ETHANOL AND OSTEOBLASTOGENESIS--ROLES OF IL1 AND TNF

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DESCRIPTION: (Adapted from the Investigator's Abstract) Epidemiological data suggest that excessive alcohol consumption may cost the US economy $2 billion annually in skeletal pathology. Patients with alcoholic bone disease display marked impairment in bone formation. Alcohol may alter bone metabolism indirectly by elevating the secretion of cytokines shown to be critical factors in postmenopausal osteoporosis. It has been demonstrated that the cytokines interleukin- I (IL-1) and tumor necrosis factor (TNF) mediate bone loss due to estrogen deficiency by increasing bone resorption and decreasing bone formation. Furthermore, clinical studies show that these cytokines are over-produced in alcohol- induced liver disease. A relatively new clinical procedure for lengthening bones is distraction osteogenesis (DO). One can isolate and study the effects of ethanol exposure on bone formation, in the context of complete nutrition, by combining this lengthening procedure with total enteral nutrition (TEN) in the rat. New bone formation during DO is well-organized and spatially isolated from bone resorptive processes. Preliminary results demonstrate that protein and mRNA representing low to medium abundance genes can be detected in the new bone formed during DO. Further, chronic ethanol exposure with the TEN model decreases tibial-bending strength, inhibits bone formation during DO, and increases the expression of IL- I and TNF in the liver. Importantly, treatment of ethanol-exposed rats with IL-1 and TNF antagonists restores bone formation. The aims of this project are to modulate the local activities of IL-1 and TNF during DO and fracture healing in adult male rats, determine the efficacy of cytokine antagonist delivery by gene therapy, and develop a novel murine DO/TEN model. The investigators hypothesize that ethanol-induced inhibition of bone formation in humans and rodents is mediated by IL-1 and TNF. The long-term goals of this research are to determine the mechanisms underlying ethanol's anti-osteoblastic actions and to complete gene therapy trials in rodents that may support the application of cytokine antagonists in orthopedic procedures.