DIFFERENT MOLECULAR MECHANISMS UNDERLIE ETHANOL-INDUCED BONE LOSS IN CYCLING AND PREGNANT RATS

Authors: SHANKAR, KARTIK - ACNC/UAMS; HIDESTRAND, MATS - ACNC/UAMS; HALEY, RANI - ACNC/ACH; HOUGE, WILLIAM - UAMS; SKINNER, ROBERT - UAMS; JO, CHAN-HEE - UAMS; SIMPSON, PIPPA - ACHRI/UAMS; LUMPKIN, CHARLES - UAMS; ARONSON, JAMES - ACHRI/UAMS; BADGER, THOMAS - ACNC/UAMS; RONIS, MARTIN - ACNC/UAMS

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/10/2005
Publication Date: 1/10/2006
Citation: Shankar, K., Hidestrand, M., Haley, R., Houge, W., Skinner, R.A., Jo, C., Simpson, P.M., Lumpkin, C.K., Aronson, J., Badger, T.M., Ronis, M.J. 2006. Different molecular mechanisms underlie ethanol-induced bone loss in cycling and pregnant rats. Endocrinology. 147(1):166-178.

Interpretive Summary: Consumption of alcohol (ethanol) during pregnancy remains an important public health issue, primarily due the effects on the growing baby. However, the harmful effects of alcohol on the mother, especially on the maternal skeleton, remain unclear. To examine this issue we have undertaken studies using either pregnant or non-pregnant rats and fed them nutritionally sufficient diets either with or without alcohol. The studies show that consumption of alcohol is harmful to the bones, as both the density and mineral content of the bones (and hence strength) were decreased in rats consuming alcohol. Further, critical differences were observed in the way alcohol causes this decrease in bone health between the non-pregnant and pregnant rats. It appears that in pregnant rats alcohol decreases the numbers of cells that form new bone, also called osteoblasts. However, in non-pregnant rats consuming similar levels of alcohol every day, the predominant effect is an increase in the numbers of cells that degrade bone (osteoclasts). Further studies show that the critical hormone, 17 beta-estradiol, that is important in maintaining good bone, is decreased in following alcohol consumption in non-pregnant rats, thus leading to increases in osteoclasts and bone loss.

Technical Abstract: Chronic ethanol (EtOH) consumption can result in osteopenia. In the current study we examined the modulation of EtOH-induced bone-loss during pregnancy. Non-pregnant and pregnant dams were intragastrically infused either control or EtOH-containing diets throughout gestation (GD5 through 20 or an equivalent period of 15 days) by total enteral nutrition (TEN). The effects of EtOH (8.5 to 14 g/kg/d) on tibial bone mineral density (BMD), mineral content (BMC) and area (BMA) were assessed at GD20 via peripheral quantitative computerized tomography (pQCT). EtOH caused a dose-dependent decrease in BMD and BMC without affecting BMA. Trabecular BMD and BMC were significantly lower in EtOH-treated, non-pregnant dams compared to pregnant cohorts at the same infused dose of EtOH and UEC concentrations. Static histomorphometric analysis of tibiae from pregnant rats following EtOH treatment showed decreased osteoblast and osteoid surface, indicating inhibited bone formation while EtOH-treated cycling rats showed higher osteoclast and eroded surface indicative of increased bone resorption. Circulating osteocalcin and 1,25 (OH)2 vitamin D3 were lower in both EtOH-fed non-pregnant and pregnant rats. Gene expression of osteoclast markers, 70 kDa v-ATPase and tartrate resistant acid phosphatase were increased selectively in non-pregnant EtOH-treated rats, but not in pregnant rats. Moreover, only non-pregnant EtOH-fed rats showed induction in bone marrow RANK-L mRNA and decreased circulating 17-'-estradiol levels. Our data suggest that EtOH-induced bone loss in pregnant rats is mainly due to inhibited bone formation, while in non-pregnant rats the data are consistent with increased osteoclast activation and bone resorption concomitant with decreased estradiol levels.