Calciprotein particles as potential etiologic agents of idiopathic preterm birth.
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.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.
Lydia L
LL
Shook
Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
Catalin S
CS
Buhimschi
Center for Perinatal Research, Research Institute at Nationwide Children's Hospital, Columbus, OH 43215, USA.
Antonette T
AT
Dulay
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.
Megan E
ME
McCarthy
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.
John T
JT
Hardy
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510, USA.
Christina M
CM
Duzyj Buniak
Center for Perinatal Research, Research Institute at Nationwide Children's Hospital, Columbus, OH 43215, USA.
Guomao
G
Zhao
Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, OH 43210, USA. irina.buhimschi@nationwidechildrens.org.|Center for Perinatal Research, Research Institute at Nationwide Children's Hospital, Columbus, OH 43215, USA.|Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43215, USA.
Irina A
IA
Buhimschi
D000328:Adult; D000653:Amniotic Fluid / Q000737:chemistry; D002114:Calcinosis / Q000150:complications*; D002118:Calcium / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D017886:Durapatite / Q000737:chemistry*; D004912:Erythrocytes / Q000166:cytology; D005321:Extraembryonic Membranes / Q000378:metabolism; D005260:Female; D005322:Premature Rupture of Fetal Membranes; D006801:Humans; D007249:Inflammation; D015675:Osteocalcin / Q000378:metabolism; D010710:Phosphates / Q000737:chemistry; D011247:Pregnancy; D011262:Pregnancy Trimester, Second; D011263:Pregnancy Trimester, Third; D047928:Premature Birth / Q000209:etiology*; D055815:Young Adult; D060749:alpha-2-HS-Glycoprotein / Q000737:chemistry*
D010710:Phosphates; D060749:alpha-2-HS-Glycoprotein; D015675:Osteocalcin; D017886:Durapatite; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D002118:Calcium