The low‐expression programming of 11β‐HSD2 mediates osteoporosis susceptibility induced by prenatal caffeine exposure in male offspring rats

Abstract

Background and Purpose Prenatal caffeine exposure (PCE) can cause developmental toxicity of long bones in offspring, but the long‐term effects and the underlying mechanism have not been fully clarified. Here, we investigated the effects of PCE peak bone mass accumulation and osteoporosis susceptibility in offspring and its intrauterine programming mechanism. Experimental Approach Pregnant Wistar rats were administrated intragastrically with saline or caffeine (120 mg·kg−1·day−1) on gestational days 9–20. The serum and bone samples were collected from the fetal and postnatal offspring for bone mass, genes expression and corticosterone analysis. Then, rat bone marrow mesenchymal stem cells (BMSCs) were treated with corticosterone in vitro to confirm the molecular mechanism. Key Results PCE caused fetal bone dysplasia in male and female offspring. In adulthood, PCE reduced peak bone mass and increased osteoporosis susceptibility in male offspring but not in females. Meanwhile, PCE only decreased the H3K9ac and expression levels of 11β‐hydroxysteroid dehydrogenase 2 (11β‐HSD2) before and after birth in the male offspring but not in the females. Moreover, the high level of corticosterone induced by PCE down‐regulated the H3K9ac and expression levels of 11β‐HSD2 through promoting glucocorticoid receptor (GR; NR3C1) into the nucleus of bone marrow mesenchymal stem cells (BMSCs) and recruiting histone deacetylase 11 (HDAC11) binding to 11β‐HSD2 promoter region, which further enhanced the effect of corticosterone on suppressing osteogenic function of BMSCs. Conclusion and Implications PCE caused osteoporosis susceptibility in male adult offspring, which attributed to the low‐functional programming of 11β‐HSD2 induced by corticosterone via GR/HDAC11 signalling.

The selection and identification of compound housekeeping genes for quantitative real‐time polymerase chain reaction analysis in rat fetal kidney

“…Therefore, it is necessary to evaluate the expression stability of housekeeping genes in a specific model and select appropriate ones according to the actual situation. At present, the studies on fetal‐originated diseases are increasing (Liu et al, 2020; Xiao et al, 2020; Zhang et al, 2020), but the expression stability of housekeeping gene under the relevant models has not been comprehensively and systematically studied. DuBois et al found that the maternal low‐protein diet changed the expression levels of housekeeping genes in an age, sex, and organ‐dependent manner in rat offspring (DuBois et al, 2013).…”

Prenatal caffeine exposure caused H‐type blood vessel‐related long bone dysplasia via miR375/CTGF signaling

“…30 At 30 mg/kg•d, the changes of multiple indicators were significant, and there was a significant dose-dependent relationship with different doses of 30, 60, and 120 mg/kg•d. [30][31][32] Therefore, to fully reflect the developmental toxicity of caffeine and obtain a stable IUGR model, we used a maximum concentration of 120 mg/kg•d caffeine in this study. Thus, caffeine concentrations of 30, 60, and 120 mg/kg•d were selected for the animal experiment in this study.…”

HDAC11, an emerging therapeutic target for metabolic disorders

“…( Figure 1 ) In addition, a recent study shows that HDAC11 contributes to osteoporosis susceptibility and reduced peak bone mass through a mechanism of 11β-HSD2’s low-functional programming. This is triggered by corticosterone through GR/HDAC11 signaling, which amplifies the effect of corticosterone on inhibiting the function of BMSCs in osteogenesis ( 141 , 142 ). However, studies on diabetic osteoporosis, lipoid nephrosis, fatty liver disease and obesity cardiomyopathy are still lacking.…”