A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

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.

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Item Type:	Article
Authors/Creators:	Arnold, N.D. https://orcid.org/0000-0002-4317-5738 Pickworth, J.A. https://orcid.org/0000-0002-7199-364X West, L.E. Dawson, S. Carvalho, J.A. Casbolt, H. Braithwaite, A.T. https://orcid.org/0000-0003-3228-2172 Iremonger, J. Renshall, L. Germaschewski, V. McCourt, M. Bland-Ward, P. Kowash, H. Hameed, A.G. https://orcid.org/0000-0002-2128-2081 Rothman, A.M.K. https://orcid.org/0000-0002-7847-4500 Frid, M.G. Roger Thompson, A.A. Evans, H.R. Southwood, M. Morrell, N.W. Crossman, D.C. Whyte, M.K.B. Stenmark, K.R. Newman, C.M. Kiely, D.G. https://orcid.org/0000-0003-0184-6502 Francis, S.E. https://orcid.org/0000-0001-6552-0339 Lawrie, A. https://orcid.org/0000-0003-4192-9505
Copyright, Publisher and Additional Information:	© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 23 October 2019 Published (online): 15 November 2019 Published: 15 November 2019
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Funding Information:	Funder Grant number BRITISH HEART FOUNDATION FS/13/48/30453 MEDICAL RESEARCH COUNCIL MR/L023040/1 MEDICAL RESEARCH COUNCIL G0800318/1 MEDICAL RESEARCH COUNCIL MR/L023040/1 BRITISH HEART FOUNDATION 33808 BRITISH HEART FOUNDATION FS/18/13/33281
Depositing User:	Symplectic Sheffield
Date Deposited:	02 Dec 2019 10:12
Last Modified:	02 Dec 2019 10:13
Status:	Published
Publisher:	Nature Research
Refereed:	Yes
Identification Number:	10.1038/s41467-019-13139-9
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:153921

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A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

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