Placenta-Derived Osteoprotegerin Is Required for Glucose Homeostasis in Gestational Diabetes Mellitus

Abstract

Osteoprotegerin (OPG) is involved in various biological processes, including bone remodeling, vascular calcification and pancreatic β-cell function. Although some clinical studies have shown an increase in serum OPG level during pregnancy, the role of OPG in gestational diabetes mellitus (GDM) is largely unknown. Therefore, we explored the effect of OPG in metabolic homeostasis during pregnancy. We initially evaluated serum OPG levels using ELISA and western blotting techniques on samples from GDM patients. We also assessed OPG expression levels in maternal mice. We then used blastocysts transduced with lentiviruses capable of trophoblast-specific transgene expression to establish placenta-specific OPG knockdown or overexpression mouse models for functional and mechanistic investigation after embryo transplantation. We found that OPG expression was positively associated with GDM in clinical samples, and OPG levels were significantly increased in GDM patient sera and term placenta. Serum OPG was significantly increased in maternal compared to non-pregnant mice, and expression levels of OPG were the highest in placenta compared with other organs, including bone, liver and pancreas. OPG was also significantly increased in pregnant mice fed a high-fat diet (HFD). Placenta-specific OPG knockdown induced glucose intolerance, decreased β-cell proliferation and decreased serum insulin levels, whereas placenta-specific OPG overexpression promoted glucose tolerance and enhanced β-cell proliferation, which increased serum insulin production and decreased fetal weight in HFD-feeding pregnant mice. Placenta-derived OPG (pl-OPG) regulated glucose homeostasis during pregnancy via enhancement of β-cell proliferation, which suggests a potential therapeutic application of OPG for GDM.

Roles of osteoprotegerin in endocrine and metabolic disorders through receptor activator of nuclear factor kappa-B ligand/receptor activator of nuclear factor kappa-B signaling

“…Retrospective clinical studies showed that the circulating levels of OPG in women with a history of GDM were significantly increased compared to normal women later in life, and they were positively correlated with various metabolic diseases with a high incidence later in life ( Akinci et al, 2011 ; Telejko et al, 2015 ). We also have proven that placenta-derived OPG could regulate β-cell proliferation and glucose metabolism in placental glucose involved in glucose homeostasis in pregnant mice ( Huang et al, 2020 ). OPG could promote glucose homeostasis during pregnancy, while there is no direct evidence to prove that OPG regulates hypertension during pregnancy.…”

“…RANKL can bind to RANK on neighboring cells and activate NF-κB signaling to regulate biological processes, such as the cell cycle, proliferation, differentiation, and apoptosis ( Blomberg Jensen et al, 2021 ). RANKL is involved in regulating many processes, such as immune surveillance, bone resorption, monocyte chemotaxis, fibrosis, β-cell proliferation, and glucose homeostasis ( Bernardi et al, 2016 ; Huang et al, 2020 ). RANKL can be found in membrane-bound and soluble forms, in which RANKL binds to two other RANKL molecules to form a trimer that binds to the receptor RANK ( Rinotas et al, 2020 ).…”

Placental Transcriptome Adaptations to Maternal Nutrient Restriction in Sheep

“…MSTN , a negative regulator of muscle development, may also be involved in cytokine production and glucose metabolism, and has been associated with preeclampsia and IUGR in human pregnancies [ 36 , 37 ]. TNFRSF11B , also known as osteoprotegerin, is a secreted factor that is a key regulator in bone metabolism, but is also pro-angiogenic, and has been associated with preeclampsia and diabetes mellitus in human pregnancies [ 38 , 39 ]. WNT9B drives mesenchymal–epithelial transitions in the urogenital system during organogenesis [ 40 ].…”

Aquaporin-8 transports hydrogen peroxide to regulate granulosa cell autophagy

“…Total RNA was isolated by the previous description ( Huang et al, 2020b ) using the TRIzol reagent (10296010, Invitrogen) and quantified using a NanoVueTM Plus Spectrophotometer (GE Healthcare, Buckinghamshire, United Kingdom). The A260/A280 ratio of the optical density was measured using the NanoVueTM Plus Spectrophotometer.…”