The tonicity-responsive enhancer binding protein (TonEBP) plays an important role in intervertebral disc and axial skeleton embryogenesis. However, the contribution of this osmoregulatory transcription factor in postnatal intervertebral disc homeostasis is not known in vivo. Here, we show for the first time that TonEBP-deficient mice have pronounced age-related degeneration of the intervertebral disc with annular and endplate herniations. Using FTIR-imaging spectroscopy, quantitative immunohistochemistry, and tissue-specific transcriptomic analysis, we provide morphological and molecular evidence that the overall phenotype is driven by a replacement of water-binding proteoglycans with fibrocartilaginous matrix. Whereas TonEBP deficiency in the AF compartment caused tissue fibrosis associated with alterations in actin cytoskeleton and adhesion molecules, predominant changes in pro-inflammatory pathways were seen in the NP compartment of mutants, underscoring disc compartment-specific effects. Additionally, TonEBP-deficient mice presented with compromised trabecular bone properties of vertebrae. These results provide the first in vivo support to the long-held hypothesis that TonEBP is crucial for postnatal homeostasis of the spine and controls a multitude of functions in addition to cellular osmoadaptation.

中文翻译：

---

TonEBP缺乏会加速椎间盘退变，这是由于基质重塑，细胞骨架重排和促炎基因表达的变化所致。

张力调节增强剂结合蛋白（TonEBP）在椎间盘和轴向骨骼胚胎发生中起重要作用。然而，这种渗透调节性转录因子在出生后椎间盘稳态中的作用在体内是未知的。在这里，我们首次显示TonEBP缺陷小鼠已表现出与年龄相关的椎间盘退变，并伴有环状和终板突出。使用FTIR成像光谱学，定量免疫组织化学和组织特异性转录组学分析，我们提供了形态学和分子学证据，表明整体表型是由水结合蛋白多糖替换为纤维软骨基质而驱动的。AF室中的TonEBP缺乏会导致与肌动蛋白细胞骨架和粘附分子改变相关的组织纤维化，而在突变体的NP室中则发现促炎途径的主要变化，这突出了椎间盘室的特异性作用。此外，TonEBP缺陷小鼠的椎骨小梁骨特性受损。这些结果首次为体内长期支持的假说提供了体内支持，该假说是TonEBP对于产后脊柱稳态至关重要，并且除了细胞渗透适应性外还控制多种功能。