Targeting cartilage EGFR pathway for osteoarthritis treatment

Authors

Yulong Wei, University of Pennsylvania Perelman School of Medicine
Lijun Luo, University of Pennsylvania
Tao Gui, University of Pennsylvania Perelman School of Medicine
Feifan Yu, Alphathera LLC
Lesan Yan, University of Pennsylvania
Lutian Yao, University of Pennsylvania Perelman School of Medicine
Leilei Zhong, University of Pennsylvania Perelman School of Medicine
Wei Yu, University of Pennsylvania Perelman School of Medicine
Biao Han, Drexel University
Jay M. Patel, University of Pennsylvania Perelman School of Medicine
Jessica F. Liu, University of Pennsylvania
Frank Beier, Schulich School of Medicine & Dentistry
Lawrence Scott Levin, University of Pennsylvania Perelman School of Medicine
Charles Nelson, University of Pennsylvania Perelman School of Medicine
Zengwu Shao, Tongji Medical College
Lin Han, Drexel University
Robert L. Mauck, University of Pennsylvania Perelman School of Medicine
Andrew Tsourkas, University of Pennsylvania
Jaimo Ahn, University of Pennsylvania Perelman School of Medicine
Zhiliang Cheng, University of Pennsylvania
Ling Qin, University of Pennsylvania Perelman School of Medicine

Document Type

Article

Publication Date

1-1-2021

Journal

Science Translational Medicine

Volume

13

Issue

576

URL with Digital Object Identifier

10.1126/SCITRANSLMED.ABB3946

Abstract

© 2021 The Authors. 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.