University of Iowa, Iowa City, IA 52242, USA.
Wellesley College, Boston, MA 02481, USA.
Sci Transl Med. 2018 Feb 7;10(427). doi: 10.1126/scitranslmed.aan5372.
We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or -acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA.
我们测试了在严重创伤后抑制机械反应性关节软骨细胞线粒体并防止氧化损伤是否代表一种可行的预防创伤后骨关节炎（PTOA）的范例。我们使用了一种适合人类手术技术的猪后踝关节关节内骨折（IAF）模型，并且与人类踝关节具有极好的解剖相似性。在 IAF 之后，分别使用戊巴比妥或 N-乙酰半胱氨酸（NAC）注射以抑制软骨细胞电子传递或下游氧化应激。通过分光光度酶测定或谷胱甘肽/谷胱甘肽二硫化物测定以及氧化应激的免疫组织化学测量来确认效果。IAF 后给予戊巴比妥或 NAC 可在 6 个月时提供对 PTOA 的实质性保护，包括保持糖胺聚糖含量、降低组织学疾病评分和使软骨细胞代谢功能正常化。这些数据支持在损伤后靶向软骨细胞代谢的治疗潜力，并表明线粒体在介导 PTOA 中起重要作用。
