TRANSGLUTAMINASE PROMOTES CPPD DISEASE IN AGING JOINTS

描述(摘自申请者摘要)：焦磷酸钙 二水合物(CPPD)沉积病是一种常见的退行性疾病 优先影响老年人的关节炎。慢性阻塞性肺疾病的原因分析 老化的关节软骨中的晶体形成尚不清楚，尽管有许多 正常软骨矿化过程有相似之处 生长板和病理性矿化导致慢性阻塞性肺疾病。 目前的证据表明，CPPD晶体的形成是过量的结果 软骨细胞对无机焦磷酸盐(PPI)的精加工，并发生在 或在关节软骨小泡(ACV)周围和改变的部位 软骨基质。已知的促进CPPD晶体形成的过程是 通过转化生长因子β获得强大而独特的增强 (转化生长因子-β)，它以潜伏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)催化一种 独特的蛋白质翻译后修饰，导致不同的 在各种组织中的生物效应。TGase最近被发现 在生长板软骨细胞矿化过程中。尽管TGase参与了 其他组织中细胞衰老和转化生长因子-β的激活过程及其作用 在关节软骨中的作用仍不明确。申请人的实验室 发现显著高水平的活性TGase和II型TGase蛋白 老年猪关节软骨细胞与青年猪关节软骨细胞的比较 猪。TGase抑制剂抑制PPI的形成并降低其水平 激活的转化生长因子-β由老软骨细胞分泌，条件不利于 CPPD晶体的形成。假设TGase增加 老化关节软骨中的活动导致CPPD晶体形成和 由此产生的退行性关节炎。因此，此应用程序 建议：1)研究TGase在CPPD沉积中的作用 探讨其在LTGF-β激活、细胞外基质调控中的作用 和阿昔洛韦诱导的猪模型的矿化；2)探索其调控 调控因素对猪关节软骨中TGase活性的影响 CPPD晶体的形成；以及3)将这些发现推广到老年人类 关节软骨和慢性阻塞性肺疾病对软骨的影响。的目标是 这些研究旨在了解TGase在衰老过程中的作用和调节 关节软骨与慢性阻塞性肺疾病的关系。这 多功能酶是新药理的新靶点 针对这种常见退行性疾病的药物影响我们的 人口迅速老龄化。

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.