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.
Highlights
Pulmonary arterial hypertension (PAH) is a rare but fatal disease
Since OPG is linked with bone remodelling[20] we examined whether antibody blockade of OPG would induce an osteoporotic phenotype but no detrimental effect of the anti-OPG antibody treatment was observed on either bone volume, trabecular number or trabecular thickness as assessed by microCT analysis (Fig. 1m–o)
We sought to investigate candidate bone marrow-derived cell-types that could release OPG and drive the PAH pathophysiology. Since both endothelial[21] and mesenchymal[22] progenitors have been implicated in PAH, and are present in remodelled arteries we investigated the expression of OPG in pulmonary artery smooth muscle cells (PASMCs) (SMC), pulmonary artery fibroblasts (PA-Fib) and fibrocytes isolated from the hypoxic neonatal calf model of PAH23 and blood outgrowth endothelial cells (BOEC)[24]
Summary
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). 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 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. Combination of current PAH therapies with our anti-OPG antibody demonstrated an improved response in both haemodynamics and pulmonary vascular remodelling over standard of care PAH therapies alone
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