Mitogen‐inducible gene‐6 partly mediates the inhibitory effects of prenatal dexamethasone exposure on endochondral ossification in long bones of fetal rats

Abstract

BACKGROUND AND PURPOSEPrenatal exposure to dexamethasone slows down fetal linear growth and bone mineralization but the regulatory mechanism remains unknown. Here we assessed how dexamethasone regulates bone development in the fetus. EXPERIMENTAL APPROACHDexamethasone (1 mg·kg À1 ·day À1 ) was injected subcutaneously every morning in pregnant rats from gestational day (GD)9 to GD20. Fetal femurs and tibias were harvested at GD20 for histological and gene expression analysis. Femurs of 12-week-old female offspring were harvested for microCT (μCT) measurement. Primary chondrocytes were treated with dexamethasone (10, 50, 250 and 1000 nM). KEY RESULTSPrenatal dexamethasone exposure resulted in accumulation of hypertrophic chondrocytes and delayed formation of the primary ossification centre in fetal long bone. The retardation was accompanied by reduced maturation of hypertrophic chondrocytes, decreased osteoclast number and down-regulated expression of osteocalcin and bone sialoprotein in long bone. In addition, the mitogen-inducible gene-6 (Mig6) and osteoprotegerin (OPG) expression were stimulated, and the receptor activator of NF-κB ligand (RANKL) expression was repressed. Moreover, dexamethasone activated OPG and repressed RANKL expression in both primary chondrocytes and primary osteoblasts, and the knockdown of Mig6 abolished the effect of dexamethasone on OPG expression. Further, μCT measurement showed loss of bone mass in femur of 12-week-old offspring with prenatal dexamethasone exposure. CONCLUSIONS AND IMPLICATIONSPrenatal dexamethasone exposure delays endochondral ossification by suppressing chondrocyte maturation and osteoclast differentiation, which may be partly mediated by Mig6 activation in bone. Bone development retardation in the fetus may be associated with reduced bone mass in later life. Abbreviations

Suppressed osteoclast differentiation at the chondro-osseous junction mediates endochondral ossification retardation in long bones of Wistar fetal rats with prenatal ethanol exposure

“…Our recent work and work from other groups demonstrated that synthetic glucocorticoid dexamethasone can up-regulate the expression of OPG (Swanson et al, 2006;Zhang et al, 2016), and prenatal dexamethasone exposure can retard bone development in fetus, which is closely associated with low bone mass in later life of offspring (Cheng et al, 2014). Consistent with this, our present study showed that CORT but not ethanol activated the mRNA expression of OPG in chondrocytes without affecting the expression of RANKL, and mifepristone block the activating effect of CORT on OPG expression.…”

Cellular senescence mediates the detrimental effect of prenatal dexamethasone exposure on postnatal long bone growth in mice offspring

“…Our previous work demonstrated that continuous PDE during GD 9-20 retards long bone development in fetal rats and leads to low bone mass in adult rat offspring [7], and further delineated that PDE at dose higher than 0.8 mg/kg/day during GD 12-14 developed severe retardation of long bone development in fetal mice [6]. In the present study, the data clearly indicate that PDE at 1.2 mg/kg/day during GD 12-14 induces low bone mass in 12-week-old mice offspring.…”

“…In addition, clinical trial data show that lower birth weight is associated with lower peak bone mass in adult offspring [4,5]. Evidence from experimental animal models by our group and others demonstrate that prenatal dexamethasone exposure (PDE) impairs long bone development in fetal animals [6][7][8][9], reduces bone mass in adult offspring [7,10]. These data imply that developmental overexposure to glucocorticoid alters bone programming and results in less bone mass in offspring.…”

Cellular senescence mediates the detrimental effect of prenatal dexamethasone exposure on postnatal long bone growth in mice offspring

“…Our previous work demonstrated that continuous PDE during GD 9-20 leads to low bone mass in adult rat offspring [7], and further delineated that PDE at dose higher than 0.8 mg kg ̶ 1 day ̶ 1 during GD 12-14 developed severe retardation in bone development in new born mice [6]. In the present study, the data clearly indicate that PDE at 1.2 mg kg ̶ 1 day ̶ 1 during GD 12-14 induced low bone mass in 12-…”

“…In addition, clinical trial data show that lower birth weight is associated with lower peak bone mass in adult offspring [4,5]. Evidence from experimental animal models by our group and others demonstrate that prenatal dexamethasone exposure (PDE) impairs long bone development in fetal mice and rat [6,7], reduces bone mass in adult rat offspring [7]. These data imply that developmental overexposure to glucocorticoid alters bone programming and results in less bone mass, while few studies have identified the cellular targets of prenatal glucocorticoid exposure in the developing bone.…”