骨关节炎
软骨
表皮生长因子受体
阿格里坎
吉非替尼
癌症研究
医学
生长因子
表皮生长因子
内科学
受体
内分泌学
免疫学
化学
病理
关节软骨
解剖
替代医学
作者
Yulong Wei,Lijun Luo,Tao Gui,Feifan Yu,Lesan Yan,Lutian Yao,Leilei Zhong,Wei Yu,Biao Han,Jay M. Patel,Jessica F. Liu,Frank Beier,L. Scott Levin,Charles L. Nelson,Shuilin Wu,Dick Heinegård,Robert L. Mauck,Andrew Tsourkas,Jaimo Ahn,Zhiliang Cheng,Ling Qin
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2021-01-13
卷期号:13 (576)
被引量:98
标识
DOI:10.1126/scitranslmed.abb3946
摘要
Osteoarthritis (OA) is a widespread joint disease for which there are no disease-modifying treatments. Previously, we found that mice with cartilage-specific epidermal growth factor receptor (EGFR) deficiency developed accelerated knee OA. To test whether the EGFR pathway can be targeted as a potential OA therapy, we constructed two cartilage-specific EGFR overactivation models in mice by overexpressing heparin binding EGF-like growth factor (HBEGF), an EGFR ligand. Compared to wild type, Col2-Cre HBEGF-overexpressing mice had persistently enlarged articular cartilage from adolescence, due to an expanded pool of chondroprogenitors with elevated proliferation ability, survival rate, and lubricant production. Adult Col2-Cre HBEGF-overexpressing mice and Aggrecan-CreER HBEGF-overexpressing mice were resistant to cartilage degeneration and other signs of OA after surgical destabilization of the medial meniscus (DMM). Treating mice with gefitinib, an EGFR inhibitor, abolished the protective action against OA in HBEGF-overexpressing mice. Polymeric micellar nanoparticles (NPs) conjugated with transforming growth factor-α (TGFα), a potent EGFR ligand, were stable and nontoxic and had long joint retention, high cartilage uptake, and penetration capabilities. Intra-articular delivery of TGFα-NPs effectively attenuated surgery-induced OA cartilage degeneration, subchondral bone plate sclerosis, and joint pain. Genetic or pharmacologic activation of EGFR revealed no obvious side effects in knee joints and major vital organs in mice. Together, our studies demonstrate the feasibility of using nanotechnology to target EGFR signaling for OA treatment.
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