Abstract：
Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degeneration and subchondral bone remodelling. Currently, conservative treatment strategies cannot effectively alleviate the progression of OA. In this study, we used computer network analysis to show that Nitisinone (NTBC) is closely related to extracellular matrix degradation in OA and mainly interferes with the TNF-α signaling pathway. NTBC is an orphan drug used to treat hereditary type I tyrosinemia by altering phenylalanine/tyrosine metabolic flow. In this study, we found that NTBC effectively reduced chondrocyte inflammation and extracellular matrix degradation induced by TNF-α. Mechanistically, NTBC inhibited the cGAS/STING signaling pathway and reduced activation of the STING-dependent NF-κB pathway to alleviate inflammation. In addition, NTBC inhibited osteoclastogenesis and delayed the occurrence of subchondral bone remodelling. In mice with ACLT-induced osteoarthritis, intra-articular injection of NTBC significantly reduced cartilage degradation and subchondral bone remodelling. NTBC showed impressive therapeutic efficacy as a potential pharmaceutical intervention for the treatment of OA.
摘要：
骨关节炎（OA）是一种以软骨退化和软骨下骨重塑为特征的慢性退行性关节病。目前,保守治疗策略不能有效缓解OA的进展.在这项研究中,我们用计算机网络分析显示，在OA中，Nitisinone（NTBC）与细胞外基质降解密切相关，主要干扰TNF-α信号通路。NTBC是一种孤儿药，用于通过改变苯丙氨酸/酪氨酸代谢流来治疗遗传性I型酪氨酸血症。在这项研究中,我们发现NTBC可有效减少TNF-α诱导的软骨细胞炎症和细胞外基质降解。机械上,NTBC抑制cGAS/STING信号通路并减少STING依赖性NF-κB通路的激活以减轻炎症。此外,NTBC抑制破骨细胞生成并延迟软骨下骨重塑的发生。在ACLT诱导的骨关节炎小鼠中，NTBC关节内注射可显着减少软骨降解和软骨下骨重塑。NTBC作为治疗OA的潜在药物干预显示出令人印象深刻的治疗效果。
