TRANSGLUTAMINASE PROMOTES CPPD DISEASE IN AGING JOINTS

转谷氨酰胺酶促进老化关节中的 CPPD 疾病

• 批准号: 2561477
• 负责人: Ann K Rosenthal
• 金额: $ 11.52万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-15 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2561477
• 关键词: Carnivora; aging; animal tissue; articular cartilage; bioassay; chondrocytes; enzyme activity; extracellular matrix proteins; human tissue; mature animal; organ culture; polymerase chain reaction; protein glutamine gamma glutamyltransferase; protein structure function; pseudogout; swine; tissue /cell culture; transforming growth factors; western blottings

DESCRIPTION (Adapted from the Applicant's Abstract): Calcium pyrophosphate dihydrate (CPPD) deposition disease is a common form of degenerative arthritis that preferentially affects the elderly. The causes of CPPD crystal formation in aging articular cartilage are unknown, although many similarities exist between processes of normal cartilage mineralization in growth plate and those of pathologic mineralizing causing CPPD disease. Current evidence suggests that CPPD crystal formation results from excess elaboration of inorganic pyrophosphate (PPi) by chondrocytes, and occurs in or around articular cartilage vesicles (ACVs) and at sites of altered cartilage matrix. The processes known to promote CPPD crystal formation are strongly and uniquely enhanced by transforming growth factor beta (TGF-beta), which is stored in cartilage matrix in a latent biologically inactive form (LTGF-beta). The enzyme transglutaminase (TGase) catalyzes a unique post-translational modification of proteins, resulting in diverse biological effects in various tissues. TGase has recently been identified in mineralizing growth plate chondrocytes. Although TGase participates in processes of cell aging and LTGF-beta activation in other tissues, its role in articular cartilage remains undefined. The applicant's laboratory discovered strikingly high levels of active TGase and type II TGase protein in articular chondrocytes from old pigs compared to chondrocytes from young pigs. Inhibitors of TGase suppress PPi elaboration and reduce levels of activated TGF-beta secreted by old chondrocytes, conditions unfavorable to the formation of CPPD crystals. It is hypothesized that increased TGase activity in aging articular cartilage leads to CPPD crystal formation and the resultant degenerative arthritis. As a consequence, this application proposes to: 1) examine the function of TGase in CPPD deposition by exploring its role in LTGF-beta activation, extracellular matrix modulation, and ACV-induced mineralization in a porcine model; 2) explore the regulation of TGase activity in porcine articular cartilage by factors which modulate CPPD crystal formation; and 3) extend these findings to aging human articular cartilage and cartilage affected by CPPD disease. The goal of these studies is to understand the role and regulation of TGase in aging articular cartilage as it relates to CPPD deposition disease. This multifunctional enzyme represents a novel target for new pharmacologic agents directed against this common degenerative disease affecting our rapidly aging population.

描述（改编自申请人的摘要）：焦磷酸钙钙 二氢（CPPD）沉积疾病是退化的一种常见形式 优先影响老年人的关节炎。 CPPD的原因 衰老关节软骨中的晶体形成是未知的，尽管许多 正常软骨矿化过程之间存在相似之处 生长板和导致CPPD疾病的病理矿化化。 当前的证据表明，CPPD晶体形成是由于过量的 用软骨细胞阐述无机焦磷酸（PPI），并发生在 或附近关节软骨囊泡（ACV）和变化的位置 软骨矩阵。 已知促进CPPD晶体形成的过程是 通过转化生长因子beta来强烈而独特地增强 （tgf-beta），它存储在潜在生物学上的软骨基质中 非活性形式（LTGF-BETA）。 酶转谷氨酰胺酶（TGase）催化A 蛋白质的独特翻译后修饰，导致多种多样 各种组织中的生物学作用。 最近已经确定了TGASE 在矿化生长板中软骨细胞。 虽然TGASE参加 其他组织中细胞衰老和LTGF-β激活的过程，其作用 在关节软骨中仍然不确定。 申请人的实验室 发现高水平的活性TGase和II型TGASE蛋白 与年轻的软骨细胞相比，在旧猪的关节软骨细胞中 猪。 TGase抑制剂抑制PPI阐述并降低水平 被旧软骨细胞分泌的激活的TGF-β，条件不利 CPPD晶体的形成。 假设Tgase增加了 衰老的关节软骨的活性导致CPPD晶体形成和 由此产生的退行性关节炎。 结果，此应用程序 提出：1）检查TGase在CPPD沉积中的功能 探索其在LTGF-β激活中的作用，细胞外基质调制， 和ACV诱导的猪模型中的矿化； 2）探索法规 通过调节的因素，猪关节软骨中的Tgase活性 CPPD晶体形成； 3）将这些发现扩展到衰老的人 受CPPD疾病影响的关节软骨和软骨。 目标 这些研究是了解TGase在衰老中的作用和调节 与CPPD沉积疾病有关的关节软骨。 这 多功能酶代表了新药理的新靶标 针对这种影响我们的常见退行性疾病的代理人 人口迅速老龄化。