Research ArticlePreterm Birth

Calciprotein particles as potential etiologic agents of idiopathic preterm birth

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Science Translational Medicine  09 Nov 2016:
Vol. 8, Issue 364, pp. 364ra154
DOI: 10.1126/scitranslmed.aah4707

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A particular trigger for preterm birth

Preterm birth is a common cause of neonatal death and disability worldwide. It is often triggered by premature rupture of membranes, but in most cases, it is not clear what causes this rupture, and there is no specific way to treat or prevent it. Shook et al. have shed some light on this mystery by identifying mineral-protein complexes called calciprotein particles in the amniotic fluid and fetal membranes from women with this condition. Although it is not yet clear how the particles promote membrane rupture and how this condition can be treated, the findings of this study suggest that it may be possible to interfere with this process through interventions that maintain a normal protein-mineral balance.

Abstract

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.

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