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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #196946
Title: THE ROLE OF REDUCED PLASMA ESTRADIOL AND IMPAIRED ESTROGEN SIGNALING IN ALCHOLO-INDUCED BONE LOSS

Author
item RONIS, MARTIN - ACNC/UAMS
item CHEN, JINRAN - ACHC/UAMS
item HALEY, RANI - ACNC
item SHANKAR, KARTIK - ACNC/UAMS
item HIDESTRAND, MATS - ACNC/UAMS
item LUMPKIN, CHARLES - ACNC/UAMS
item BADGER, THOMAS - ACNC/UAMS

Submitted to: Alcoholism: Clinical and Experimental
Publication Type: Abstract Only
Publication Acceptance Date: 5/26/2006
Publication Date: 9/10/2006
Citation: Ronis, M.J., Chen, J., Haley, R., Shankar, K., Hidestrand, M., Lumpkin, C.K., Badger, T.M. 2006. The role of reduced plasma estradiol and impaired estrogen signaling in alcholo-induced bone loss [abstract]. Alcoholism: Clinical and Experimental Research. 30(s2):49A.

Interpretive Summary: Osteoporosis is a bone loss primarily related to the reduced estrogen production that occurs with menopause. Alcohol intake is a known risk factor for osteoporosis. However, the molecular mechanisms remain in dispute. One disturbing statistic is that a relatively large number of American women drink alcohol during pregnancy, and we have been studying the effects of diet and nutritional status on the health effects of alcohol consumption on both the mother and the offspring. We have previously shown more alcoholic bone loss in non-pregnant females compared to pregnant rats. The pregnancy protection appeared to involve higher levels of the female hormone estradiol. In the current study, we showed that estradiol supplementation can prevent alcohol-induced bone loss in non-pregnant females. These results suggest that this treatment could be effective in alcoholic osteoporosis in women.

Technical Abstract: Ethanol-induced bone loss in female rats is predominantly associated with bone resorption as the result of increased osteoclastogenesis and is associated with significant reduction of plasma estradiol (E2). pQCT analysis demonstrated decreases in tibial trabecular and total bone mineral density (P < 0.05) in female Sprague-Dawley rats fed an ethanol-containing diet (12 g/kg/d) for 3 weeks using total enteral nutrition. This was accompanied by induction of RANKL mRNA in bone marrow (P < 0.05). Bone loss by EtOH was prevented by treatment with E2. Measurement of serum ratLAPS suggested that E2 reversed osteoclast-mediated bone resorption. In primary osteoblasts, EtOH stimulated RANKL mRNA expression dose-dependently. E2 treatment suppressed RANKL expression and also blocked the induction of RANKL by EtOH (P < 0.05). Estrogen receptors alpha and beta were expressed in osteoblasts, and the effect of E2 on EtOH-induced RANKL expression was reversed by pre-treatment with the estrogen receptor antagonist ICI 182,780 (P < 0.05). Moreover, E2 blocked EtOH-induced osteoclastogenesis in a primary osteoblast and osteoclast precursor co-culture system. Class I alcohol dehydrogenase, but not cytochrome P450 2E1, was induced by EtOH in osteoblasts (P < 0.05). Acetaldehyde, the product of EtOH oxidation by ADH, induced RANKL, while the ADH inhibitor 4-methylpyrazole (4-MP) and the antioxidant N-acetylcysteine abolished EtOH-induced RANKL expression (P < 0.05). We found that EtOH stimulated the phosphorylation of extracellular signal-regulated kinase (ERK) and inhibition of ERK phosphorylation by PD98059 blocked the EtOH induction of RANKL in osteoblasts (P < 0.05). These data suggest that EtOH metabolism by ADH in osteoblasts results in oxidative stress and increased RANKL expression via an ERK-dependent signaling pathway. Thus, EtOH appears to induce bone resorption in cycling females by reducing plasma E2 and by stimulating RANKL expression in osteoblasts via inhibitory cross-talk with E2 signaling pathways.