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Journal article
Targeting cartilage EGFR pathway for osteoarthritis treatment
Science translational medicine, v 13(576)
13 Jan 2021
PMID: 33441426
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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Details
- Title
- Targeting cartilage EGFR pathway for osteoarthritis treatment
- Creators
- Yulong Wei - Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.Lijun Luo - University of PennsylvaniaTao Gui - University of PennsylvaniaFeifan Yu - AlphaTheraLesan Yan - University of PennsylvaniaLutian Yao - University of PennsylvaniaLeilei Zhong - University of PennsylvaniaWei Yu - Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.Biao Han - School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104, USAJay M Patel - University of PennsylvaniaJessica F Liu - University of PennsylvaniaFrank Beier - Western UniversityLawrence Scott Levin - University of PennsylvaniaCharles Nelson - University of PennsylvaniaZengwu Shao - Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022,China)Lin Han - Drexel UniversityRobert L Mauck - University of PennsylvaniaAndrew Tsourkas - University of PennsylvaniaJaimo Ahn - University of PennsylvaniaZhiliang Cheng - University of PennsylvaniaLing Qin - University of Pennsylvania
- Publication Details
- Science translational medicine, v 13(576)
- Publisher
- American Association for the Advancement of Science (AAAS)
- Grant note
- R01 AG067698 / NIA NIH HHS R01 AR066098 / NIAMS NIH HHS R01 NS100892 / NINDS NIH HHS P30 AR069619 / NIAMS NIH HHS R01 DK095803 / NIDDK NIH HHS R01 AR074490 / NIAMS NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000608364400004
- Scopus ID
- 2-s2.0-85099998865
- Other Identifier
- 991019168175504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Medicine, Research & Experimental