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A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

Author

Listed:
  • Nadine D. Arnold

    (University of Sheffield)

  • Josephine A. Pickworth

    (University of Sheffield)

  • Laura E. West

    (University of Sheffield)

  • Sarah Dawson

    (University of Sheffield)

  • Joana A. Carvalho

    (Kymab Ltd, Babraham Research Campus)

  • Helen Casbolt

    (University of Sheffield)

  • Adam T. Braithwaite

    (University of Sheffield)

  • James Iremonger

    (University of Sheffield)

  • Lewis Renshall

    (University of Sheffield)

  • Volker Germaschewski

    (Kymab Ltd, Babraham Research Campus)

  • Matthew McCourt

    (Kymab Ltd, Babraham Research Campus)

  • Philip Bland-Ward

    (Kymab Ltd, Babraham Research Campus)

  • Hager Kowash

    (University of Sheffield)

  • Abdul G. Hameed

    (University of Sheffield)

  • Alexander M. K. Rothman

    (University of Sheffield)

  • Maria G. Frid

    (University of Colorado Anschutz Medical Campus)

  • A. A. Roger Thompson

    (University of Sheffield)

  • Holly R. Evans

    (University of Sheffield)

  • Mark Southwood

    (University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospital)

  • Nicholas W. Morrell

    (University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospital)

  • David C. Crossman

    (University of St. Andrews, St)

  • Moira K. B. Whyte

    (University of Edinburgh, The Queens Medical Research Institute)

  • Kurt R. Stenmark

    (University of Colorado Anschutz Medical Campus)

  • Christopher M. Newman

    (University of Sheffield)

  • David G. Kiely

    (University of Sheffield
    Sheffield Teaching Hospitals Foundation Trust, Royal Hallamshire Hospital)

  • Sheila E. Francis

    (University of Sheffield)

  • Allan Lawrie

    (University of Sheffield)

Abstract

Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive pulmonary vascular remodelling that drives PAH. Osteoprotegerin (OPG) is increased within serum and lesions of patients with idiopathic PAH and is a mitogen and migratory stimulus for pulmonary artery smooth muscle cells (PASMCs). Here, we report that the pro-proliferative and migratory phenotype in PASMCs stimulated with OPG is mediated via the Fas receptor and that treatment with a human antibody targeting OPG can attenuate pulmonary vascular remodelling associated with PAH in multiple rodent models of early and late treatment. We also demonstrate that the therapeutic efficacy of the anti-OPG antibody approach in the presence of standard of care vasodilator therapy is mediated by a reduction in pulmonary vascular remodelling. Targeting OPG with a therapeutic antibody is a potential treatment strategy in PAH.

Suggested Citation

  • Nadine D. Arnold & Josephine A. Pickworth & Laura E. West & Sarah Dawson & Joana A. Carvalho & Helen Casbolt & Adam T. Braithwaite & James Iremonger & Lewis Renshall & Volker Germaschewski & Matthew M, 2019. "A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13139-9
    DOI: 10.1038/s41467-019-13139-9
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