Abstract：
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 Sdc4 global knockout (KO) mice as a function of age. Micro-computed tomography showed that Sdc4 deletion severely reduced vertebral trabecular and cortical bone mass, and biomechanical properties of vertebrae were significantly altered in Sdc4 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.
摘要：
Syndecan4(Sdc4),细胞表面硫酸乙酰肝素蛋白聚糖，已知在炎症环境中由髓核细胞调节基质分解代谢。然而,Sdc4在脊柱老化中的作用从未被探索过。在这里，我们分析了Sdc4整体敲除（KO）小鼠的脊髓表型与年龄的关系。显微计算机断层扫描显示，Sdc4缺失严重降低了椎体小梁和皮质骨量，在Sdc4KO小鼠中，椎骨的生物力学特性发生了显着改变。椎骨的这些变化可能是由于KO小鼠的破骨细胞活性升高。组织学评估显示椎间盘中微妙的表型变化。成像-傅立叶变换-红外分析表明，与野生型小鼠相比，KO的年轻成年髓核（NP）和纤维环（AF）中成熟胶原蛋白交联的相对比率降低。此外,KO小鼠NP区室中相对硫酸软骨素水平升高。使用CompBio对NP组织进行转录组学分析，基于AI的工具显示与硫酸乙酰肝素GAG降解的显著失调相关的生物学主题，线粒体代谢，自噬,内质网（ER）相关的错误折叠蛋白过程和ER对高尔基体蛋白的加工。总的来说,这项研究强调了Sdc4在微调小鼠椎间盘的椎骨稳态和细胞外基质稳态中的重要作用。
