Mechanical overloading and aging are two essential factors for osteoarthritis (OA) development. Mitochondria have been identified as a mechano-transducer situated between extracellular mechanical signals and chondrocyte biology, but their roles and the associated mechanisms in mechanical stress-associated chondrocyte senescence and OA have not been elucidated. Herein, we found that PDZ domain containing 1 (PDZK1), one of the PDZ proteins, which belongs to the Na⁺/H⁺ Exchanger (NHE) regulatory factor family, is a key factor in biomechanically induced mitochondrial dysfunction and chondrocyte senescence during OA progression. PDZK1 is reduced by mechanical overload, and is diminished in the articular cartilage of OA patients, aged mice and OA mice. Pdzk1 knockout in chondrocytes exacerbates mechanical overload-induced cartilage degeneration, whereas intraarticular injection of adeno-associated virus-expressing PDZK1 had a therapeutic effect. Moreover, PDZK1 loss impaired chondrocyte mitochondrial function with accumulated damaged mitochondria, decreased mitochondrion DNA (mtDNA) content and increased reactive oxygen species (ROS) production. PDZK1 supplementation or mitoubiquinone (MitoQ) application alleviated chondrocyte senescence and cartilage degeneration and significantly protected chondrocyte mitochondrial functions. MRNA sequencing in articular cartilage from Pdzk1 knockout mice and controls showed that PDZK1 deficiency in chondrocytes interfered with mitochondrial function through inhibiting Hmgcs2 by increasing its ubiquitination. Our results suggested that PDZK1 deficiency plays a crucial role in mediating excessive mechanical load-induced chondrocyte senescence and is associated with mitochondrial dysfunction. PDZK1 overexpression or preservation of mitochondrial functions by MitoQ might present a new therapeutic approach for mechanical overload-induced OA.

机械超负荷和衰老是骨关节炎（OA）发展的两个重要因素。线粒体已被确定为位于细胞外机械信号和软骨细胞生物学之间的机械转导器，但其在机械应力相关软骨细胞衰老和 OA 中的作用和相关机制尚未阐明。在此，我们发现PDZ蛋白之一的PDZ结构域1（PDZK1）属于Na ⁺ /H ⁺交换器（NHE）调节因子家族，是OA过程中生物力学诱导的线粒体功能障碍和软骨细胞衰老的关键因素进展。 PDZK1 因机械超负荷而减少，并且在 OA 患者、老年小鼠和 OA 小鼠的关节软骨中减少。软骨细胞中的Pdzk1敲除会加剧机械过载引起的软骨退变，而关节内注射表达腺相关病毒的 PDZK1 则具有治疗作用。此外，PDZK1 缺失会损害软骨细胞线粒体功能，导致线粒体损伤累积、线粒体 DNA (mtDNA) 含量减少和活性氧 (ROS) 产生增加。补充PDZK1或应用线粒体泛醌（MitoQ）可减轻软骨细胞衰老和软骨退化，并显着保护软骨细胞线粒体功能。对Pdzk1敲除小鼠和对照组的关节软骨进行 mRNA 测序表明，软骨细胞中的 PDZK1 缺陷通过增加 Hmgcs2 的泛素化来抑制 Hmgcs2，从而干扰线粒体功能。 我们的结果表明，PDZK1 缺陷在介导过度机械负荷诱导的软骨细胞衰老中起着至关重要的作用，并且与线粒体功能障碍有关。 PDZK1 过度表达或 MitoQ 保留线粒体功能可能为机械超负荷诱导的 OA 提供一种新的治疗方法。