Axis Placenta Dysfunction in Gestational Diabetes Mellitus is Associated with Trophoblast Autocrine Osteocalcin

Osteocalcin (OCN) is associated with gestational diabetes mellitus (GDM) in epidemiology, but whether these mechanisms contribute to placenta dysfunction has yet to be established. 36 patients with GDM and 40 matched normal controls in Guangxi Zhuang Autonomous Region Woman and Children Hospital from April to June 2018 were recruited. OCN, inflammatory cytokines, and related biochemical indexes of maternal serum and umbilical vein serum were analyzed, and placental tissue samples were used for transcriptome sequencing. In vitro and ex vivo the expression of OCN during osteogenesis and the production of OCN by trophocyte, and OCN impact on trophocyte were evaluated. There have no differences in maternal serum OCN. The levels of OCN, tartrate-resistant acid phosphatase 5b and adiponectin in umbilical vein serum were lower in the GDM group than in the normal controls group in the Umbilical vein serum. Umbilical vein serum OCN levels negatively correlated with adiponectin and positively correlated with leptin. Immunohistochemically staining of placenta and osteogenic induction experiment of JAR cells revealed the existence of OCN and GPRC6A endocrine axis in trophoblast. We identified 16 correlated gene modules through a weighted gene co-expression network analysis. Seven of these modules were associated with both adiponectin and leptin, involving in processes related to insulin signaling pathway, fatty acid metabolism and inflammatory factor pathways. Suppressed OCN was associated with placenta dysfunction in GDM. OCN-GPRC6A feedback loop exists in trophoblast, highlighting a novel signaling pathway for placenta dysfunction in GDM.

骨钙素（Osteocalcin, OCN）在流行病学研究中与妊娠期糖尿病（gestational diabetes mellitus, GDM）存在关联，但其相关机制是否参与胎盘功能不全的发生仍有待明确。本研究于2018年4月至6月在广西壮族自治区妇幼保健院招募了36例GDM患者及40例匹配的正常对照受试者，对母体血清与脐静脉血清中的骨钙素、炎症细胞因子及相关生化指标进行检测分析，并采集胎盘组织样本开展转录组测序。随后通过体外及离体实验，评估骨钙素在成骨过程中的表达水平、滋养细胞产生骨钙素的能力，以及骨钙素对滋养细胞的影响。研究结果显示，母体血清骨钙素水平无组间差异；与正常对照组相比，GDM组脐静脉血清中的骨钙素、抗酒石酸酸性磷酸酶5b及脂联素水平均显著降低。脐静脉血清骨钙素水平与脂联素呈负相关，与瘦素呈正相关。胎盘免疫组织化学染色及JAR细胞成骨诱导实验证实，滋养细胞中存在骨钙素与GPRC6A内分泌轴。通过加权基因共表达网络分析（weighted gene co-expression network analysis），本研究共鉴定出16个相关基因模块，其中7个模块同时与脂联素和瘦素相关，涉及胰岛素信号通路、脂肪酸代谢及炎症因子通路等生物学过程。GDM患者中骨钙素表达受抑与胎盘功能不全密切相关；滋养细胞中存在OCN-GPRC6A反馈环路，这为阐明GDM相关胎盘功能不全的发病机制提供了全新的信号通路视角。