JBMR：弥漫性特发性骨质增生症（DISH）小鼠模型制备成功

来自加拿大西安大略大学（Western University）的科学家在关节炎研究取得了突破性进展，有望更好地了解一种最常见形式的关节炎内在机制。

根据关节炎协会（ The Arthritis Society），继骨性关节炎之后，弥漫性特发性骨质增生症（DISH）是第二种最常见关节炎。该病影响着北美6~12%的人口，通常患者年龄超过50岁。DISH被定义为一种退行性关节炎，其特征是颈部及背部椎骨两侧过量的矿物沉积。DISH症状包括脊椎疼痛、僵硬、吞咽困难、脊髓神经损伤。DISH的病因尚未知，目前也无具体的治疗办法。

现在，西安大略大学骨骼肌关节倡议组织与美国罗切斯特梅奥诊所的科学家，合作发现了有史以来首个DISH疾病模型。相关研究已发表于《骨骼与矿物质研究》（Journal of Bone and Mineral Research）杂志上。

该模型将首次使研究人员能够揭开DISH及相关疾病的内在机制。这些机制研究成果，最终将使科学家能够测试新药的治疗药物，来逆转或延缓人类DISH疾病的进程。

研究人员发现，平衡型核苷转运蛋白1（ENT1）基因缺陷型转基因小鼠，出现了脊髓结构异常钙化（矿化），这种矿化类似于人类DISH疾病中的脊髓矿化，研究指明了腺苷在DISH疾病异常矿化中的作用。

编译自：Arthritis Research: Mouse Model of Diffuse Idiopathic Skeletal Hyperostosis Discovered

doi:10.1002/jbmr.1826
PMC:
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Loss of equilibrative nucleoside transporter 1 (ENT1) in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis (DISH) in humans.

Sumeeta Warraich, Derek B. J. Bone, Diana Quinonez, et al

Abstract：Diffuse idiopathic skeletal hyperostosis (DISH) is a non-inflammatory 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-CT 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. ? 2012 American Society for Bone and Mineral Research.