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Title: ESTRADIOL PROTECTS AGAINST ETHANOL-INDUCED BONE LOSS BY INHIBITING UP REGULATION OF RANKL IN OSTEOBLASTS

Author
item CHEN, JIN-RAN - ACNC/UAMS
item HALEY, RANI - ACNC
item HIDESTRAND, MATS - ACNC/UAMS
item SHANKAR, KARTIK - ACNC/UAMS
item LIU, XIAOLI - ACNC/UAMS
item LUMPLIN, CHARLES - ACH/UAMS
item BADGER, THOMAS - ACNC/UAMS
item RONIS, MARTIN - ACNC/UAMS

Submitted to: Endocrine Society Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 4/27/2006
Publication Date: 6/23/2006
Citation: Chen, J., Haley, R.L., Hidestrand, M., Shankar, K., Liu, X., Lumplin, C.K., Badger, T.M., Ronis, M.J. 2006. Estradiol protects against ethanol-induced bone loss by inhibiting up regulation of rankl in osteoblasts [abstract]. Endocrine Society, 88th Annual Meeting, June 23-27, 2006, Boston, Massachusetts. 2006 CDROM. Program No. P3-66.

Interpretive Summary: Chronic alcohol intake is well known to cause harmful bone effect and increase fracture risk in men and women. The reasons why alcohol consumption results in bone loss and an interaction between alcohol and female hormones are currently not well understood. To investigate the effects of female hormones such as estradiol and progesterone on alcohol-induced bone loss, we let experimental animal rats drink alcohol for 3 weeks. Using bone density measurement machine peripheral quantitative computerized tomography and gene detection technology, significant bone loss was observed. The bone loss caused by alcohol could be prevented by treatment with female hormone estradiol in those experimental rats. Addition of one of other birth control pill component progesterone did not enhance the beneficial effect of estradiol alone. The main reason why alcohol and female hormone interacted on bone loss was also addressed. We found that alcohol digest enzyme Class I alcohol dehydrogenase was present in bone cells. By different regulation of alcohol dehydrogenase and other cellular enzyme call extracellular signal-regulated kinase by alcohol and estradiol, the genes responsible for bone formation and bone resorbtion were controlled. These observations suggest that female hormone estradiol prevents alcohol-induced bone loss by opposing the regulation of bone resorbtion gene, and thereby provides a new strategy for treatment of alcohol-induced osteoporosis.

Technical Abstract: Lactation-induced bone loss is promptly restored in the post-weaning period by a process of anabolic rebuilding, the endocrine and molecular basis of which still remains enigmatic. Ethanol (EtOH) consumption during this post-weaning period prevents the recovery of bone density and may be a significant risk factor in predisposing to later-life osteoporosis. To investigate the molecular mechanisms underlying EtOH-induced inhibition of anabolic rebuilding, time impregnated Sprague Dawley rats (n = 10/group) were intragastrically cannulated. Litters were culled to 5 female and 5 male pups/dam and total litter weights/per dam equalized. All dams were chow-fed ad libitum throughout gestation and lactation until weaning (PND17). Following weaning, dams were fed either isocaloric control or EtOH (13 g/kg/d) containing liquid diets at 220 Kcal/kg/d, via total enteral nutrition. In separate experiments, control and EtOH-fed groups were given either recombinant sTNF-R1 (2 mg/kg, sc, in PBS every other day, Amgen, Thousand Oaks, CA) or dietary N-acetyl cysteine (NAC, 1.2 g/kg/d). After two weeks of infusion, all rats were sacrificed and serum, left and right tibia were collected. pQCT analyses showed that trabecular BMD was 21% lower in the EtOH-fed group compared to control rats at 2 weeks post-weaning. 'Ct analyses showed increased trabecular spacing (approx. 200%) and decreased BV/TV (to approx. 45% of control) and connective density (to approx. 33% of control) by EtOH (p<0.05). Dietary NAC consumption reversed both the loss in trabecular BMD and changes observed by 'CT. Histomorphometric analyses of H&E stained tibia from EtOH-fed rats revealed marked (approx. 300%) increase in fat volume (fatV/TV) and profound reduction (to approx. 40% of control) in BV/TV, suggesting a shift in commitment and/or differentiation of osteoblast progenitor cells towards adipocyte lineage. Consistent with these data, mRNA expression of adipocyte specific PPAR-' and aP2 was increased (p<0.05) in bone-marrow of EtOH-fed rats. NAC consumption remarkably reversed the adipogenic changes induced by EtOH, suggesting a role for oxidative stress in this process. In addition, immunostaining of TNF-' was approx. 500% greater in EtOH-fed rats, an effect abolished by NAC treatment. Further, treatment of rats with sTNF-R1 also rescued rats from EtOH-induced bone loss, mechanistically linking increased oxidative stress and TNF-' in mediating EtOH-bone loss and altered differentiation of osteoblast precursors into adipocytes.