Mechanisms of Bone Loss in Pediatric Crohn Disease

小儿克罗恩病骨质流失的机制

• 批准号: 6945686
• 负责人: FRANCISCO A SYLVESTER
• 金额: $ 21.07万
• 依托单位: ST. FRANCIS HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6945686
• 关键词: Crohn' s disease; T lymphocyte; adolescence (12-20); atomic absorption spectrometry; biological signal transduction; blood chemistry; bone development disorder; bone morphogenetic proteins; cell differentiation; cell line; clinical research; endoscopy; interferon gamma; laboratory mouse; medical complication; middle childhood (6-11); organ culture; osteoblasts; osteogenesis; pathologic bone resorption; pathologic process; patient oriented research; photon absorptiometry; stable isotope diagnosis; urinalysis; western blottings

DESCRIPTION (provided by applicant): Our application proposes to examine the mechanisms by which bone formation is impaired in pediatric Crohn disease. Crohn disease is a chronic inflammatory disorder of the gastrointestinal tract. Bone mineral density is decreased in about 50% of patients at the time of diagnosis, before exposure to corticosteroids. Our studies have shown that biochemical markers of bone turnover are significantly decreased in newly diagnosed children with Crohn disease. We hypothesize that bone formation is reduced in these children, We believe that this is secondary to the inflammatory response present in this disorder. In Crohn disease, CD4+Thl cells are characteristically activated and secrete interferon (IFN)-gamma, among other products. We have shown that IFN-gamma plays a critical role in the inhibition of osteoblast differentiation and function in vitro by activated T cells. We hypothesize that IFN-g blocks the signal transduction of bone morphogenetic protein (BMP)-2, a critical factor in early osteoblast development. Our specific aims are: 1. To examine calcium (Ca) absorption, excretion, and incorporation into bone in newly diagnosed children with Crohn disease using stable Ca isotopes. Concurrently we will determine bone mineral density, measure biochemical markers of osteoblast activity and bone matrix degradation and then correlate these parameters with clinical variables such as the pediatric Crohn disease activity index and IFN-gamma synthesis by activated T cells from the peripheral circulation and inflamed colon. 2. To examine the effects of IFN-gamma on components of the BMP-2 signaling cascade in cells of the osteoblast lineage obtained from mice with chronic colonic inflammation (Interleukin-10 knockout mice) and in a mouse bone marrow stromal cell line (ST-2 cells). Our studies will involve a unique collaboration of experts in pediatric gastroenterology, bone cell biology, signal transduction, and human nutrition and will provide important insight into the mechanisms of bone loss in Crohn disease and other childhood diseases characterized by abnormal T cell activation.

描述（由申请人提供）：我们的申请提议检查小儿克罗恩病中骨骼形成的机制。克罗恩病是胃肠道的慢性炎症性疾病。在诊断时，在暴露于皮质类固醇之前，大约50％的患者骨矿物质密度降低。我们的研究表明，新诊断的克罗恩病儿童的骨转换生化标志物显着降低。我们假设这些儿童骨形成减少，我们认为这是该疾病中存在的炎症反应的继发性。在克罗恩病中，CD4+THL细胞具有特征性激活，并分泌干扰素（IFN）-Gamma等产品。我们已经表明，IFN-gamma在激活的T细胞在体外抑制成骨细胞分化和功能中起着至关重要的作用。我们假设IFN-G会阻止骨形态发生蛋白（BMP）-2的信号转导，这是早期成骨细胞发育的关键因素。我们的具体目的是：1。使用稳定的CA同位素检查钙（CA）吸收，排泄和掺入骨骼的骨骼。同时，我们将确定骨矿物质密度，测量成骨细胞活性的生化标志物和骨基质降解，然后将这些参数与临床变量相关联，例如，来自外围循环和燃烧的结肠的活化的T细胞，例如儿童Crohn疾病活性指数和IFN-GAMMA合成。 2。检查IFN-GAMMA对从具有慢性结肠炎症（白介素10敲除小鼠）和小鼠骨骨髓基质细胞系（ST-2细胞）中的小鼠获得的成骨细胞谱系中BMP-2信号级联的作用。我们的研究将涉及小儿胃肠病学专家的独特合作，骨细胞生物学，信号转导和人类营养，并将为克罗恩病和其他以异常T细胞活化为特征的克罗恩病和其他儿童疾病的骨质流失机制提供重要见解。