尿激酶受体
纤溶
发病机制
纤溶酶
基质金属蛋白酶
医学
纤溶酶原激活剂
骨关节炎
激活剂(遗传学)
细胞生物学
内科学
免疫学
癌症研究
受体
化学
内分泌学
病理
生物
生物化学
替代医学
酶
作者
Qian Wang,Guoqiang Shao,Xiaoyi Zhao,Heidi Wong,Kok‐Yong Chin,Meng Zhao,Alfa H.C. Bai,Michelle S. Bloom,Zelda Z. Love,Constance R. Chu,Zhen Cheng,William H. Robinson
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2024-03-19
标识
DOI:10.1172/jci.insight.173603
摘要
Joint injury is associated with risk for development of osteoarthritis (OA). Increasing evidence suggests that activation of fibrinolysis is involved in OA pathogenesis. However, the role of the fibrinolytic pathway is not well understood. Here we showed that the fibrinolytic pathway, which includes plasminogen/plasmin, tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA) and the uPA receptor (uPAR), were dysregulated in human OA joints. Pharmacological inhibition of plasmin attenuated OA progression in a destabilization of the medial meniscus (DMM) mouse model, while genetic deficiency of plasmin activator inhibitor (PAI-1), or injection of plasmin, exacerbated OA. We detected increased uptake of uPA/uPAR in mouse OA joints by microPET/CT imaging. In vitro studies identified that plasmin promotes OA development through multiple mechanisms, including the degradation of lubricin and cartilage proteoglycans, induction of inflammatory and degradative mediators. We showed that uPA and uPAR produced inflammatory and degradative mediators by activating the PI3K, PDK1, AKT, and ERK signaling cascades, and activates matrix metalloproteinases (pro-MMPs) to degrade proteoglycan. Together, we demonstrated that fibrinolysis contributes to the development of OA through multiple mechanisms and suggested that therapeutic targeting of the fibrinolysis pathway can prevent or slow development of OA.
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