ANK and Joint Ankylosis in Spondylitis

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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.