osteoprotegerin and Familial-Primary-Pulmonary-Hypertension

Osteoprotegerin (tnfsf11b, OPG) is a soluble member of the TNF superfamily originally described as an important regulator of osteoclastogenesis almost 20years ago. OPG is a heparin-binding secreted glycoprotein that exists as a 55-62kDa monomer or a 110-120kDa disulphide-linked homodimer. Acting as a soluble decoy receptor for RANKL, OPG actively regulates RANK signalling, and thereby osteoclastogenesis. OPG has subsequently been shown to also be a decoy receptor TNF related apoptosis inducing-ligand (tnfsf10, TRAIL, Apo2L). TRAIL is a type II transmembrane protein that is widely expressed in a variety of human tissues, including the spleen, lung, and prostate. Through binding to TRAIL, OPG can inhibit TRAIL-induced apoptosis of cancer cells. More recently, OPG has been demonstrated to be secreted by, and influence, vascular smooth muscle cells phenotype particularly related to vascular calcification and pulmonary vascular remodelling. In pulmonary artery smooth muscle cell (PASMC) suppression of BMP, induction of 5-HT and IL-1 signalling have been shown to stimulate the release of OPG in vitro, which causes cell migration and proliferation. Patients with idiopathic PAH (IPAH) demonstrate increased circulating and tissue levels of OPG, and circulating serum levels predict survival. In pre-clinical models, OPG levels correlate with disease severity. Since OPG is a naturally circulating protein, we are investigating the potential of novel biologic antibody therapies to rescue PAH phenotype in disease models. Further pre-clinical and mechanistic data are forthcoming, but we believe current published data identify OPG as an exciting and novel therapeutic target in PAH.

Topics: Animals; Biological Products; Blood Pressure; Drug Design; Familial Primary Pulmonary Hypertension; Humans; Molecular Targeted Therapy; Osteoclasts; Osteoprotegerin; Severity of Illness Index

Pulmonary arterial hypertension (PAH) is a fatal condition driven by a progressive remodelling of the small pulmonary arteries through sustained vasoconstriction, and vascular cell proliferation. This process causes a substantial reduction in luminal area increasing pulmonary vascular resistance and blood pressure leading to right heart failure. Current medical therapies can alleviate some symptoms and reduce the vasoconstrictive aspects of disease but new treatments are required that target the vascular cell proliferation if we are to develop new therapies. Expression of the tumour necrosis factor related apoptosis-inducing ligand (TRAIL) and osteoprotegerin (OPG) proteins are increased in IPAH. Specifically OPG is increased within the serum of patients with idiopathic pulmonary arterial hypertension (IPAH) and has prognostic utility, and both OPG and TRAIL are increased within pulmonary vascular lesions of patients with IPAH, and are mitogens for pulmonary artery smooth muscle cells in vitro. We have demonstrated that genetic deletion, or antibody blockade of TRAIL prevents, and critically reverses the development of PAH in multiple rodent models. The role OPG plays in this process both through interacting with TRAIL, and indirectly through other mechanisms is currently unclear these but data highlight the critical importance of this pathway in PAH pathogenesis, and its potential for future therapies.

Topics: Animals; Familial Primary Pulmonary Hypertension; Humans; Myocytes, Smooth Muscle; Osteoprotegerin; TNF-Related Apoptosis-Inducing Ligand

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.

Topics: Animals; Antibodies; Cell Movement; Disease Models, Animal; Familial Primary Pulmonary Hypertension; Humans; Male; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Osteoprotegerin; Protein Binding; Pulmonary Artery; Rats; Rats, Wistar; Vascular Remodeling