Abnormal mechanical load is a main risk factor of intervertebral disc degeneration (IDD), and cellular senescence is a pathological change in IDD. In addition, extracellular matrix (ECM) stiffness promotes human nucleus pulposus cells (hNPCs) senescence. However, the molecular mechanism underlying mechano-induced cellular senescence and IDD progression is not yet fully elucidated. First, we demonstrated that mechano-stress promoted hNPCs senescence via NF-κB signaling. Subsequently, we identified periostin as the main mechano-responsive molecule in hNPCs through unbiased sequencing, which was transcriptionally upregulated by NF-κB p65; moreover, secreted periostin by senescent hNPCs further promoted senescence and upregulated the catabolic process in hNPCs through activating NF-κB, forming a positive loop. Both Postn (encoding periostin) knockdown via siRNA and periostin inactivation via neutralizing antibodies alleviated IDD and NPCs senescence. Furthermore, we found that mechano-stress initiated the positive feedback of NF-κB and periostin via PIEZO1. PIEZO1 activation by Yoda1 induced severe IDD in rat tails without compression, and Postn knockdown alleviated the Yoda1-induced IDD in vivo. Here, we reported for the first time that self-amplifying loop of NF-κB and periostin initiated via PIEZO1 under mechano-stress accelerated NPCs senescence, leading to IDD. Furthermore, periostin neutralizing antibodies, which may serve as potential therapeutic agents for IDD, interrupted this loop.

机械负荷异常是椎间盘退变（IDD）的主要危险因素，细胞衰老是IDD的病理改变。此外，细胞外基质（ECM）硬度会促进人髓核细胞（hNPC）衰老。然而，机械诱导细胞衰老和 IDD 进展的分子机制尚未完全阐明。首先，我们证明机械应激通过 NF-κB 信号传导促进 hNPC 衰老。随后，我们通过无偏测序确定了骨膜素是 hNPC 中主要的机械响应分子，其转录受到 NF-κB p65 的上调；此外，衰老hNPCs分泌的骨膜素通过激活NF-κB进一步促进衰老并上调hNPCs的分解代谢过程，形成正循环。通过 siRNA 敲低Postn （编码骨膜素）和通过中和抗体灭活骨膜素均可减轻 IDD 和 NPC 的衰老。此外，我们发现机械应力通过 PIEZO1 启动 NF-κB 和骨膜素的正反馈。Yoda1 激活 PIEZO1 在未受压的情况下诱导大鼠尾部严重 IDD，而Postn敲低则减轻了 Yoda1 诱导的体内IDD 。在这里，我们首次报道了在机械应力下通过 PIEZO1 启动的 NF-κB 和骨膜素的自我放大环加速了 NPC 衰老，导致 IDD。此外，骨膜素中和抗体（可能作为 IDD 的潜在治疗剂）中断了这一循环。