Calciprotein particles as potential etiologic agents of idiopathic preterm birth.
Calciprotein particles as potential etiologic agents of idiopathic preterm birth.
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钙蛋白颗粒作为特发性早产的潜在病因。
DOI：
10.1126/scitranslmed.aah4707
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发表时间：
2016
影响因子：
17.1
通讯作者：
Buhimschi,IrinaA
中科院分区：
文献类型：
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作者：
Shook,LydiaL;Buhimschi,CatalinS;Dulay,AntonetteT;McCarthy,MeganE;Hardy,JohnT;DuzyjBuniak,ChristinaM;Zhao,Guomao;Buhimschi,IrinaA
早产（PTB）是新生儿发病率和死亡率的主要原因，并且通常在没有可识别原因的早产胎膜早破（PPROM）之前发生。病理性钙化是指羟基磷灰石（HA）在非骨骼组织中的沉积，与动脉粥样硬化和血管破裂等退行性疾病有关。在致病机制中，HA异常聚集成钙蛋白颗粒（CPP）和HA诱导的间充质细胞分化成骨细胞（异位成骨）已被牵连。我们探讨了CPP在人羊水（AF）中形成，在胎膜中存款，并与PTB的致病途径机制相关的假设。我们发现，特发性PPROM妇女的胎膜经常显示异位钙化和成骨细胞分化标志物表达的证据。胎球蛋白-A的浓度，异位钙化的内源性抑制剂，降低AF的特发性PPROM的情况下，这反映了他们的功能能力降低，以抑制钙化。使用无菌AF的长期培养物，我们证明了HA与内源性蛋白（包括胎球蛋白A）的共聚集。胎球蛋白-HA聚集体在体外以类似于CPP的模式表现出进行性生长。当应用于绒毛膜外植体，AF衍生的CPP诱导的结构和功能的病理影响重演PPROM指出。我们的研究结果表明，AF中蛋白质-矿物质平衡的破坏刺激CPP的形成和沉积，这可能是特发性PPROM的病因。因此，旨在维持孕妇内源性HA形成和胎球蛋白储备之间平衡的治疗或饮食干预可能在预防PTB中发挥作用。
Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality and is often preceded by preterm premature rupture of the membranes (PPROM) without an identifiable cause. Pathological calcification, the deposition of hydroxyapatite (HA) in nonskeletal tissues, has been implicated in degenerative diseases including atherosclerosis and aneurism rupture. Among pathogenic mechanisms, the aberrant aggregation of HA into calciprotein particles (CPPs) and the HA-induced differentiation of mesenchymal cells into osteoblasts (ectopic osteogenesis) have been implicated. We explored the hypothesis that CPPs form in human amniotic fluid (AF), deposit in fetal membranes, and are linked mechanistically to pathogenic pathways favoring PTB. We demonstrated that fetal membranes from women with idiopathic PPROM frequently show evidence of ectopic calcification and expression of osteoblastic differentiation markers. Concentrations of fetuin-A, an endogenous inhibitor of ectopic calcification, were decreased in AF of idiopathic PPROM cases, which reflected their reduced functional capacity to inhibit calcification. Using long-term cultures of sterile AF, we demonstrated coaggregation of HA with endogenous proteins, including fetuin-A. The fetuin-HA aggregates exhibited progressive growth in vitro in a pattern similar to CPPs. When applied to amniochorion explants, AF-derived CPPs induced structural and functional pathological effects recapitulating those noted for PPROM. Our results demonstrate that disruption of protein-mineral homeostasis in AF stimulates the formation and deposition of CPPs, which may represent etiologic agents of idiopathic PPROM. Therapeutic or dietary interventions aimed at maintaining the balance between endogenous HA formation and fetuin reserve in pregnant women may therefore have a role in preventing PTB.