Early activation of the beta-catenin pathway in osteocytes is mediated by nitric oxide, phosphatidyl inositol-3 kinase/Akt, and focal adhesion kinase

A. Santos, A.D. Bakker, B. Zandieh Doulabi, J.M.A. de Blieck-Hogervorst, J. Klein-Nulend

    Research output: Contribution to JournalArticleAcademicpeer-review

    Abstract

    Bone mechanotransduction is vital for skeletal integrity. Osteocytes are thought to be the cellular structures that sense physical forces and transform these signals into a biological response. The Wnt/β-catenin signaling pathway has been identified as one of the signaling pathways that is activated in response to mechanical loading, but the molecular events that lead to an activation of this pathway in osteocytes are not well understood. We assessed whether nitric oxide, focal adhesion kinase, and/or the phosphatidyl inositol-3 kinase/Akt signaling pathway mediate loading-induced β-catenin pathway activation in MLO-Y4 osteocytes. We found that mechanical stimulation by pulsating fluid flow (PFF, 0.7 ± 0.3 Pa, 5 Hz) for 30 min induced β-catenin stabilization and activation of the Wnt/β-catenin signaling pathway. The PFF-induced stabilization of β-catenin and activation of the β-catenin signaling pathway was abolished by adding focal kinase inhibitor FAK inhibitor-14 (50 μM), or phosphatidyl inositol-3 kinase inhibitor LY-294002 (50 μM). Addition of nitric oxide synthase inhibitor l-NAME (1.0 mM) also abolished PFF-induced stabilization of β-catenin. This suggests that mechanical loading activates the β-catenin signaling pathway by a mechanism involving nitric oxide, focal adhesion kinase, and the Akt signaling pathway. These data provide a framework for understanding the role of β-catenin in mechanical adaptation of bone. © 2009 Elsevier Inc. All rights reserved.
    Original languageEnglish
    Pages (from-to)364-369
    JournalBiochemical and Biophysical Research Communications
    Volume391
    Issue number1
    DOIs
    Publication statusPublished - 2010

    Fingerprint

    Osteocytes
    Catenins
    Focal Adhesion Protein-Tyrosine Kinases
    beta Catenin
    Phosphatidylinositols
    Nitric Oxide
    Phosphotransferases
    Chemical activation
    Wnt Signaling Pathway
    Stabilization
    Bone
    Bone and Bones
    Pulsatile Flow
    2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
    Cellular Structures
    Nitric Oxide Synthase
    Flow of fluids

    Cite this

    Santos, A. ; Bakker, A.D. ; Zandieh Doulabi, B. ; de Blieck-Hogervorst, J.M.A. ; Klein-Nulend, J. / Early activation of the beta-catenin pathway in osteocytes is mediated by nitric oxide, phosphatidyl inositol-3 kinase/Akt, and focal adhesion kinase. In: Biochemical and Biophysical Research Communications. 2010 ; Vol. 391, No. 1. pp. 364-369.
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    abstract = "Bone mechanotransduction is vital for skeletal integrity. Osteocytes are thought to be the cellular structures that sense physical forces and transform these signals into a biological response. The Wnt/β-catenin signaling pathway has been identified as one of the signaling pathways that is activated in response to mechanical loading, but the molecular events that lead to an activation of this pathway in osteocytes are not well understood. We assessed whether nitric oxide, focal adhesion kinase, and/or the phosphatidyl inositol-3 kinase/Akt signaling pathway mediate loading-induced β-catenin pathway activation in MLO-Y4 osteocytes. We found that mechanical stimulation by pulsating fluid flow (PFF, 0.7 ± 0.3 Pa, 5 Hz) for 30 min induced β-catenin stabilization and activation of the Wnt/β-catenin signaling pathway. The PFF-induced stabilization of β-catenin and activation of the β-catenin signaling pathway was abolished by adding focal kinase inhibitor FAK inhibitor-14 (50 μM), or phosphatidyl inositol-3 kinase inhibitor LY-294002 (50 μM). Addition of nitric oxide synthase inhibitor l-NAME (1.0 mM) also abolished PFF-induced stabilization of β-catenin. This suggests that mechanical loading activates the β-catenin signaling pathway by a mechanism involving nitric oxide, focal adhesion kinase, and the Akt signaling pathway. These data provide a framework for understanding the role of β-catenin in mechanical adaptation of bone. {\circledC} 2009 Elsevier Inc. All rights reserved.",
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    Early activation of the beta-catenin pathway in osteocytes is mediated by nitric oxide, phosphatidyl inositol-3 kinase/Akt, and focal adhesion kinase. / Santos, A.; Bakker, A.D.; Zandieh Doulabi, B.; de Blieck-Hogervorst, J.M.A.; Klein-Nulend, J.

    In: Biochemical and Biophysical Research Communications, Vol. 391, No. 1, 2010, p. 364-369.

    Research output: Contribution to JournalArticleAcademicpeer-review

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    AB - Bone mechanotransduction is vital for skeletal integrity. Osteocytes are thought to be the cellular structures that sense physical forces and transform these signals into a biological response. The Wnt/β-catenin signaling pathway has been identified as one of the signaling pathways that is activated in response to mechanical loading, but the molecular events that lead to an activation of this pathway in osteocytes are not well understood. We assessed whether nitric oxide, focal adhesion kinase, and/or the phosphatidyl inositol-3 kinase/Akt signaling pathway mediate loading-induced β-catenin pathway activation in MLO-Y4 osteocytes. We found that mechanical stimulation by pulsating fluid flow (PFF, 0.7 ± 0.3 Pa, 5 Hz) for 30 min induced β-catenin stabilization and activation of the Wnt/β-catenin signaling pathway. The PFF-induced stabilization of β-catenin and activation of the β-catenin signaling pathway was abolished by adding focal kinase inhibitor FAK inhibitor-14 (50 μM), or phosphatidyl inositol-3 kinase inhibitor LY-294002 (50 μM). Addition of nitric oxide synthase inhibitor l-NAME (1.0 mM) also abolished PFF-induced stabilization of β-catenin. This suggests that mechanical loading activates the β-catenin signaling pathway by a mechanism involving nitric oxide, focal adhesion kinase, and the Akt signaling pathway. These data provide a framework for understanding the role of β-catenin in mechanical adaptation of bone. © 2009 Elsevier Inc. All rights reserved.

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