Lis Grzegorz J, Czubek Urszula, Jasek-Gajda Ewa, Łoboda Agnieszka, Dulak Józef, Nessler Jadwiga, Kapelak Bogusław, Sadowski Jerzy, Litwin Jan A
Pol Arch Med Wewn. 2016;126(3):149-58. doi: 10.20452/pamw.3326. Epub 2016 Mar 22.
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.
钙化性主动脉瓣疾病与炎症和钙化相关，因此参与破骨细胞生成和炎症的骨保护素（OPG）、核因子κB受体激活剂（RANK）及其配体（RANKL）系统可能在瓣膜退变中起重要作用。
本研究旨在评估循环中的OPG、可溶性RANKL（sRANKL）和其他骨代谢标志物是否能预测狭窄瓣膜中破骨细胞的存在，并评估它们对退变模式的影响。
本研究纳入60例行瓣膜置换手术的主动脉瓣狭窄患者，随后根据瓣膜内是否存在破骨细胞分为两组：有破骨细胞组（n = 12）和无破骨细胞组（n = 48）。手术前，我们检测了血清中OPG、sRANKL、骨钙素、骨桥蛋白、肿瘤坏死因子α（TNF-α）、白细胞介素（IL）1β和IL-6的水平。采用免疫组织化学和形态计量学方法确定瓣膜钙化、脂质蓄积、新生血管形成的程度，以及巨噬细胞的数量和表型。
与无破骨细胞组相比，瓣膜内有破骨细胞的患者OPG水平较低（P = 0.0006）和TNF-α水平较低（P = 0.02），患糖尿病的频率较低（P = 0.04）。他们的瓣膜骨化发生率较高（P = 0.002），总巨噬细胞计数（P = 0.008）和M2巨噬细胞计数较高（P = 0.0002），新生血管形成增加（P = 0.003），脂质蓄积较少（P = 0.04）。他们还显示瓣膜钙化与年龄呈负相关（r = -0.79，P = 0.002），而在无破骨细胞的患者中未观察到这种相关性。在多变量分析中，循环OPG水平低和无糖尿病是瓣膜内破骨细胞分化的预测因素。
狭窄瓣膜中存在破骨细胞，伴有循环OPG水平低和M2巨噬细胞比例增加，可能代表钙化性主动脉瓣疾病中一种具有特定调节钙化过程的变异型。
