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.