Submitted to: Journal of Pharmacology and Experimental Therapeutics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2002
Publication Date: 12/5/2002
Citation: PERRIEN, D.S., BROWN, E.C., FLETCHER, T.W., IRBY, D.J., ARONSON, J., GAO, G.G., SKINNER, R.A., HOGUE, W.R., FEIGE, U., SUVA, L.J., RONIS, M.J., BADGER, T.M., LUMPKIN, C.K. INTERLEUKIN-1 AND TUMOR NECROSIS FACTOR ANTAGONISTS ATTENUATE ETHANOL-INDUCED INHIBITION OF BONE FORMATION IN A RAT MODEL OF DISTRACTION OSTEOGENESIS. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS. 2002. v. 303(3). p. 904-908.
Interpretive Summary: The ACNC is interested in the effects of diet and nutritional status on bone development. We use two models to study this: 1) total enteral nutrition in which we can alter any dietary factor and control nutritional status; and 2) distraction osteogenesis which is a process used to lengthen bones in children. We have employed alcohol as a means to block bone formation and to allow us to probe the bone formation and learn the mechanisms by which it occur and the role of diet. We found in this study that and two important factors that regulate bone formation, IL-1 and TNF, can overcome the deleterious effects of alcohol on rapid bone formation, indicating that these factors are important in the process of bone development. Further studies will focus on specific dietary factors that regulate these factors.
Technical 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 over-expression of interleukin (IL-1) and tumor necrosis factor (TNF) 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 plus/minus 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/21 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.