Institute for Cardiogenetics, Universität zu Lübeck; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany, University Heart Centre Lübeck, 23562, Lübeck, Germany.
Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
Sci Rep. 2018 Apr 11;8(1):5812. doi: 10.1038/s41598-018-24228-y.
Cardiovascular calcification is associated with high risk of vascular disease. This involves macrophage infiltration of injured vascular tissue and osteoclast-related processes. Splenic monocytes from mice, that are predisposed (C3H) or resistant (B6) to calcification, were isolated and differentiated in vitro with M-CSF to generate macrophages, which aggregate to form multinucleated (MN) cells in the presence of RANKL. MN cell formation was significantly decreased in monocytes from resistant compared with calcifying mice. Conditioned media from C3H macrophages strongly induced calcification in vitro. However, medium from B6 macrophages inhibited calcification. An increase in ICAM-1 was detected in conditioned media from C3H macrophages compared with B6, suggesting a key role for this molecule in calcification processes. Due to natural genetic loss of Abcc6, the causal gene for cardiac calcification, C3H mice have reduced plasma levels of inorganic pyrophosphate (PPi), a potential calcification inhibitor. Supplementation of C3H mice with PPi or Etidronate prevented but did not completely reverse cardiac calcification. Our data provide strong evidence of the pathogenesis of macrophages and MNs during tissue calcification and suggest PPi or its analogue Etidronate as a potential inhibitor of MN formation and calcification. Furthermore, the adhesion molecule ICAM-1 was shown to play a key role in calcification.
心血管钙化与血管疾病的高风险相关。这涉及到巨噬细胞浸润受损的血管组织和破骨细胞相关的过程。易发生（C3H）或抵抗（B6）钙化的小鼠脾脏单核细胞被分离并在体外用 M-CSF 分化为巨噬细胞，在存在 RANKL 的情况下，这些巨噬细胞聚集形成多核（MN）细胞。与易发生钙化的小鼠相比，来自抵抗钙化小鼠的单核细胞中 MN 细胞的形成明显减少。来自 C3H 巨噬细胞的条件培养基在体外强烈诱导钙化。然而，B6 巨噬细胞的培养基抑制了钙化。与 B6 相比，C3H 巨噬细胞的条件培养基中检测到 ICAM-1 的增加，表明该分子在钙化过程中起关键作用。由于心脏钙化的致病基因 Abcc6 的自然遗传缺失，C3H 小鼠的血浆无机焦磷酸盐（PPi）水平降低，PPi 是一种潜在的钙化抑制剂。用 PPi 或依替膦酸补充 C3H 小鼠可预防但不能完全逆转心脏钙化。我们的数据提供了组织钙化过程中巨噬细胞和 MN 的发病机制的有力证据，并表明 PPi 或其类似物依替膦酸可能是 MN 形成和钙化的潜在抑制剂。此外，黏附分子 ICAM-1 被证明在钙化中起关键作用。
