Spondyloarthritis (SpA) is a chronic inflammatory disease of peripheral and axial joints, characterized by the infiltration of immune cells into the synovium, enthesis and bone marrow. Joint destruction in SpA is characterized by aberrant bone remodeling, with a very high pain burden. Despite major advances in inflammation control, patients with SpA continue to experience disabling chronic pain. Our pilot data suggest that synovial fibroblasts from patients with SpA and from SpA mouse models differentially express pain-promoting mediators, resulting in sensitization of joint nociceptors and neuroplasticity of the sensory innervation of the joint. No studies to date have explored pain mechanisms unique to SpA or examined these processes in disease specific models of SpA.

Here, we propose to address this major unmet need. We will characterize pain-related behaviors and document concomitant changes in axial and peripheral joint innervation in two mouse models of SpA with complementary disease-relevant immunopathological mechanisms. Furthermore, we will examine the cellular source of molecular drivers of sensitization and pain as well as neuroplasticity (neurotrophins and axonal guidance proteins) using single cell RNA sequencing in human and murine tissues. “Decode SpA Pain” will set the stage for in-depth mechanistic research into SpA pain, will generate new insights into the fundamental role of fibroblasts in directing nociceptor hyperexcitability and plasticity, and will enable future work aimed at validating novel therapeutic targets for pain control