Osteoprotegerin affects clinical phenotypes and cell biology in lymphangioleiomyomatosis (LAM)

Wednesday, October 26, 2011 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center	NHLBI	CLIN/CULT/AGING/DISPREV-26

Authors

• W Steagall
• G Pacheco-Rodriguez
• C Glasgow
• Y Ikeda
• J Lin
• J Moss

Abstract

Osteoprotegerin, a soluble member of the tumor necrosis factor family of receptors, promotes smooth muscle cell proliferation and migration and may act as a survival factor for tumor cells. Lymphangioleiomyomatosis (LAM), a multisystem disease affecting primarily women, is caused by proliferation of smooth muscle-like cells (LAM cells) in lung, lymphatics, and kidneys, resulting in cystic lung destruction, chylous effusions, and angiomyolipomas. We investigated the role of osteoprotegerin in the pathogenesis of lymphangioleiomyomatosis. Concentrations of osteoprotegerin were significantly higher in serum from lymphangioleiomyomatosis patients than healthy volunteers. Polymorphisms in the osteoprotegerin gene were associated with both susceptibility to disease and multiple functional manifestations, such as rates of decline in both FEV1 and DLCO. Osteoprotegerin stimulated proliferation of cells cultured from explanted LAM lungs, and specifically induced migration of LAM cells with loss of heterozygosity for the Tuberous Sclerosis Complex-2 (TSC2) gene. Cells with TSC2 loss of heterozygosity contained osteoprotegerin receptors. Reactivities to anti-osteoprotegerin and anti-gp100 antibodies colocalized in LAM lung nodules. Osteoprotegerin mRNA was expressed by LAM lung nodules. Osteoprotegerin may have multiple roles in the pathogenesis of lymphangioleiomyomatosis, serving as both an autocrine and systemic factor.

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