ETHANOL AND OSTEOBLASTOGENESIS--ROLES OF IL1 AND TNF

描述：（改编自研究者摘要）流行病学数据表明，过度饮酒可能使美国经济每年在骨骼病理学上损失20亿美元。酒精性骨病患者表现出明显的骨形成障碍。酒精可能通过提高细胞因子的分泌间接改变骨代谢，而细胞因子是绝经后骨质疏松症的关键因素。研究表明，细胞因子白介素-1 （IL-1）和肿瘤坏死因子（TNF）通过增加骨吸收和减少骨形成介导雌激素缺乏引起的骨质流失。此外，临床研究表明，这些细胞因子在酒精引起的肝病中过量产生。牵张成骨术（DO）是一种相对较新的临床增骨术。我们可以分离和研究乙醇暴露对骨形成的影响，在完全营养的情况下，通过将这种延长过程与大鼠的全肠内营养（TEN）相结合。DO期间的新骨形成组织良好，在空间上与骨吸收过程分离。初步结果表明，在DO期间形成的新骨中可以检测到代表低至中等丰度基因的蛋白质和mRNA。此外，在TEN模型中，慢性乙醇暴露会降低胫骨弯曲强度，抑制DO期间的骨形成，并增加肝脏中IL- I和TNF的表达。重要的是，用IL-1和TNF拮抗剂治疗暴露于乙醇的大鼠可以恢复骨形成。本项目的目的是在成年雄性大鼠DO和骨折愈合过程中调节IL-1和TNF的局部活性，通过基因治疗确定细胞因子拮抗剂递送的效果，并建立一种新的小鼠DO/TEN模型。研究人员假设乙醇诱导的人类和啮齿动物骨形成的抑制是由IL-1和TNF介导的。本研究的长期目标是确定乙醇抗成骨作用的机制，并在啮齿动物中完成基因治疗试验，这可能支持细胞因子拮抗剂在骨科手术中的应用。

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.