SOX9 plays an important role in chondrocyte differentiation and, in the developing axial skeleton, maintains the notochord and the demarcation of intervertebral disc compartments. Diminished expression is linked to campomelic dysplasia, resulting in severe scoliosis and progressive disc degeneration. However, the specific functions of SOX9 in the adult spinal column and disc are largely unknown. Accordingly, employing a strategy to conditionally delete Sox9 in Acan-expressing cells (Acan^CreERT2Sox9^fl/fl), we delineated these functions in the adult intervertebral disc. Acan^CreERT2Sox9^fl/fl mice (Sox9^cKO) showed extensive and progressive remodeling of the extracellular matrix in nucleus pulposus (NP) and annulus fibrosus (AF), consistent with human disc degeneration. Progressive degeneration of the cartilaginous endplates (EP) was also evident in Sox9^cKO mice, and it preceded morphological changes seen in the NP and AF compartments. Fate mapping using tdTomato reporter, EdU chase, and quantitative immunohistological studies demonstrated that SOX9 is crucial for disc cell survival and phenotype maintenance. Microarray analysis showed that Sox9 regulated distinct compartment-specific transcriptomic landscapes, with prominent contributions to the ECM, cytoskeleton-related, and metabolic pathways in the NP and ion transport, the cell cycle, and signaling pathways in the AF. In summary, our work provides new insights into disc degeneration in Sox9^cKO mice at the cellular, molecular, and transcriptional levels, underscoring tissue-specific roles of this transcription factor. Our findings may direct future cell therapies targeting SOX9 to mitigate disc degeneration.

SOX9 在软骨细胞分化中起重要作用，并且在发育中的轴向骨骼中，维持脊索和椎间盘隔室的分界。表达减少与 Campomelic 发育不良有关，导致严重的脊柱侧弯和进行性椎间盘退变。然而，SOX9 在成人脊柱和椎间盘中的具体功能在很大程度上是未知的。因此，采用一种策略在Acan表达细胞 ( Acan ^CreERT2 Sox9 ^{fl/ f l} ) 中有条件地删除Sox9，我们在成人椎间盘中描绘了这些功能。Acan ^CreERT2 Sox9 ^{fl/ f l}小鼠（Sox9^cKO ) 显示髓核 (NP) 和纤维环 (AF) 中细胞外基质的广泛和渐进性重塑，与人类椎间盘退变一致。软骨终板 (EP) 的进行性退化在 Sox9 ^cKO小鼠中也很明显，并且它先于 NP 和 AF 室中的形态变化。使用tdTomato报告基因、EdU 追踪和定量免疫组织学研究的命运图谱表明，SOX9 对椎间盘细胞存活和表型维持至关重要。微阵列分析表明，Sox9调节了不同的室特异性转录组学景观，对 NP 和离子转运中的 ECM、细胞骨架相关和代谢途径、细胞周期和 AF 中的信号通路做出了突出贡献。总之，我们的工作在细胞、分子和转录水平上为Sox9 ^cKO小鼠椎间盘退变提供了新的见解，强调了该转录因子的组织特异性作用。我们的发现可能会指导未来针对 SOX9 的细胞疗法以减轻椎间盘退变。