ANK and Joint Ankylosis in Spondylitis

脊柱炎中的 ANK 和关节强直

• 批准号: 6873387
• 负责人: Robert A. Terkeltaub
• 金额: $ 19.06万
• 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/6873387
• 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：（申请人提供）： 反应性骨膜骨形成和炎症后骨化性关节强直通常发生在脊柱关节炎的韧带附着点（附着点）。可能导致虚弱的活动能力丧失和肺活量减少。在脊柱关节炎中，滑膜和韧带免疫反应驱动的炎症如何被转导为骨性强直还没有很好的定义。在这里，我们将研究一个典型的自发性脊椎关节病模型，其特征是滑膜炎和外周关节和椎间骨强直的ank/ank小鼠，表达一个天然的截短突变体的ANK，一个多通道跨膜蛋白，已知的通道细胞内Ppi的细胞外。PPi是羟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。基于新的数据，包括mRNA微阵列分析，我们提出了范式转移假说，即ANK功能缺陷刺激病理性软骨内骨化在附着点通过表达炎症介质vanin-1泛酰巯基乙胺酶，我们观察到促进软骨形成，和趋化因子GRO α，促进软骨细胞成熟和钙化。首先，我们将确定在ank/ank小鼠的附着点处软骨样化生自发发展的基本机制，并在此过程中测试vanin-1的特定作用。我们将测试的假设，即ANK缺陷，细胞外PPi耗竭，vanin-1协同促进软骨形成通过改变氧化还原状态和调节wnt信号和N-钙粘蛋白在间充质多能细胞的表达。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小鼠骨关节强直的“表型拯救”。第二，我们将测试KC/GRO α在ank/ank小鼠的滑膜炎自发发展以及在脊髓附着点和周围关节滑膜处的软骨样化生部位的钙化中的作用。我们将通过将小鼠与现有的、表型正常的KC/GRO α缺失小鼠杂交来测试ank/ank小鼠骨关节强直的“表型拯救”。这些研究将为脊柱关节炎的附着点骨融合确定新的靶点。