A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension
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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.
Arnold , N D , Pickworth , J A , West , L E , Dawson , S , Carvalho , J A , Casbolt , H , Braithwaite , A T , Iremonger , J , Renshall , L , Germaschewski , V , McCourt , M , Bland-Ward , P , Kowash , H , Hameed , A G , Rothman , A M K , 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 , Francis , S E & Lawrie , A 2019 , ' A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension ' , Nature Communications , vol. 10 , 5183 . https://doi.org/10.1038/s41467-019-13139-9
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DescriptionFunding for this study was provided by a British Heart Foundation Senior Basic Science Research Fellow (FS/13/48/30453 and FS/18/52/33808, AL), Medical Research Council Career Development Award (G0800318, AL); Medical Research Council Confidence In Concepts (MC/PC12022), Medical Research Council Developmental Pathway Funding Scheme (MR/L023040/1), British Heart Foundation Clinical Research Training Fellowship (FS/08/061/25740, AGH); Medical Research Council Clinical Research Training Fellowship (MR/K002406/1) and Wellcome Trust Clinical Research Career Development Fellowship (206632/Z/17/Z), AMKR, British Heart Foundation Intermediate Clinical Fellowship (FS/18/13/33281, AART), National Institute for Health Research Sheffield Cardiovascular Biomedical Research Unit (NA/JP/DC); Cambridge National Institute of Health Research Biomedical Research Centre.
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