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Binge Alcohol-Induced Bone Damage is Accompanied by Differential Expression of Bone Remodeling-Related Genes in Rat Vertebral Bone

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Abstract

Binge alcohol-related bone damage is prevented by concurrent administration of bisphosphonates, suggesting an activation of bone resorption with patterned alcohol exposure. Although chronic alcohol abuse is known to cause osteopenia, little is known about the effects of binge drinking on bone metabolism. We examined the effects of binge alcohol exposure on the relationship between bone damage and modulation of bone remodeling-specific gene expression profiles. Our hypothesis was that bone damage observed in young adult rats after binge alcohol exposure is associated with differential expression of bone remodeling-related gene expression. We further hypothesized that this differential gene expression specific to bone remodeling (bone resorption or formation related) would be influenced by the duration of binge alcohol exposure. Binge alcohol (3 g/kg, i.p.) was administered on 3 consecutive days each week, for 1 or 4 weeks, to adult male rats. Matched control animals were injected with an equal volume of isotonic saline. Lumbar vertebrae, L4-5, were analyzed for the presence of bone damage by quantitative computed tomography and compressive strength analysis. Total RNA was isolated from an adjacent vertebrae (L3), and whole transcriptome gene expression data were obtained for each sample. The expression levels of a subset of bone formation and resorption-associated differentially expressed genes were validated by quantitative reverse transcriptase–polymerase chain reaction. Bone loss was not observed after 1 week of treatment but was observed after four binge alcohol cycles with a 23% decrease in cancellous bone mineral density and 17% decrease in vertebral compressive strength compared with control values (P < 0.05). We observed that the duration of binge alcohol treatment influenced the modulation of expression profiles for genes that regulate the bone formation process. The expression of key bone formation-related marker genes such as osteocalcin and alkaline phosphatase were significantly reduced (P < 0.05) after acute binge alcohol exposure, and expression of regulators of osteoblast activity such as bone morphogenetic proteins and parathyroid hormone receptor displayed significantly (P < 0.05) decreased differential expression. The expression of sclerostin, a key canonical Wnt inhibitory protein, was significantly increased after acute binge alcohol treatment. The expression of important regulators of osteoclast maturation and activity such as NF-κβ (nuclear factor κβ) ligand (RANKL) and interleukin-6 were significantly increased (P < 0.05) by binge alcohol, and osteoprotegerin levels were significantly decreased (P < 0.05) in vertebral bone. These results show that expression patterns of several key bone remodeling genes are significantly perturbed by binge alcohol treatment, suggesting that perturbation of gene expression associated with bone remodeling may be one mechanism contributing to the disruption of bone mass homeostasis and subsequent bone loss observed after binge alcohol exposure in rodents.

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References

  1. Bilke DD, Genant HK, Cann C, Recker RR, Halloran BP, Strewler GJ (1985) Bone disease in alcohol abuse. Ann Intern Med 103:42–48

    Google Scholar 

  2. Farley JR, Fitzsimmons R, Taylor AK, Jorch UM, Lau KH (1988) Direct effects of ethanol on bone resorption and formation in vitro. Arch Biochem Biophys 238:305–314

    Article  Google Scholar 

  3. Friday KE, Howard GA (1991) Ethanol inhibits human bone cell proliferation and function in vitro. Metabolism 40:562–565

    Article  PubMed  CAS  Google Scholar 

  4. Wezeman FH, Emanuele MA, Emanuele NV, Moskal SF, Woods M, Suri M, Steiner J, LaPaglia N (1999) Chronic alcohol consumption during male rat adolescence impairs skeletal development through effects on osteoblast gene expression, bone mineral density and bone strength. Alcohol Clin Exp Res 23:1534–1542

    PubMed  CAS  Google Scholar 

  5. Baran DT, Teitelbaum SL, Bergfeld MA, Parker G, Cruvant EM, Avioli LV (1980) Effect of alcohol ingestion on bone and mineral metabolism in rats. Am J Physiol E507–E510

  6. Preedy VR, Sherwood RA, Akpoguma CO, Black D (1991) The urinary excretion of the collagen degradation markers pyridinoline and deoxypridinoline in an experimental rat model of alcoholic bone disease. Alcohol Alcohol 26:191–198

    PubMed  CAS  Google Scholar 

  7. Zhang J, Dai J, Lin D-L, Habib P, Smith P, Murtha J, Fu Z, Yao Z, Qi Y, Keller ET (2002) Osteoprotegerin abrogates chronic alcohol ingestion-induced bone loss in mice. J Bone Miner Res 17:1256–1263

    Article  PubMed  CAS  Google Scholar 

  8. Callaci JJ, Juknelis D, Patwardhan A, Sartori M, Frost N, Wezeman FH (2004) The effects of binge alcohol exposure on bone resorption and biomechanical and structural properties are offset by concurrent bisphosphonate treatment. Alcohol Clin Exp Res 28:182–191

    Article  PubMed  Google Scholar 

  9. Stewart TL, Ralston SH (2000) Role of genetic factors in the pathogenesis of osteoporosis. J Endocrinol 166:235–245

    Article  PubMed  CAS  Google Scholar 

  10. Turner RT, Wronski TJ, Zhang M, Kidder LS, Bloomfield SA, Sibonga JD (1998) Effects of ethanol on gene expression in rat bone: transient dose-dependent changes in mRNA levels for bone matrix proteins, skeletal growth factors and cytokines are followed by reductions in bone formation. Alcohol Clin Exp Res 22:1591–1599

    PubMed  CAS  Google Scholar 

  11. McHugh KP, Hodivala-Dilke K, Zheng MH, Namba N, Lam J, Novack D, Feng X, Ross FP, Hynes RO, Teitelbaum SL (2000) Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 105:433–440

    Article  PubMed  CAS  Google Scholar 

  12. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Jüppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML, Osteoporosis-Pseudoglioma Syndrome Collaborative Group (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523

    Article  PubMed  CAS  Google Scholar 

  13. Himes R, Wezeman FH, Callaci JJ (2008) Identification of novel bone-specific targets of binge alcohol and ibandronate by transcriptome analysis. Alcohol Clin Exp Res 3:1167–1180

    Article  Google Scholar 

  14. Read JP, Beattie M, Chamberlain R, Merrill JE (2008) Beyond the “Binge” threshold: heavy drinking patterns and their association with alcohol involvement indices in college students. Addict Behav 33:225–234

    Article  PubMed  Google Scholar 

  15. Callaci JJ, Juknelis D, Patwardhan D, Wezeman FH (2006) Binge alcohol treatment increases vertebral bone loss following ovariectomy: compensation by intermittent parathyroid hormone. Alcohol Clin Exp Res 30:665–672

    Article  PubMed  CAS  Google Scholar 

  16. Wezeman FH, Juknelis D, Himes R, Callaci JJ (2007) Vitamin D and ibandronate prevent cancellous bone loss associated with binge alcohol treatment in male rats. Bone 41:639–645

    Article  PubMed  CAS  Google Scholar 

  17. Nation JR, Burkey RT, Grover CA (1993) Lead/ethanol interactions. II: phamacokinetics. Alcohol 10:363–367

    Article  PubMed  CAS  Google Scholar 

  18. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-−ΔΔCT method. Methods 25:402–408

    Article  PubMed  CAS  Google Scholar 

  19. Penland S, Hoplight B, Obernier J, Crews FT (2001) Effects of nicotine on ethanol dependence and brain damage. Alcohol 24:45–54

    Article  PubMed  CAS  Google Scholar 

  20. Becker HC (2000) Animal models of alcohol withdrawal. Alcohol Res Health 24:105–113

    PubMed  CAS  Google Scholar 

  21. Turner RT (2000) Skeletal response to alcohol. Alcohol Clin Exp Res 24:1693–1701

    Article  PubMed  CAS  Google Scholar 

  22. Chen JR, Haley RL, Hidestrand M, Shankar K, Liu X, Lumpkin CK, Simpson PM, Badger TM, Ronis MJ (2006) Estradiol protects against ethanol-induced bone loss by inhibiting up-regulation of receptor activator of nuclear factor-kappaβ ligand in osteoblasts. J Pharmacol Exp Ther 319:1182–1190

    Article  PubMed  CAS  Google Scholar 

  23. Torricelli P, Fini M, Giavaresi G, Borsari V, Rimondini L, Rimondini R, Carrassi A, Giardino R (2007) Intermittent exposure to ethanol vapor affects osteoblast behavior more severely than estrogen deficiency does; in vitro study on rat osteoblasts. Toxicology 237:168–176

    Article  PubMed  CAS  Google Scholar 

  24. Hannan MT, Felson DT, Dawson-Hughes B, Tucker KL, Cupples LA, Wilson PW, Kiel DP (2000) Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study. Bone Miner Res 15:710–720

    Article  CAS  Google Scholar 

  25. Sampath TK, Maliakal JC, Hauschka PV, Jones WK, Sasak H, Tucker RF, White KH, Coughlin JE, Tucker MM, Pang RH (1992) Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro. J Biol Chem 267:20352–20362

    PubMed  CAS  Google Scholar 

  26. van Bezooijen RL, Roelen BA, Visser A, van der Wee-Pals L, de Wilt E, Karperien M, Hamersma H, Papapoulos SE, ten Dijke P, Löwik CW (2004) Sclerostin is an osteocyte-expressed negative regulator of bone formation, but not a classical BMP antagonist. J Exp Med 199:805–814

    Article  PubMed  Google Scholar 

  27. Winkler DG, Sutherland MK, Geoghegan JC, Yu C, Hayes T, Skonier JE, Shpektor D, Jonas M, Kovacevich BR, Staehling-Hampton K, Appleby M, Brunkow ME, Latham JA (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22:6267–6276

    Article  PubMed  CAS  Google Scholar 

  28. Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (1997) A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390(6656):175–179

    Article  PubMed  CAS  Google Scholar 

  29. Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Lüthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R, Boyle WJ (1997) Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89:309–319

    Article  PubMed  CAS  Google Scholar 

  30. Johnson ML (2004) The high bone mass family—the role of Wnt/Lrp5 signaling in the regulation of bone mass. J Muskuloskelet Neuronal Interact 4:135–138

    CAS  Google Scholar 

  31. Dai J, Lin D, Zhang J, Habib P, Smith P, Murtha J, Fu Z, Yao Z, Qi Y, Keller ET (2000) Chronic alcohol ingestion induces osteoclastogenesis and bone loss through IL-6 in mice. J Clin Invest 106:887–895

    Article  PubMed  CAS  Google Scholar 

  32. Palmqvist P, Persson E, Conaway HH, Lerner UH (2002) IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol 169:3353–3362

    PubMed  CAS  Google Scholar 

  33. Wezeman FH, Juknelis D, Frost N, Callaci JJ (2003) spine mineral density and vertebral body height are altered by alcohol consumption in growing male and female rats. Alcohol 31:1–6

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopaedic Surgery and Rehabilitation, Loyola University Stritch School of Medicine, 2160 S. First Ave., Maywood, IL, 60153, USA

    John J. Callaci, Ryan Himes, Kristen Lauing, Frederick H. Wezeman & Kirstyn Brownson

  2. Alcohol Research Program, Loyola University Stritch School of Medicine, Maywood, IL, USA

    John J. Callaci, Kristen Lauing & Frederick H. Wezeman

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  1. John J. Callaci
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  2. Ryan Himes
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  3. Kristen Lauing
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  4. Frederick H. Wezeman
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  5. Kirstyn Brownson
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Correspondence to John J. Callaci.

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Callaci, J.J., Himes, R., Lauing, K. et al. Binge Alcohol-Induced Bone Damage is Accompanied by Differential Expression of Bone Remodeling-Related Genes in Rat Vertebral Bone. Calcif Tissue Int 84, 474–484 (2009). https://doi.org/10.1007/s00223-009-9240-z

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  • DOI: https://doi.org/10.1007/s00223-009-9240-z

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