MECHANISM OF OSTEOPOROSIS IN IL-4 TRANSGENIC MICE

骨质疏松症是发病率和骨质疏松症的一个重要且不断增长的原因 美国的死亡率。骨组织中产生的细胞因子可以 对骨吸收和骨形成的影响，并可能在 骨质疏松的发病机制。明确病理生理机制 导致骨质疏松症，包括细胞因子介导的机制，有 由于缺乏方便的动物模型而受到阻碍。这项建议 试图确定导致小鼠产生lck-IL-4的机制 转基因总是会导致严重的骨质疏松症。在lck-IL-4中 转基因是细胞因子白介素4(IL-4)的转录 由淋巴特异蛋白的近端启动子引导 酪氨酸激酶基因，lck。这导致IL-4的表达增加 通过胸腺的T细胞，在较小程度上，通过外周 和骨髓淋巴样细胞。据推测，这一发展 Lck-IL-4小鼠的骨质疏松需要转基因表达， 尤其是在骨组织内。这将通过生成 LCK-IL-4小鼠的额外品系以及通过确定是否：a)抗IL-4 抗体治疗改善骨质疏松症；b)转基因表达通过 骨髓T细胞与疾病严重程度呈正相关；c) 骨质疏松症需要并可由lck-IL-4过继转移 外周T细胞；d)lck-IL-4小鼠的骨质疏松被治愈 野生型骨髓移植。如果这些预测都不是 都是正确的，那么就可以假设转基因整合已经破坏了 或者改变了一种内源性基因，这可能对骨骼至关重要 动态平衡；这个基因将被克隆和鉴定。或者， 如果这些预测中的任何一个是正确的，那么更多的转基因小鼠将 选择性地限制增加的IL-4的产生 到成骨细胞。这将直接测试当地增加的IL-4 骨组织中产生的物质足以导致骨质疏松。在……里面 在上述研究的同时，成骨细胞和破骨细胞在 将通过酶组织化学和免疫组织化学方法对骨骼进行原位评估 以及组织形态计量学。将对血清进行检测以排除 代谢和/或内分泌紊乱是骨质疏松症的原因。 这些研究应该会为研究糖尿病的发病机制提供新的见解。 以及IL-4在骨质疏松症中可能发挥的作用。他们可能会 还指出了系统免疫治疗的潜在陷阱 IL-4等细胞因子。

Osteoporosis is a significant and growing cause of morbidity and mortality in the United States. Cytokines produced in bone tissue can impact on bone resorption and formation, and may also play a role in the pathogenesis of osteoporosis. Defining the pathophysiologic mechanisms which cause osteoporosis, including cytokine-mediated mechanisms, has been hampered by the lack of convenient animal models. This proposal seeks to define the mechanisms which lead mice bearing in lck-IL-4 transgene to invariably develop severe osteoporosis. In the lck-IL-4 transgene, the transcription of the cytokine, interleukin-4 (IL-4), is directed by the proximal promoter of the lymphoid-specific protein tyrosine kinase gene, lck. This results in increased expression of IL-4 by T-lineage cells of the thymus, and, to a lesser extent, by peripheral and bone marrow lymphoid cells. It is hypothesized that the development of osteoporosis in lck-IL-4 mice requires transgene expression, particularly within bone tissue. This will be tested by generating additional lines of lck-IL-4 mice and by determining if: a) anti-IL-4 antibody treatment ameliorates osteoporosis; b) transgene expression by bone marrow T cells positively correlates with disease severity; c) osteoporosis requires, and can be adoptively transferred by, lck-IL-4 peripheral T cells; d) osteoporosis in lck-IL-4 mice is cured by transplantation with wild-type bone marrow. If none of these predictions are correct, it will be assumed that transgene integration has disrupted or altered an endogenous gene, which may be critical for bone homeostasis; this gene will be cloned and characterized. Alternatively, if any of these predictions are correct, additional transgenic mice will be generated in which increased IL-4 production is selectively limited to osteoblasts. This will directly test whether locally-increased IL-4 production in bone tissue is sufficient to induce osteoporosis. In parallel with the above studies, osteoblast and osteoclast function in bone will be assessed in situ by enzymo- and immuno-histochemical assays as well as by histomorphometry. Serum will be assayed to exclude metabolic and/or endocrinologic disorders as the cause of osteoporosis. These studies should provide new insights in to the pathogenesis of osteoporosis, and the role that IL-4 may play in this disease. They may also point out potential pitfalls of systemic immunotherapy with cytokines such as IL-4.