Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan, is known to regulate matrix catabolism by nucleus pulposus cells in an inflammatory milieu. However, the role of SDC4 in the aging spine has never been explored. Here we analyzed the spinal phenotype of global knockout (KO) mice as a function of age. Micro-computed tomography showed that deletion severely reduced vertebral trabecular and cortical bone mass, and biomechanical properties of vertebrae were significantly altered in KO mice. These changes in vertebral bone were likely due to elevated osteoclastic activity. The histological assessment showed subtle phenotypic changes in the intervertebral disc. Imaging-Fourier transform-infrared analyses showed a reduced relative ratio of mature collagen crosslinks in young adult nucleus pulposus (NP) and annulus fibrosus (AF) of KO compared to wildtype discs. Additionally, relative chondroitin sulfate levels increased in the NP compartment of the KO mice. Transcriptomic analysis of NP tissue using CompBio, an AI-based tool showed biological themes associated with prominent dysregulation of heparan sulfate GAG degradation, mitochondria metabolism, autophagy, endoplasmic reticulum (ER)-associated misfolded protein processes and ER to Golgi protein processing. Overall, this study highlights the important role of SDC4 in fine-tuning vertebral bone homeostasis and extracellular matrix homeostasis in the mouse intervertebral disc.

中文翻译：

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Sdc4缺失扰乱椎间盘基质稳态并促进衰老小鼠脊柱的早期骨质减少


Syndecan 4 (SDC4) 是一种细胞表面硫酸乙酰肝素蛋白聚糖，已知可调节炎症环境中髓核细胞的基质分解代谢。然而，SDC4 在脊柱衰老中的作用从未被探索过。在这里，我们分析了全局基因敲除（KO）小鼠的脊髓表型作为年龄的函数。微型计算机断层扫描显示，敲除小鼠的椎骨骨小梁和皮质骨量严重减少，椎骨的生物力学特性也显着改变。椎骨的这些变化可能是由于破骨细胞活性升高所致。组织学评估显示椎间盘有细微的表型变化。成像-傅里叶变换-红外分析显示，与野生型椎间盘相比，KO 的年轻成人髓核 (NP) 和纤维环 (AF) 中成熟胶原交联的相对比例降低。此外，KO 小鼠 NP 区室中的相对硫酸软骨素水平增加。使用基于 AI 的工具 CompBio 对 NP 组织进行转录组分析，显示了与硫酸乙酰肝素 GAG 降解、线粒体代谢、自噬、内质网 (ER) 相关错误折叠蛋白过程以及 ER 到高尔基体蛋白加工的显着失调相关的生物学主题。总的来说，这项研究强调了SDC4在微调小鼠椎间盘中椎骨稳态和细胞外基质稳态中的重要作用。