ANK and Joint Ankylosis in Spondylitis

脊柱炎中的 ANK 和关节强直

• 批准号: 7002744
• 负责人: Robert A. Terkeltaub
• 金额: $ 18.61万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002744
• 关键词: bone development disorder; bone morphogenetic proteins; cadherins; cartilage development; connective tissue; gel mobility shift assay; genetically modified animals; glutathione; inflammation; inhibitor /antagonist; joint stiffness; joints; laboratory mouse; laboratory rat; membrane proteins; pathologic process; pluripotent stem cells; rheumatoid arthritis; spondylitis; stromal cells; thiols; tissue /cell culture; transcription factor; transfection; transforming growth factors

DESCRIPTION: (provided by the applicant): Reactive periosteal bone formation and post-inflammatory ossific joint ankylosis commonly develop at sites of ligamentous attachment to bone (entheses) in spondyloarthritis. Debilitating mobility loss and lung capacity reduction can result. How synovial and ligamentous immune response-driven inflammation are transduced to bony ankylosis in spondyloarthritis is not well defined. Here, we will study a classic model of spontaneous spondyloarthropathy characterized by synovitis and peripheral joint and intervertebral bony ankylosis in the ank/ank mouse, which express a natural truncation mutant of ANK, a multiple-pass transmembrane protein known to channel intracellular Ppi to the cell exterior. PPi, a potent physiologic inhibitor of hydroxyapatite deposition, has heretofore only been recognized as a regulator of calcium phosphate crystal growth. Based on novel data including mRNA microarray profiling, we propose the paradigm-shifting hypothesis that deficient ANK function stimulates pathologic endochondral ossification at entheses via expression of the inflammatory mediator vanin-1 pantetheinase, which we observe to promote chondrogenesis, and the chemokine GROa, which promotes chondrocyte maturation and calcification. First, we will define the basic mechanism for spontaneous development of chondroid metaplasia at entheses of ank/ank mice, and in doing so, test the specific role of vanin-1. We will test the hypothesis that ANK deficiency, extracellular PPi depletion, and vanin-1 synergistically promote chondrogenesis via an altered redox state and modulation of wnt signaling and N-cadherin expression in mesenchymal pluripotential cells. We also will test for "phenotype rescue" of ank/ank mouse bony ankylosis by crossing the mice with existing, phenotypically normal vanin-1 null mice. Second, we will test the role of KC/GROa in the spontaneous development of synovitis as well as calcification at sites of chondroid metaplasia at sponal entheses and periperal joint synovia of ank/ank mice. We will test for "phenotype rescue" of ank/ank mouse bony ankylosis by crossing the mice with existing, phenotypically normal KC/GROa null mice. These studies will identify novel targets for enthesopathic bone fusion in spondyloarthritis.

描述：（由申请人提供）： 反应性骨膜骨形成和炎症后骨化关节强直通常发生在脊柱关节炎的韧带附着点（附着点）处。可能会导致活动能力丧失和肺活量减少。滑膜和韧带免疫反应驱动的炎症如何转化为脊柱关节炎的骨强直尚不清楚。在这里，我们将研究 ank/ank 小鼠自发性脊柱关节病的经典模型，其特征是滑膜炎、外周关节和椎间骨强直，该模型表达 ANK 的天然截短突变体，ANK 是一种多通道跨膜蛋白，已知可将细胞内 Ppi 引导至细胞外部。 PPi 是羟基磷灰石沉积的有效生理抑制剂，迄今为止仅被认为是磷酸钙晶体生长的调节剂。基于包括 mRNA 微阵列分析在内的新数据，我们提出了范式转换假设，即 ANK 功能缺陷通过表达炎症介质 vanin-1 泛酰蛋白酶（我们观察到促进软骨形成）和趋化因子 GROa（促进软骨细胞成熟和钙化）的表达来刺激附着点的病理性软骨内骨化。首先，我们将定义 ank/ank 小鼠附着点软骨样化生自发发育的基本机制，并在此过程中测试 vanin-1 的具体作用。我们将检验以下假设：ANK 缺陷、细胞外 PPi 耗竭和 vanin-1 通过改变氧化还原状态以及调节间充质多能细胞中的 wnt 信号传导和 N-钙粘蛋白表达来协同促进软骨形成。我们还将通过将小鼠与现有的、表型正常的 vanin-1 缺失小鼠杂交来测试 ank/ank 小鼠骨强直的“表型拯救”。其次，我们将测试 KC/GROa 在滑膜炎自发发生以及 ank/ank 小鼠脊柱附着点和周围关节滑膜软骨样化生部位钙化中的作用。我们将通过将小鼠与现有的、表型正常的 KC/GROa 缺失小鼠杂交来测试 ank/ank 小鼠骨性强直的“表型拯救”。这些研究将确定脊柱关节炎附着点骨融合的新靶点。