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Objectives: The purpose of our study was to characterise spatiotemporal features of disease progression in people with diffuse idiopathic skeletal hyperostosis (DISH), early-phase DISH, and those not meeting either criterion who had repeated CT scans of the thoracic spine., Methods: A retrospective study was designed in collaboration with the Rochester Epidemiology Project to evaluate completeness of ectopic bridging across the thoracic spine and corresponding disease status over an average of 2.7 years (range from 0.2 to 15.0 years) in a cohort of 83 female and 74 male individuals., Results: Over 15% of individuals displayed changes in imaging features over time that resulted in a revised diagnosis along the continuum of DISH. Early-phase DISH was marked by new involvement of previously unaffected motion segments, estimated to occur over 2.1 years. Advanced presentations of DISH were marked by increased prevalence of complete bridging (average two of three available motion segments), estimated to occur over 2.6-2.9 years. Localised nodules of ectopic mineralisation external to and within the intervertebral disc were regularly observed in early-phase DISH., Conclusions: This is the first characterisation of spatiotemporal features across all phases of DISH, indicating that progression of DISH is characterised by distinct features at different phases along the disease continuum. Localised nodules of mineralisation in the spinal ligaments and within the intervertebral discs coincident with early phases of the disease may be a key factor in the pathogenesis of DISH., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: DISH is a common musculoskeletal disorder; however, the imaging features and disease continuum from early to advanced stages is poorly understood. The purpose of this study was to evaluate the prevalence of DISH and early-phase DISH in an American population and to assess the extent and pattern of ectopic mineralization across the thoracic spine., Methods: Data were retrieved in collaboration with the Rochester Epidemiology Project. We conducted a retrospective image evaluation of a sample of individuals over 19 years of age with CT of the thoracic spine from a Northern US catchment area. Stratified random sampling by age and sex was used to populate the study. We examined the prevalence and extent of ectopic mineralization along the thoracic spine using previously established criteria., Results: A total of 1536 unique images (766 female and 770 male individuals) including 16 710 motion segments were evaluated for imaging features of the continuum of DISH. Collectively, 40.5% of all motion segments evaluated displayed evidence of ectopic mineralization in the thoracic spine. The prevalence of early-phase DISH was 13.2% (10.4% of female and 15.8% of male individuals). The prevalence of established DISH was 14.2% (7.4% of female and 20.9% of male individuals). Remarkable heterogeneity was detected in individuals within each disease classification, based on the extent of the thoracic spine affected and degree of mineralization., Conclusions: The continuum of imaging features associated with DISH is detected in more than one in four adults and both sexes in an American population., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by progressive calcification of spinal tissues; however, the impact of calcification on pain and function is poorly understood. This study examined the association between progressive ectopic spine calcification in mice lacking equilibrative nucleoside transporter 1 (ENT1 -/- ), a preclinical model of DISH, and behavioral indicators of pain., Methods: A longitudinal study design was used to assess radiating pain, axial discomfort, and physical function in wild-type and ENT1 -/- mice at 2, 4, and 6 months. At endpoint, spinal cords were isolated for immunohistochemical analysis of astrocytes (GFAP), microglia (IBA1), and nociceptive innervation (CGRP)., Results: Increased spine calcification in ENT1 -/- mice was associated with reductions in flexmaze exploration, vertical activity in an open field, and self-supporting behavior in tail suspension, suggesting flexion-induced discomfort or stiffness. Grip force during the axial stretch was also reduced in ENT1 -/- mice at 6 months of age. Increased CGRP immunoreactivity was detected in the spinal cords of female and male ENT1 -/- mice compared to wild-type. GFAP- and IBA1-immunoreactivity were increased in female ENT1 -/- mice compared to wild-type, suggesting an increase in nociceptive innervation., Conclusion: These data suggest that ENT1 -/- mice experience axial discomfort and/or stiffness and importantly that these features are detected during the early stages of spine calcification., (© 2023. The Author(s).)

Diffuse idiopathic skeletal hyperostosis (DISH) is a non-inflammatory spondyloarthropathy identified radiographically by calcification of the ligaments and/or entheses along the anterolateral aspect of the vertebral column. The etiology and pathogenesis of calcifications are unknown, and the diagnosis of DISH is currently based on radiographic criteria associated with advanced disease. To characterize the features of calcifications associated with DISH, we used micro-computed tomographic imaging to evaluate a cohort of 19 human cadaveric vertebral columns. Fifty-three percent of the cohort (n = 10; 3 females, 7 males, mean age of death = 81 years, range 67-94) met the radiographic criteria for DISH, with calcification of four or more contiguous vertebral segments. In almost all cases, the lower thoracic regions (T8-12) were affected by calcifications, consisting primarily of large, horizontal outgrowths of bony material. In contrast, calcifications localized to the upper thoracic regions demonstrated variability in their presentation and were categorized as either "continuous vertical bands" or "discontinuous-patchy" lesions. In addition to the variable morphology of the calcifications, our analysis demonstrated remarkable heterogeneity in the densities of calcifications, ranging from internal components below the density of cortical bone to regions of hyper-dense material that exceeded cortical bone. These findings establish that the current radiographic criteria for DISH capture heterogeneous presentations of ectopic spine calcification that can be differentiated based on morphology and density. These findings may indicate a naturally heterogenous disease, potential stage(s) in the natural progression of DISH, or distinct pathologies of ectopic calcifications. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res., (© 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Equilibrative nucleoside transporter 1 (ENT1) mediates passage of adenosine across the plasma membrane. We reported previously that mice lacking ENT1 (ENT1(-/-)) exhibit progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis (DISH) in humans. Here, we investigated mechanisms underlying aberrant mineralization in ENT1(-/-) mice. Micro-CT revealed ectopic mineralization of spinal tissues in both male and female ENT1(-/-) mice, involving the annulus fibrosus of the intervertebral discs (IVDs) of older mice. IVDs were isolated from wild-type and ENT1(-/-) mice at 2months of age (prior to disc mineralization), 4, and 6months of age (disc mineralization present) and processed for real-time PCR, cell isolation, or histology. Relative to the expression of ENTs in other tissues, ENT1 was the primary nucleoside transporter expressed in wild-type IVDs and mediated the functional uptake of [(3)H]2-chloroadenosine by annulus fibrosus cells. No differences in candidate gene expression were detected in IVDs from ENT1(-/-) and wild-type mice at 2 or 4months of age. However, at 6months of age, expression of genes that inhibit biomineralization Mgp, Enpp1, Ank, and Spp1 were reduced in IVDs from ENT1(-/-) mice. To assess whether changes detected in ENT1(-/-) mice were cell autonomous, annulus fibrosus cell cultures were established. Compared to wild-type cells, cells isolated from ENT1(-/-) IVDs at 2 or 6months of age demonstrated greater activity of alkaline phosphatase, a promoter of biomineralization. Cells from 2-month-old ENT1(-/-) mice also showed greater mineralization than wild-type. Interestingly, altered localization of alkaline phosphatase activity was detected in the inner annulus fibrosus of ENT1(-/-) mice in vivo. Alkaline phosphatase activity, together with the marked reduction in mineralization inhibitors, is consistent with the mineralization of IVDs seen in ENT1(-/-) mice at older ages. These findings establish that both cell-autonomous and systemic mechanisms contribute to ectopic mineralization in ENT1(-/-) mice., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory spondyloarthropathy, characterized by ectopic calcification of spinal tissues. Symptoms include spine pain and stiffness, and in severe cases dysphagia and spinal cord compression. The etiology of DISH is unknown and there are no specific treatments. Recent studies have suggested a role for purine metabolism in the regulation of biomineralization. Equilibrative nucleoside transporter 1 (ENT1) transfers hydrophilic nucleosides, such as adenosine, across the plasma membrane. In mice lacking ENT1, we observed the development of calcified lesions resembling DISH. By 12 months of age, ENT1(-/-) mice exhibited signs of spine stiffness, hind limb dysfunction, and paralysis. Micro-computed tomography (µCT) revealed ectopic mineralization of paraspinal tissues in the cervical-thoracic region at 2 months of age, which extended to the lumbar and caudal regions with advancing age. Energy-dispersive X-ray microanalysis of lesions revealed a high content of calcium and phosphorus with a ratio similar to that of cortical bone. At 12 months of age, histological examination of ENT1(-/-) mice revealed large, irregular accumulations of eosinophilic material in paraspinal ligaments and entheses, intervertebral discs, and sternocostal articulations. There was no evidence of mineralization in appendicular joints or blood vessels, indicating specificity for the axial skeleton. Plasma adenosine levels were significantly greater in ENT1(-/-) mice than in wild-type, consistent with loss of ENT1--a primary adenosine uptake pathway. There was a significant reduction in the expression of Enpp1, Ank, and Alpl in intervertebral discs from ENT1(-/-) mice compared to wild-type mice. Elevated plasma levels of inorganic pyrophosphate in ENT1(-/-) mice indicated generalized disruption of pyrophosphate homeostasis. This is the first report of a role for ENT1 in regulating the calcification of soft tissues. Moreover, ENT1(-/-) mice may be a useful model for investigating pathogenesis and evaluating therapeutics for the prevention of mineralization in DISH and related disorders., (Copyright © 2013 American Society for Bone and Mineral Research.)