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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #226958
Title: Ethanol alters estrogen receptor signaling and activates senescence pathways in osteoblasts while estradiol attenuates ethanol effects

Author
item CHEN, JINRAN - ACNC/AUAMS
item LAZARENKO, OXANA - ACNC/UAMS
item HALEY, RANI - UAMS
item BADGER, THOMAS - ACNC/UAMS
item RONIS, MARTIN - ACNC/UAMS

Submitted to: American Society for Bone and Mineral Research
Publication Type: Abstract Only
Publication Acceptance Date: 6/1/2008
Publication Date: 9/15/2008
Citation: Chen, J., Lazarenko, O.P., Haley, R.L., Badger, T.M., Ronis, M.J. 2008. Ethanol alters estrogen receptor signaling and activates senescence pathways in osteoblasts while estradiol attenuates ethanol effects [abstract]. American Society for Bone and Mineral Research. 635. Available: http://www.asbmr.org/secure/FINAL_Abstract_Book.pdf.

Interpretive Summary:

Technical Abstract: Epidemiological and animal studies suggest that chronic alcohol consumption increases the risk of osteoporosis. However, the mechanisms underlying alcohol-induced bone loss are largely unknown. Using bone from chronic ethanol (EtOH) infused cycling female rats and osteoblastic cells in vitro, we have been able to determine the direct effects of ethanol (EtOH) and the interaction with estrogen signaling pathways in osteoblasts. We found that EtOH increased (P<0.05) estrogen receptor alpha (ER alpha) and beta (ER beta) RNA and encoded ER alpha protein levels in bone in vivo and in osteoblasts in vitro when analyzed by real-time RT-PCR and Western blotting. Treatment with 17 beta-estradiol (E2) subcutaneously, in vivo, or pre-treatment of osteoblasts with E2, in vitro, antagonized all the effects of EtOH on ER expression in bone and osteoblastic cells (P<0.05). ER alpha agonist propylpyrazoletriol (PPT) and ERß beta agonist diarylpropionitrile (DPN) attenuated (P<0.05) EtOH-induced ER alpha and ER beta gene over expression, respectively, indicating non-ER specific actions of EtOH on osteoblasts. In addition E2 attenuated EtOH-induced activation of p53 and p21 in bone tissue in vivo and osteoblasts in vitro. UMR-106 osteoblastic cells were transiently transfected with ER alpha-ECFP for ER alpha translocation analysis, and transiently transfected with ERE-TK-Luc or p21 promoter pGL2-p21-Luc reporter plasmids with or without co-transfection of ER alpha for expression analysis using luciferase assays. Similar to estrogen receptor antagonist ICI 182,780, EtOH blocked nuclear translocation of ER alpha-ECFP in the presence of E2. EtOH down-regulated (P<0.05) the ERE-luc reporter activity; however, E2 blocked this EtOH effect in osteoblasts. On the other hand, EtOH transactivated the luciferase activity of the p21 promoter region independent of additional exogenous ERa. EtOH activated (P<0.05) senescence-associated beta-galactosidase activity in rat stromal osteoblasts, while E2 attenuated this EtOH action. We conclude that inhibitory cross-talk between EtOH and E2 in osteoblasts on ERs, p53/p21 and cell senescence provides a pathophysiologic mechanism underlying bone loss and the protective effects of estrogens in alcohol-exposed females.