Published online before print December 21, 2007

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070395

Accepted for publication September 18, 2007.

Article

Evidence of a Role for Osteoprotegerin in the Pathogenesis of Pulmonary Arterial Hypertension

Allan Lawrie^*@, Elizabeth Waterman, Mark Southwood, David Evans^*, Jay Suntharalingam, Sheila Francis^*, David Crossman^*, Peter Croucher, Nicholas Morrell, and Christopher Newman^*

From the Cardiovascular Research Unit,* Academic Unit of Urology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield; the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge; and the Academic Unit of Bone Biology, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom

^@ To whom correspondence should be addressed. E-mail: a.lawrie{at}sheffield.ac.uk.

	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.

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