Interleukin-1 and Tumor Necrosis Factor Antagonists Attenuate Ethanol-Induced Inhibition of Bone Formation in a Rat Model of Distraction Osteogenesis

  1. Daniel S. Perrien1,3,
  2. Elizabeth C. Brown1,3,
  3. Terry W. Fletcher1,
  4. David J. Irby1,
  5. James Aronson1,2,3,
  6. Guan G. Gao3,
  7. Robert A. Skinner2,
  8. William R. Hogue2,
  9. Ulrich Feige4,
  10. Larry J. Suva2,
  11. Martin J. J. Ronis1,
  12. Thomas M. Badger1 and
  13. Charles K. Lumpkin, Jr.1,3
  1. Departments of 1Pediatrics (T.W.F., D.J.I., J.A., M.J.J.R., T.M.B., C.K.L.) and 2Orthopaedics (J.A., R.A.S., W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; 3Laboratory for Limb Regeneration Research (D.S.P., E.C.B., J.A., G.G.G., C.K.L.), Arkansas Children's Hospital Research Institute, Little Rock, Arkansas; and 4Department of Inflammation Research (U.F.), Amgen, Inc., Thousand Oaks, California
  1. Dr. C. K. Lumpkin Jr., Arkansas Children's Hospital Research Institute, Slot 512-20B, 1120 Marshall St., Little Rock, AR, 72202. E-mail: lumpkincharlesk{at}uams.edu

Abstract

Chronic ethanol exposure inhibits rapid bone formation during distraction osteogenesis (DO; fracture and limb lengthening) and decreases volumetric bone mineral density (BMD) in a model of intragastric dietary infusion [total enteral nutrition (TEN)] in the rat. The hypothesis tested herein was that overexpression of interleukin (IL)-1β and tumor necrosis factor (TNF)-α mediates these deleterious effects of ethanol on the rat skeleton. Two studies (study 1, female rats; study 2, male rats) were performed to test the potential protective effects of the IL-1 and TNF antagonists: IL-1 receptor antagonist (IL-1ra) and 30-kDa polyethylene glycol-conjugated soluble TNF receptor type 1 (sTNFR1). All rats were infused with a liquid diet ± ethanol (EtOH) and underwent tibial fractures and DO. During distraction, the animals received a combination of IL-1ra (1.8–2.0 mg/kg/day) and sTNFR1 (2.0 mg/kg/2 days) or vehicle. A comparison of distracted tibial histological sections demonstrated 1) significant antagonist-related increases in bone column formation over the EtOH controls (studies 1 and 2), and 2) restoration of new bone equivalent to that of the TEN controls (study 2). In contrast, examination of intact proximal tibial metaphyses by peripheral quantitative computerized tomography revealed decreases in volumetric BMD of both EtOH control and EtOH antagonist groups (study 2). These results demonstrate that short-term systemic administration of IL-1 and TNF antagonists together protect rapid bone formation during DO from the deleterious effects of chronic ethanol but are ineffective in regard to intact bone homeostasis.

Footnotes

  • ↵1 D.S.P. and E.C.B. contributed equally to this work.

  • This study was supported in part by National Institutes of Health Grants AA12223 and AA08645. Some of these data were reported in an abstract at the Society of Toxicology 2001 annual meeting (March 25–29; San Francisco, CA).

  • DOI: 10.1124/jpet.102.039636

  • Abbreviations:
    TEN
    total enteral nutrition
    DO
    distraction osteogenesis
    BMD
    volumetric bone mineral density
    IL
    interleukin
    TNF
    tumor necrosis factor
    EtOH
    ethanol
    UEC
    urinary ethanol content
    sTNFR1
    soluble tumor necrosis factor receptor type 1
    IL-1ra
    recombinant human interleukin-1 receptor antagonist
    PBS
    phosphate-buffered saline
    veh
    vehicle
    pQCT
    peripheral quantitative computed tomography
    • Received June 25, 2002.
    • Accepted August 15, 2002.
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  1. doi: 10.1124/jpet.102.039636 JPET December 1, 2002 vol. 303 no. 3 904-908
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