LOX overexpression programming mediates the osteoclast mechanism of low peak bone mass in female offspring rats caused by pregnant dexamethasone exposure

Background Osteoporosis is a degenerative disease characterized by reduced bone mass, with low peak bone mass being the predominant manifestation during development and having an intrauterine origin. Pregnant women at risk of preterm delivery are commonly treated with dexamethasone to promote fetal lung development. However, pregnant dexamethasone exposure (PDE) can lead to reduced peak bone mass and susceptibility to osteoporosis in offspring. In this study, we aimed to investigate the mechanism of PDE-induced low peak bone mass in female offspring from the perspective of altered osteoclast developmental programming. Methods 0.2 mg/kg.d dexamethasone was injected subcutaneously into rats on gestation days (GDs) 9-20. Some pregnant rats were killed at GD20 to remove fetal rat long bones, the rest were delivered naturally, and some adult offspring rats were given ice water swimming stimulation for two weeks. Results The results showed that the fetal rat osteoclast development was inhibited in the PDE group compared with the control group. In contrast, the adult rat osteoclast function was hyperactivation with reduced peak bone mass. We further found that the promoter region methylation levels of lysyl oxidase (LOX) were decreased, the expression was increased, and the production of reactive oxygen species (ROS) was raised in PDE offspring rat long bone before and after birth. Combined in vivo and in vitro experiments, we confirmed that intrauterine dexamethasone promoted the expression and binding of the glucocorticoid receptor (GR) and estrogen receptor beta(ER beta) in osteoclasts and mediated the decrease of LOX methylation level and increase of expression through upregulation of 10-11 translocator protein 3 ( Tet3). Conclusions Taken together, we confirm that dexamethasone causes osteoclast LOX hypomethylation and high expression through the GR/ER beta/Tet3 pathway, leading to elevated ROS production and that this intrauterine epigenetic programming effect can be carried over to postnatal mediating hyperactivation in osteoclast and reduced peak bone mass in adult offspring. This study provides an experimental basis for elucidating the mechanism of osteoclastmediated intrauterine programming of low peak bone mass in female offspring of PDE and for exploring its early targets for prevention and treatment.

Automated summary

In this study, the researchers investigated the mechanism by which prenatal dexamethasone exposure leads to low peak bone mass in female offspring. They found that dexamethasone exposure inhibited the development of fetal rat osteoclasts and caused hyperactivation of adult rat osteoclasts. Through further experiments, they determined that dexamethasone influenced the methylation and expression of lysyl oxidase in osteoclasts, leading to increased production of reactive oxygen species and reduced bone mass in offspring. This study provides insights into the programming effect of prenatal dexamethasone exposure on bone health.