Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China.
Sci Adv. 2023 Feb 10;9(6):eade5584. doi: 10.1126/sciadv.ade5584. Epub 2023 Feb 8.
Osteoarthritis (OA) is a degenerative disease with a series of metabolic changes accompanied by many altered enzymes. Here, we report that the down-regulated dimethylarginine dimethylaminohydrolase-1 (DDAH1) is accompanied by increased asymmetric dimethylarginine (ADMA) in degenerated chondrocytes and in OA samples. Global or chondrocyte-conditional knockout of ADMA hydrolase accelerated OA development in mice. ADMA induces the degeneration and senescence of chondrocytes and reduces the extracellular matrix deposition, thereby accelerating OA progression. ADMA simultaneously binds to and its deubiquitinating enzyme USP7, blocking the deubiquitination effects of USP7 on and therefore leads to SOX9 degradation. The ADMA level in synovial fluids of patients with OA is increased and has predictive value for OA diagnosis with good sensitivity and specificity. Therefore, activating to reduce ADMA level might be a potential therapeutic strategy for OA treatment.
骨关节炎（OA）是一种退行性疾病，伴随着一系列代谢变化，伴有许多改变的酶。在这里，我们报告下调的二甲基精氨酸二甲氨基水解酶-1（DDAH1）伴随着退变软骨细胞和 OA 样本中不对称二甲基精氨酸（ADMA）的增加。ADMA 水解酶的全局或软骨细胞条件性敲除加速了小鼠 OA 的发展。ADMA 诱导软骨细胞的变性和衰老，并减少细胞外基质的沉积，从而加速 OA 的进展。ADMA 同时与 和其去泛素化酶 USP7 结合，阻断 USP7 对 的去泛素化作用，从而导致 SOX9 降解。OA 患者滑液中的 ADMA 水平升高，对 OA 诊断具有良好的灵敏度和特异性的预测价值。因此，激活 以降低 ADMA 水平可能是 OA 治疗的一种潜在治疗策略。
