ANK and Joint Ankylosis in Spondylitis

描述：(申请人提供)： 在脊柱关节炎中，反应性骨膜骨形成和炎症后骨化关节强直通常发生在韧带与骨(关节)附着的部位。可能会导致行动不便和肺活量减少。在脊柱性关节炎中，滑膜和韧带免疫反应驱动的炎症如何转化为骨性强直还没有很好的定义。在这里，我们将研究一种典型的自发性脊柱关节病模型，其特征是滑膜炎、周围关节和椎间骨质僵硬，该模型表达ANK的自然截断突变体，ANK是一种已知的将细胞内PPI输送到细胞外部的多通道跨膜蛋白。PPI是一种有效的羟基磷灰石沉积的生理抑制剂，到目前为止只被认为是磷酸钙晶体生长的调节剂。基于包括基因芯片的新数据，我们提出了范式转换假说，ANK功能缺陷通过炎症介质Vanin-1 Pantetheinase和趋化因子GroA的表达刺激病理性软骨内成骨，我们观察到该酶促进软骨形成，趋化因子GroA促进软骨细胞成熟和钙化。首先，我们将确定ANK/ANK小鼠肾端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。我们将验证ANK缺乏、细胞外PPI耗竭和Vanin-1通过改变间充质多潜能细胞的氧化还原状态和调节WNT信号和N-钙粘素表达而协同促进软骨形成的假说。我们还将通过与现有的表型正常的Vanin-1缺失小鼠杂交来测试ank/ank小鼠骨性强直的“表型挽救”。其次，我们将检测KC/GroA在ANK/ANK小鼠自发性滑膜炎以及在棘突和周围关节滑膜软骨样化生部位钙化中的作用。我们将通过将现有的表型正常的KC/GroA基因缺失的小鼠与这些小鼠杂交，来测试ANK/ANK小鼠骨性强直的“表型挽救”。这些研究将为脊柱关节炎的内窥性骨融合确定新的靶点。

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.