Intervertebral disc degeneration (IDD) is a major cause of discogenic pain, and is attributed to the dysfunction of nucleus pulposus, annulus fibrosus, and cartilaginous endplate (CEP). Osteopontin (OPN), a glycoprotein, is highly expressed in the CEP. However, little is known on how OPN regulates CEP homeostasis and degeneration, contributing to the pathogenesis of IDD. Here, we investigate the roles of OPN in CEP degeneration in a mouse IDD model induced by lumbar spine instability and its impact on the degeneration of endplate chondrocytes (EPCs) under pathological conditions. OPN is mainly expressed in the CEP and decreases with degeneration in mice and human patients with severe IDD. Conditional Spp1 knockout in EPCs of adult mice enhances age-related CEP degeneration and accelerates CEP remodeling during IDD. Mechanistically, OPN deficiency increases CCL2 and CCL5 production in EPCs to recruit macrophages and enhances the activation of NLRP3 inflammasome and NF-κB signaling by facilitating assembly of IRAK1-TRAF6 complex, deteriorating CEP degeneration in a spatiotemporal pattern. More importantly, pharmacological inhibition of the NF-κB/NLRP3 axis attenuates CEP degeneration in OPN-deficient IDD mice. Overall, this study highlights the importance of OPN in maintaining CEP and disc homeostasis, and proposes a promising therapeutic strategy for IDD by targeting the NF-κB/NLRP3 axis.

椎间盘退变（IDD）是椎间盘源性疼痛的主要原因，归因于髓核、纤维环和软骨终板（CEP）的功能障碍。骨桥蛋白 (OPN) 是一种糖蛋白，在 CEP 中高度表达。然而，关于 OPN 如何调节 CEP 稳态和退化，进而导致 IDD 的发病机制，人们知之甚少。在这里，我们研究了 OPN 在腰椎不稳定引起的小鼠 IDD 模型中 CEP 变性中的作用及其对病理条件下终板软骨细胞 (EPC) 变性的影响。 OPN 主要在 CEP 中表达，并在患有严重 IDD 的小鼠和人类患者中随着退化而减少。成年小鼠 EPC 中的条件性Spp1敲除会增强与年龄相关的 CEP 退化，并加速 IDD 期间的 CEP 重塑。从机制上讲，OPN 缺陷会增加 EPC 中 CCL2 和 CCL5 的产生，以招募巨噬细胞，并通过促进 IRAK1-TRAF6 复合物的组装来增强 NLRP3 炎性体和 NF-κB 信号传导的激活，从而以时空模式恶化 CEP 退化。更重要的是，NF-κB/NLRP3 轴的药理学抑制可减轻 OPN 缺陷 IDD 小鼠的 CEP 变性。总的来说，这项研究强调了 OPN 在维持 CEP 和椎间盘稳态中的重要性，并提出了一种通过靶向 NF-κB/NLRP3 轴来治疗 IDD 的有前景的策略。