A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension

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...

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Published inNature communications Vol. 10; no. 1; pp. 5183 - 18
Main Authors Arnold, Nadine D., Pickworth, Josephine A., West, Laura E., Dawson, Sarah, Carvalho, Joana A., Casbolt, Helen, Braithwaite, Adam T., Iremonger, James, Renshall, Lewis, Germaschewski, Volker, McCourt, Matthew, Bland-Ward, Philip, Kowash, Hager, Hameed, Abdul G., Rothman, Alexander M. K., Frid, Maria G., Roger Thompson, A. A., Evans, Holly R., Southwood, Mark, Morrell, Nicholas W., Crossman, David C., Whyte, Moira K. B., Stenmark, Kurt R., Newman, Christopher M., Kiely, David G., Francis, Sheila E., Lawrie, Allan
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 15.11.2019
Nature Publishing Group
Nature Portfolio
Subjects
13
13/95
38
64/110
64/60
64/86
692/308/153
692/699/75
96/1
Animal models
Animals
Antibodies
Antibodies - administration & dosage
Biomedical materials
Cell Movement - drug effects
Disease control
Disease Models, Animal
Familial Primary Pulmonary Hypertension - drug therapy
Familial Primary Pulmonary Hypertension - genetics
Familial Primary Pulmonary Hypertension - metabolism
Familial Primary Pulmonary Hypertension - physiopathology
Humanities and Social Sciences
Humans
Hypertension
Life expectancy
Life span
Male
Mice
Mice, Inbred C57BL
multidisciplinary
Muscles
Myocytes, Smooth Muscle - cytology
Myocytes, Smooth Muscle - metabolism
Osteoprotegerin
Osteoprotegerin - genetics
Osteoprotegerin - metabolism
Phenotypes
Protein Binding
Pulmonary arteries
Pulmonary artery
Pulmonary Artery - cytology
Pulmonary Artery - metabolism
Pulmonary Artery - physiopathology
Pulmonary hypertension
Rats
Rats, Wistar
Science
Science (multidisciplinary)
Smooth muscle
Therapeutic applications
Vascular Remodeling - drug effects
Online AccessGet full text
ISSN2041-1723
2041-1723
DOI10.1038/s41467-019-13139-9

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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. Pulmonary arterial hypertension (PAH) is characterised by progressive pulmonary vascular remodelling. Here, Arnold et al. develop a therapeutic antibody targeting osteoprotegerin and find it attenuates pulmonary vascular remodelling in multiple rodent models of PAH, alone or in combination with standard of care vasodilator therapy.
AbstractList 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. Pulmonary arterial hypertension (PAH) is characterised by progressive pulmonary vascular remodelling. Here, Arnold et al. develop a therapeutic antibody targeting osteoprotegerin and find it attenuates pulmonary vascular remodelling in multiple rodent models of PAH, alone or in combination with standard of care vasodilator therapy.
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.
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. Pulmonary arterial hypertension (PAH) is characterised by progressive pulmonary vascular remodelling. Here, Arnold et al. develop a therapeutic antibody targeting osteoprotegerin and find it attenuates pulmonary vascular remodelling in multiple rodent models of PAH, alone or in combination with standard of care vasodilator therapy.
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.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.
Pulmonary arterial hypertension (PAH) is characterised by progressive pulmonary vascular remodelling. Here, Arnold et al. develop a therapeutic antibody targeting osteoprotegerin and find it attenuates pulmonary vascular remodelling in multiple rodent models of PAH, alone or in combination with standard of care vasodilator therapy.
ArticleNumber 5183
Author West, Laura E.
Carvalho, Joana A.
Casbolt, Helen
Whyte, Moira K. B.
Morrell, Nicholas W.
Renshall, Lewis
Southwood, Mark
Stenmark, Kurt R.
Iremonger, James
Bland-Ward, Philip
Newman, Christopher M.
Dawson, Sarah
Frid, Maria G.
Germaschewski, Volker
Rothman, Alexander M. K.
Hameed, Abdul G.
Crossman, David C.
Arnold, Nadine D.
Evans, Holly R.
Roger Thompson, A. A.
McCourt, Matthew
Pickworth, Josephine A.
Kowash, Hager
Braithwaite, Adam T.
Lawrie, Allan
Kiely, David G.
Francis, Sheila E.
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/31729368$$D View this record in MEDLINE/PubMed
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SSID ssj0000391844
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Snippet Pulmonary arterial hypertension (PAH) is a rare but fatal disease. Current treatments increase life expectancy but have limited impact on the progressive...
Pulmonary arterial hypertension (PAH) is characterised by progressive pulmonary vascular remodelling. Here, Arnold et al. develop a therapeutic antibody...
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StartPage 5183
SubjectTerms 13
13/95
38
64/110
64/60
64/86
692/308/153
692/699/75
96/1
Animal models
Animals
Antibodies
Antibodies - administration & dosage
Biomedical materials
Cell Movement - drug effects
Disease control
Disease Models, Animal
Familial Primary Pulmonary Hypertension - drug therapy
Familial Primary Pulmonary Hypertension - genetics
Familial Primary Pulmonary Hypertension - metabolism
Familial Primary Pulmonary Hypertension - physiopathology
Humanities and Social Sciences
Humans
Hypertension
Life expectancy
Life span
Male
Mice
Mice, Inbred C57BL
multidisciplinary
Muscles
Myocytes, Smooth Muscle - cytology
Myocytes, Smooth Muscle - metabolism
Osteoprotegerin
Osteoprotegerin - genetics
Osteoprotegerin - metabolism
Phenotypes
Protein Binding
Pulmonary arteries
Pulmonary artery
Pulmonary Artery - cytology
Pulmonary Artery - metabolism
Pulmonary Artery - physiopathology
Pulmonary hypertension
Rats
Rats, Wistar
Science
Science (multidisciplinary)
Smooth muscle
Therapeutic applications
Vascular Remodeling - drug effects
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Title A therapeutic antibody targeting osteoprotegerin attenuates severe experimental pulmonary arterial hypertension
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