiogenesis in fetal mouse metatarsal explants. Bioinformatic analyses indicate that EGFL7 contains a conserved RGD/QGD motif and EGFL7-induced endothelial cell migration is significantly reduced in the presence of RGD peptides. Moreover, EGFL7 gene expression is significantly upregulated during growth plate injury repair. Together, these results demonstrate that EGFL7 expressed by bone cells regulates endothelial cell activities through integrin-mediated signaling. This study highlights the important role that EGFL7, like EGFL6, expressed in bone microenvironment plays in the regulation of angiogenesis in bone.",
    author = "Shek Chim and V. Kuek and Chow, {Siu To} and B. Lim and Jennifer Tickner and J. Zhao and R. Chung and Y. Su and G. Zhang and Wendy Erber and C.J. Xian and V.M. Rosen and Jiake Xu",
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    EGFL7 is expressed in bone microenvironment and promotes angiogenesis via ERK, STAT3, and integrin signaling cascades. / Chim, Shek; Kuek, V.; Chow, Siu To; Lim, B.; Tickner, Jennifer; Zhao, J.; Chung, R.; Su, Y.; Zhang, G.; Erber, Wendy; Xian, C.J.; Rosen, V.M.; Xu, Jiake.

    In: Journal of Cellular Physiology, Vol. 230, No. 1, 01.2015, p. 82-94.

    Research output: Contribution to journalArticle

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    T1 - EGFL7 is expressed in bone microenvironment and promotes angiogenesis via ERK, STAT3, and integrin signaling cascades

    AU - Chim, Shek

    AU - Kuek, V.

    AU - Chow, Siu To

    AU - Lim, B.

    AU - Tickner, Jennifer

    AU - Zhao, J.

    AU - Chung, R.

    AU - Su, Y.

    AU - Zhang, G.

    AU - Erber, Wendy

    AU - Xian, C.J.

    AU - Rosen, V.M.

    AU - Xu, Jiake

    PY - 2015/1

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    N2 - © 2014 Wiley Periodicals, Inc. Angiogenesis plays a pivotal role in bone formation, remodeling, and fracture healing. The regulation of angiogenesis in the bone microenvironment is highly complex and orchestrated by intercellular communication between bone cells and endothelial cells. Here, we report that EGF-like domain 7 (EGFL7), a member of the epidermal growth factor (EGF) repeat protein superfamily is expressed in both the osteoclast and osteoblast lineages, and promotes endothelial cell activities. Addition of exogenous recombinant EGFL7 potentiates SVEC (simian virus 40-transformed mouse microvascular endothelial cell line) cell migration and tube-like structure formation in vitro. Moreover, recombinant EGFL7 promotes angiogenesis featuring web-like structures in ex vivo fetal mouse metatarsal angiogenesis assay. We show that recombinant EGFL7 induces phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and focal adhesion kinase (FAK) in SVEC cells. Inhibition of ERK1/2 and STAT3 signaling impairs EGFL7-induced endothelial cell migration, and angiogenesis in fetal mouse metatarsal explants. Bioinformatic analyses indicate that EGFL7 contains a conserved RGD/QGD motif and EGFL7-induced endothelial cell migration is significantly reduced in the presence of RGD peptides. Moreover, EGFL7 gene expression is significantly upregulated during growth plate injury repair. Together, these results demonstrate that EGFL7 expressed by bone cells regulates endothelial cell activities through integrin-mediated signaling. This study highlights the important role that EGFL7, like EGFL6, expressed in bone microenvironment plays in the regulation of angiogenesis in bone.

    AB - © 2014 Wiley Periodicals, Inc. Angiogenesis plays a pivotal role in bone formation, remodeling, and fracture healing. The regulation of angiogenesis in the bone microenvironment is highly complex and orchestrated by intercellular communication between bone cells and endothelial cells. Here, we report that EGF-like domain 7 (EGFL7), a member of the epidermal growth factor (EGF) repeat protein superfamily is expressed in both the osteoclast and osteoblast lineages, and promotes endothelial cell activities. Addition of exogenous recombinant EGFL7 potentiates SVEC (simian virus 40-transformed mouse microvascular endothelial cell line) cell migration and tube-like structure formation in vitro. Moreover, recombinant EGFL7 promotes angiogenesis featuring web-like structures in ex vivo fetal mouse metatarsal angiogenesis assay. We show that recombinant EGFL7 induces phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and focal adhesion kinase (FAK) in SVEC cells. Inhibition of ERK1/2 and STAT3 signaling impairs EGFL7-induced endothelial cell migration, and angiogenesis in fetal mouse metatarsal explants. Bioinformatic analyses indicate that EGFL7 contains a conserved RGD/QGD motif and EGFL7-induced endothelial cell migration is significantly reduced in the presence of RGD peptides. Moreover, EGFL7 gene expression is significantly upregulated during growth plate injury repair. Together, these results demonstrate that EGFL7 expressed by bone cells regulates endothelial cell activities through integrin-mediated signaling. This study highlights the important role that EGFL7, like EGFL6, expressed in bone microenvironment plays in the regulation of angiogenesis in bone.

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