Estradiol protects against ethanol-induced bone loss by inhibiting up-regulation of receptor activator of nuclear factor-kappaB ligand in osteoblasts. J Pharmacol Exp Ther 2006 Dec;319(3):1182-90
Date
09/15/2006Pubmed ID
16971503DOI
10.1124/jpet.106.109454Scopus ID
2-s2.0-33751178411 (requires institutional sign-in at Scopus site) 57 CitationsAbstract
To investigate the effects of sex hormones on ethanol (EtOH)-induced bone loss, female Sprague-Dawley rats were fed control or EtOH-containing diets (12 g/kg/day) by intragastric infusion. After 3 weeks, rats receiving EtOH had significant decreases in tibial trabecular and total bone mineral density, induction of receptor activator of nuclear factor-kappaB ligand (RANKL) mRNA expression, and enhanced bone resorption, all of which were prevented by treatment with 17beta-estradiol (E(2)). The addition of progesterone did not enhance the beneficial effect of E(2) alone. Consistent with our in vivo findings, EtOH stimulated RANKL mRNA expression in cultured primary osteoblasts, and this expression was blocked by 4-methylpyrazole. Acetaldehyde also induced RANKL expression. Class 1 alcohol dehydrogenase was found to be expressed and EtOH-inducible in cultured osteoblasts, whereas CYP2E1 was undetectable. We found that EtOH induced phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducers and activators of transcription 3 (STAT3). E(2) and the mitogenactivated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059) blocked ERK and STAT3 phosphorylation and blocked RANKL induction. Moreover, E(2) completely blocked EtOH-induced osteoclastogenesis in a primary osteoblast and osteoclast precursor coculture system. The E(2) effects were estrogen receptor-mediated. Therefore, E(2) prevents EtOH-induced bone loss by opposing the induction of RANKL mRNA in osteoblasts and ethanol-induced osteoclastogenesis, through opposing effects on sustained ERK signaling.
Author List
Chen JR, Haley RL, Hidestrand M, Shankar K, Liu X, Lumpkin CK, Simpson PM, Badger TM, Ronis MJAuthor
Pippa M. Simpson PhD Adjunct Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBiomarkers
Blotting, Western
Bone Marrow
Bone Resorption
Cells, Cultured
Central Nervous System Depressants
Estradiol
Ethanol
Extracellular Signal-Regulated MAP Kinases
Female
Gene Expression
Lymphocyte Activation
NF-kappa B
Osteoblasts
Osteoclasts
Pregnancy
Progesterone
RANK Ligand
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Tomography, X-Ray Computed
Up-Regulation
