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Research ArticleDrug Discovery and Translational Medicine

Osteogenic Effects of a Potent Src-over-Abl-Selective Kinase Inhibitor in the Mouse

Richard J. Murrills, Shoichi Fukayama, Frank Boschelli, Jeanne J. Matteo, Jane Owens, Jennifer M. Golas, Dharmesh Patel, Giovan Lane, Yao-Bin Liu, Laura Carter, Jason Jussif, Vikki Spaulding, Yanong D. Wang, Diane H. Boschelli, John C. McKew, X. Jian Li, Susan Lockhead, Colleen Milligan, Yogendra P. Kharode, Veronica Diesl, Yuchen Bai, Max Follettie, Frederick J. Bex, Barry Komm and Peter V. N. Bodine
Journal of Pharmacology and Experimental Therapeutics March 2012, 340 (3) 676-687; DOI: https://doi.org/10.1124/jpet.111.185793
Richard J. Murrills
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Shoichi Fukayama
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Frank Boschelli
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Jeanne J. Matteo
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Jane Owens
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Jennifer M. Golas
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Dharmesh Patel
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Giovan Lane
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Yao-Bin Liu
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Laura Carter
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Jason Jussif
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Vikki Spaulding
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Yanong D. Wang
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Diane H. Boschelli
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John C. McKew
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X. Jian Li
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Susan Lockhead
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Colleen Milligan
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Yogendra P. Kharode
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Veronica Diesl
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Yuchen Bai
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Max Follettie
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Frederick J. Bex
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Barry Komm
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Abstract

Src-null mice have higher bone mass because of decreased bone resorption and increased bone formation, whereas Abl-null mice are osteopenic, because of decreased bone formation. Compound I, a potent inhibitor of Src in an isolated enzyme assay (IC50 0.55 nM) and a Src-dependent cell growth assay, with lower activity on equivalent Abl-based assays, potently, but biphasically, accelerated differentiation of human mesenchymal stem cells to an osteoblast phenotype (1–10 nM). Compound I (≥0.1 nM) also activated osteoblasts and induced bone formation in isolated neonatal mouse calvariae. Compound I required higher concentrations (100 nM) to inhibit differentiation and activity of osteoclasts. Transcriptional profiling (TxP) of calvaria treated with 1 μM compound I revealed down-regulation of osteoclastic genes and up-regulation of matrix genes and genes associated with the osteoblast phenotype, confirming compound I's dual effects on bone resorption and formation. In addition, calvarial TxP implicated calcitonin-related polypeptide, β (β-CGRP) as a potential mediator of compound I's osteogenic effect. In vivo, compound I (1 mg/kg s.c.) increased vertebral trabecular bone volume 21% (microcomputed tomography) in intact female mice. Increased trabecular volume was also detected histologically in a separate bone, the femur, particularly in the secondary spongiosa (100% increase), which underwent a 171% increase in bone formation rate, a 73% increase in mineralizing surface, and a 59% increase in mineral apposition rate. Similar effects were observed in ovariectomized mice with established osteopenia. We conclude that the Src inhibitor compound I is osteogenic, presumably because of its potent stimulation of osteoblast differentiation and activation, possibly mediated by β-CGRP.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.185793.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    RANK
    receptor activator of nuclear factor κ-B
    rhRANKL
    recombinant human RANK ligand
    DMSO
    dimethyl sulfoxide
    BSA
    bovine serum albumin
    CT
    computed tomography
    μCT
    microCT
    rhM-CSF
    recombinant human macrophage colony-stimulating factor
    hMSC
    human mesenchymal stem cells
    4-MUP
    4-methylumbelliferyl phosphate
    OVX
    ovariectomized
    TRAP
    tartrate-resistant acid phosphatase
    ANOVA
    analysis of variance
    PTH
    parathyroid hormone
    β-CGRP
    calcitonin-related polypeptide, β
    SFK
    Src family kinase
    IL
    interleukin
    GSEA
    gene set enrichment analysis
    ES
    enrichment score
    OPG
    osteoprotegerin
    OCP
    osteoclast precursor
    BV
    bone volume
    TV
    total volume
    BS
    bone surface
    Tb.Th
    trabecular thickness
    Tb.N
    trabecular number
    Tb.Sp
    trabecular separation
    Conn.Den
    connectivity density
    GPCR
    G protein-coupled receptor.

  • Received July 5, 2011.
  • Accepted December 6, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 340 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 340, Issue 3
1 Mar 2012
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Research ArticleDrug Discovery and Translational Medicine

Osteogenic Src Inhibitor

Richard J. Murrills, Shoichi Fukayama, Frank Boschelli, Jeanne J. Matteo, Jane Owens, Jennifer M. Golas, Dharmesh Patel, Giovan Lane, Yao-Bin Liu, Laura Carter, Jason Jussif, Vikki Spaulding, Yanong D. Wang, Diane H. Boschelli, John C. McKew, X. Jian Li, Susan Lockhead, Colleen Milligan, Yogendra P. Kharode, Veronica Diesl, Yuchen Bai, Max Follettie, Frederick J. Bex, Barry Komm and Peter V. N. Bodine
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 676-687; DOI: https://doi.org/10.1124/jpet.111.185793

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Research ArticleDrug Discovery and Translational Medicine

Osteogenic Src Inhibitor

Richard J. Murrills, Shoichi Fukayama, Frank Boschelli, Jeanne J. Matteo, Jane Owens, Jennifer M. Golas, Dharmesh Patel, Giovan Lane, Yao-Bin Liu, Laura Carter, Jason Jussif, Vikki Spaulding, Yanong D. Wang, Diane H. Boschelli, John C. McKew, X. Jian Li, Susan Lockhead, Colleen Milligan, Yogendra P. Kharode, Veronica Diesl, Yuchen Bai, Max Follettie, Frederick J. Bex, Barry Komm and Peter V. N. Bodine
Journal of Pharmacology and Experimental Therapeutics March 1, 2012, 340 (3) 676-687; DOI: https://doi.org/10.1124/jpet.111.185793
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