Influence of osteoclasts and osteoprotegerin on the mode of calcific degeneration of aortic valves.

Abstract

Calcific aortic valve disease is associated with inflammation and calcification, thus the osteoprotegerin (OPG), receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) system involved in osteoclastogenesis and inflammation may play a significant role in valve degeneration. The aim of this study was to assess whether circulating OPG, sRANKL, and other bone metabolism markers can predict the presence of osteoclasts in stenotic valves and to evaluate their impact on the mode of degeneration. The study involved 60 patients with aortic stenosis who underwent valve replacement surgery and subsequently were divided into 2 groups: osteoclastic (n = 12) and nonosteoclastic (n = 48), according to the presence or absence of intravalvular osteoclasts. Before the surgery, we measured serum levels of OPG, sRANKL, osteocalcin, osteopontin, tumor necrosis factor α (TNF-α), interleukin (IL) 1β, and IL-6. Immunohistochemistry and morphometry were used to determine the extent of valve calcification, lipid accumulation, neovascularization, and the number and phenotype of macrophages. Compared with the nonosteoclastic group, patients with intravalvular osteoclasts had lower levels of OPG (P = 0.0006) and TNF-α (P = 0.02) and less frequently had diabetes (P = 0.04). Their valves showed higher incidence of ossification (P = 0.002), higher total (P = 0.008) and M2 macrophage counts (P = 0.0002), increased neovascularization (P = 0.003), and lower accumulation of lipids (P = 0.04). They also showed a negative correlation between valve calcification and age (r = -0.79, P = 0.002), which was not observed in patients without osteoclasts. In a multivariate analysis, low circulating OPG levels and the absence of diabetes were predictors of intravalvular osteoclastic differentiation. The presence of osteoclasts in stenotic valves associated with low circulating OPG levels and an enhanced proportion of M2 macrophages can represent a variant of calcific aortic valve disease with a specifically regulated calcification process.