title: From bones to blood pressure, developing novel biologic approaches targeting the osteoprotegein pathway for pulmonary vascular disease.
abstract: 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.
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, Faculty of Medicine Dentistry and Health, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX,UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dawson
authors.affiliation: Department of Infection, Immunity and Cardiovascular Disease, Faculty of Medicine Dentistry and Health, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX,UK. Electronic address: a.lawrie@sheffield.ac.uk.
authors.forename: Allan
authors.initials: A
authors.lastname: Lawrie
mesh_terms: D000818:Animals; D001688:Biological Products / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D015195:Drug Design; D065627:Familial Primary Pulmonary Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D058990:Molecular Targeted Therapy; D010010:Osteoclasts / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D001688:Biological Products; D053244:Osteoprotegerin
keywords: Biologics; Bone; Osteoprotegerin; Pulmonary hypertension; Therapeutics; Vascular