3 years ago

From bones to blood pressure, developing novel biologic approaches targeting the osteoprotegein pathway for pulmonary vascular disease

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.

Publisher URL: www.sciencedirect.com/science

DOI: S0163725816301073

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.