ETHANOL AND OSTEOBLASTOGENESIS--ROLES OF IL1 AND TNF

描述：(改编自《调查者摘要》)流行病学数据表明，过度饮酒每年可能会给美国经济造成20亿美元的骨骼病理损失。酒精性骨病患者表现出明显的骨形成障碍。酒精可能通过增加细胞因子的分泌间接改变骨代谢，细胞因子被证明是绝经后骨质疏松症的关键因素。已有研究表明，细胞因子白介素I(IL-1)和肿瘤坏死因子(TNF)通过增加骨吸收和减少骨形成来调节雌激素缺乏所致的骨丢失。此外，临床研究表明，这些细胞因子在酒精性肝病中过度产生。一种相对较新的延长骨骼的临床方法是牵张成骨(DO)。人们可以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，来分离和研究酒精暴露对骨形成的影响。DO过程中的新骨形成组织良好，并在空间上与骨吸收过程隔离。初步结果表明，在DO过程中形成的新骨中可以检测到代表低到中等丰度基因的蛋白质和mRNA。此外，慢性酒精暴露与TEN模型降低了胫骨的弯曲强度，抑制了DO期间的骨形成，并增加了肝脏中IL-I和TNF的表达。重要的是，用IL-1和肿瘤坏死因子拮抗剂治疗酒精暴露的大鼠可以恢复骨形成。本课题的目的是调节成年雄性大鼠DO和骨折愈合过程中局部IL-1和TNF的活性，确定细胞因子拮抗剂基因治疗的有效性，并建立一种新的小鼠DO/TEN模型。研究人员假设，乙醇对人类和啮齿类动物骨形成的抑制是由IL-1和肿瘤坏死因子介导的。这项研究的长期目标是确定乙醇抗成骨作用的潜在机制，并完成啮齿动物的基因治疗试验，以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.