title: Evidence of a role for osteoprotegerin in the pathogenesis of pulmonary arterial hypertension.
abstract: Pulmonary artery smooth muscle cell (PA-SMC) migration and proliferation are key processes in the pathogenesis of pulmonary arterial hypertension (PAH). Recent information suggests that abnormalities in the bone morphogenetic protein (BMP) receptor 2 (BMP-R2) signaling pathway are important in PAH pathogenesis. It remains unclear whether and how this pathway interacts with, for example, serotonin (5-HT) and inflammation to trigger and/or sustain the development of PAH. The secreted glycoprotein osteoprotegerin (OPG) is emerging as an important regulatory molecule in vascular biology and is modulated by BMPs, 5-HT, and interleukin-1 in other cell types. However, whether OPG is expressed by PA-SMCs within PAH lesions and plays a role in PAH is unknown. Immunohistochemistry of human PAH lesions demonstrated increased OPG expression, and OPG was significantly increased in idiopathic PAH patient serum. Recombinant OPG stimulated proliferation and migration of PA-SMCs in vitro, and BMP-R2 RNA interference increased OPG secretion. Additionally, both 5-HT and interleukin-1 also increased OPG secretion. These data are the first to demonstrate that OPG is increased in PAH and that it can regulate PA-SMC proliferation and migration. OPG may provide a common link between the different pathways associated with the disease, potentially playing an important role in the pathogenesis of PAH.
authors.affiliation: Cardiovascular Research Unit, University of Sheffield School of Medicine and Biomedical Sciences, LU123, L-Floor Royal Hallamshire Hospital, Glossop Rd., Sheffield, S10 2JF, UK. a.lawrie@sheffield.ac.uk
authors.forename: Allan
authors.initials: A
authors.lastname: Lawrie
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Waterman
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.forename: David
authors.initials: D
authors.lastname: Evans
authors.forename: Jay
authors.initials: J
authors.lastname: Suntharalingam
authors.forename: Sheila
authors.initials: S
authors.lastname: Francis
authors.forename: David
authors.initials: D
authors.lastname: Crossman
authors.forename: Peter
authors.initials: P
authors.lastname: Croucher
authors.forename: Nicholas
authors.initials: N
authors.lastname: Morrell
authors.forename: Christopher
authors.initials: C
authors.lastname: Newman
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology*; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D053244:Osteoprotegerin / Q000378:metabolism / Q000502:physiology*; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology
chemical_list: D007375:Interleukin-1; D053244:Osteoprotegerin