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: 2909687
• 负责人: Ann K Rosenthal
• 金额: $ 11.47万
• 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/2909687
• 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 二水合物（CPPD）沉积病是一种常见的退行性病变形式 关节炎优先影响老年人。 CPPD 的原因 老化关节软骨中的晶体形成尚不清楚，尽管许多 正常软骨矿化过程之间存在相似之处 生长板和引起 CPPD 疾病的病理矿化的板。 目前的证据表明 CPPD 晶体的形成是由于过量 软骨细胞合成无机焦磷酸盐 (PPi)，发生在 或关节软骨囊泡 (ACV) 周围以及改变的部位 软骨基质。 已知促进 CPPD 晶体形成的过程是 通过转化生长因子 β 得到强烈而独特的增强 （TGF-β），以潜在的生物学方式储存在软骨基质中 非活性形式（LTGF-β）。 转谷氨酰胺酶 (TGase) 催化 蛋白质独特的翻译后修饰，产生多种 各种组织中的生物效应。 TGase最近被鉴定 矿化生长板软骨细胞。 虽然TGase参与 细胞衰老过程和其他组织中 LTGF-β 激活及其作用 尤其是关节软骨仍未明确。 申请人实验室 发现了惊人高水平的活性 TGase 和 II 型 TGase 蛋白 老猪的关节软骨细胞与年轻猪的软骨细胞相比 猪。 TGase 抑制剂可抑制 PPi 的合成并降低 老软骨细胞分泌的活化TGF-β，不利于其生长的条件 CPPD晶体的形成。 据推测，TGase 增加 老化关节软骨中的活性导致 CPPD 晶体形成 由此产生的退行性关节炎。 因此，这个应用程序 建议：1）通过以下方式检查 TGase 在 CPPD 沉积中的功能： 探索其在 LTGF-β 激活、细胞外基质调节、 猪模型中 ACV 诱导的矿化； 2）探索监管 调节因素对猪关节软骨中 TGase 活性的影响 CPPD晶体形成； 3）将这些发现扩展到老年人 关节软骨和受 CPPD 疾病影响的软骨。 目标是 这些研究是为了了解TGase在衰老中的作用和调节 关节软骨与 CPPD 沉积病有关。 这 多功能酶代表了新药理学的新靶标 针对这种影响我们的常见退行性疾病的药物 人口迅速老龄化。