HMGB1 Induces Secretion of Matrix Vesicles by Macrophages to Enhance Ectopic Mineralization.
HMGB1 Induces Secretion of Matrix Vesicles by Macrophages to Enhance Ectopic Mineralization.
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HMGB1 诱导巨噬细胞分泌基质囊泡以增强异位矿化
DOI：
10.1371/journal.pone.0156686
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hu HY
中科院分区：
文献类型：
--
作者：
Chen Q;Bei JJ;Liu C;Feng SB;Zhao WB;Zhou Z;Yu ZP;Du XJ;Hu HY
许多临床状况与异位矿化（EM）有关。这种病理性生物矿化过程是复杂的，尚未完全阐明，但认为是在基质囊泡（MV）内开始的。我们推测高迁移率族蛋白1（HMGB 1）是一种与生理和病理条件下的生物矿化过程相关的细胞因子，通过促进巨噬细胞分泌MVs诱导EM。在这项研究中，我们发现HMGB 1显着促进巨噬细胞的MV分泌，随后导致矿物质沉积在高Ca/Pi培养基中。钙化MV的透射电子显微镜显示囊泡内部形成羟基磷灰石晶体。皮下注射HMGB 1处理的细胞衍生的MV到小鼠中显示出更大的启动区域矿化的潜力。机制实验表明，HMGB 1激活中性鞘磷脂酶2（nSMase 2），涉及晚期糖基化终产物（AGEs）受体和p38 MAPK（nSMase 2上游）。用GW 4869抑制nSM酶2或用SB-239063抑制p38 MAPK可防止MV分泌和矿物质沉积。总的来说，HMGB 1至少部分通过RAGE/p38 MAPK/nSMase 2信号通路诱导巨噬细胞分泌MV。因此，我们的研究结果揭示了一种新的机制，HMGB 1诱导异位矿化。
Numerous clinical conditions have been linked to ectopic mineralization (EM). This process of pathological biomineralization is complex and not fully elucidated, but thought to be started within matrix vesicles (MVs). We hypothesized that high mobility group box 1 (HMGB1), a cytokine associated with biomineralizing process under physiological and pathological conditions, induces EM via promoting MVs secretion from macrophages. In this study, we found that HMGB1 significantly promoted secretion of MVs from macrophages and subsequently led to mineral deposition in elevated Ca/Pi medium in vitro. Transmission electron microscopy of calcifying MVs showed formation of hydroxyapatite crystals in the vesicle interior. Subcutaneous injection into mice with MVs derived from HMGB1-treated cells showed a greater potential to initiate regional mineralization. Mechanistic experiments revealed that HMGB1 activated neutral sphingomyelinase2 (nSMase2) that involved the receptor for advanced glycation end products (RAGE) and p38 MAPK (upstream of nSMase2). Inhibition of nSMase2 with GW4869 or p38 MAPK with SB-239063 prevented MVs secretion and mineral deposition. Collectively, HMGB1 induces MVs secretion from macrophages at least in part, via the RAGE/p38 MAPK/nSMase2 signaling pathway. Our findings thus reveal a novel mechanism by which HMGB1 induces ectopic mineralization.