TGF BETA AND PROGRESSIVE ANKYLOSIS

TGF Beta 与进行性强直

• 批准号: 2875463
• 负责人: HOLLIS Elaine KRUG
• 金额: $ 10万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2875463
• 关键词: 3T3 cells; SDS polyacrylamide gel electrophoresis; binding proteins; biological signal transduction; bone development disorder; calcium flux; cell proliferation; citrates; fibroblasts; growth factor receptors; horseradish peroxidase; immunocytochemistry; joint ligament; joint stiffness; laboratory mouse; light microscopy; pathologic process; radiotracer; receptor binding; spine disorder; spondylitis; tissue /cell culture; transforming growth factors; western blottings

Murine Progressive Ankylosis (MPA), is a spontaneous disorder in mice resulting from an autosomal recessive genetic mutation (a n k) on chromosome 15. It begins as a proliferative synovitis which evolves into chondroid metaplasia and enchondral ossification with ankylosis of peripheral joints and axial skeleton. MPA is dramatically similar to ankylosing spondylitis. Extensive studies indicate that the disease is not immunologically mediated. Disease progression and joint ankylosis in MPA is strikingly inhibited by early treatment with phosphocitrate (PC). This inhibition is accompanied by a decrease in synovial proliferation and persists 2-3 weeks after discontinuation of therapy. PC is known to modulate intracellular calcium levels and inhibit calcium accumulation in matrix vesicles in other systems. The mechanism(s) by which PC inhibits MPA disease progression remain to be identified. We have preliminary data which indicates that spinal ligament fibroblasts from MPA mice proliferate in vitro to a greater extent than nonaffected controls when stimulated with TGFbeta. PC inhibits this hyperresponsiveness to TGFbeta at doses of 10-3 M. The overall goal of this project is to define the pathogenic mechanisms responsible for the excessive bone production in MPA. The striking in vivo inhibitory effects of phosphocitrate on MPA disease progression and the altered in vitro proliferative responses of spinal ligament fibroblasts to TGFbeta, an important osteogenic growth factor, are important clues to understanding the cellular processes that produce ankylosis in this model. We plan to define mechanisms responsible for this altered in vitro proliferation in MPA fibroblasts by: 1) characterizing the TGFbeta receptor(s) present on MPA and normal spinal ligament fibroblasts and 2) defining their function and relationship to development in articular tissues.

小鼠进行性强直 (MPA) 是一种小鼠自发性疾病 由常染色体隐性基因突变 (an k) 引起 15 号染色体。它开始于增殖性滑膜炎，随后演变为 分为软骨样化生和软骨内骨化伴强直 周边关节和轴向骨骼。 MPA 与 强直性脊柱炎。大量研究表明该病是 不是免疫介导的。 MPA 的疾病进展和关节强直受到显着抑制 通过早期使用磷酸柠檬酸盐（PC）治疗。 这种抑制作用是 伴随滑膜增殖减少并持续 2-3 停止治疗后几周。 众所周知，PC 可以调节 细胞内钙水平并抑制基质中的钙积累 其他系统中的囊泡。 PC 抑制 MPA 的机制 疾病进展仍有待确定。 我们有初步数据 这表明 MPA 小鼠的脊髓韧带成纤维细胞 体外增殖程度高于未受影响的对照组 用 TGFbeta 刺激。 PC 抑制这种过度反应 TGFbeta 剂量为 10-3 M。 该项目的总体目标是确定致病机制 MPA 中骨生成过多的原因。引人注目的 磷酸柠檬酸盐对 MPA 疾病进展的体内抑制作用 脊髓韧带体外增殖反应的改变 成纤维细胞转化为重要的成骨生长因子 TGFbeta 了解产生的细胞过程的重要线索 该模型中的强直。 我们计划定义负责的机制 这通过以下方式改变了 MPA 成纤维细胞的体外增殖：1) 表征 MPA 和正常脊髓上存在的 TGFbeta 受体 韧带成纤维细胞和 2) 定义其功能及其关系 关节组织的发育。