title: Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model.
abstract: Osteoarthritis (OA) is a degenerative joint disease and a major cause of pain and disability in older adults. We have previously identified epidermal growth factor receptor (EGFR) signaling as an important regulator of cartilage matrix degradation during epiphyseal cartilage development. To study its function in OA progression, we performed surgical destabilization of the medial meniscus (DMM) to induce OA in two mouse models with reduced EGFR activity, one with genetic modification (Egfr(Wa5/+) mice) and the other one with pharmacological inhibition (gefitinib treatment). Histological analyses and scoring at 3 months post-surgery revealed increased cartilage destruction and accelerated OA progression in both mouse models. TUNEL staining demonstrated that EGFR signaling protects chondrocytes from OA-induced apoptosis, which was further confirmed in primary chondrocyte culture. Immunohistochemistry showed increased aggrecan degradation in these mouse models, which coincides with elevated amounts of ADAMTS5 and matrix metalloproteinase 13 (MMP13), the principle proteinases responsible for aggrecan degradation, in the articular cartilage after DMM surgery. Furthermore, hypoxia-inducible factor 2α (HIF2α), a critical catabolic transcription factor stimulating MMP13 expression during OA, was also upregulated in mice with reduced EGFR signaling. Taken together, our findings demonstrate a primarily protective role of EGFR during OA progression by regulating chondrocyte survival and cartilage degradation.
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania , Philadelphia, PA, USA ; Department of Physiology, School of Basic Medical Sciences, Wuhan University , Wuhan, China.
authors.forename: Xianrong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania , Philadelphia, PA, USA ; Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital , Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania , Philadelphia, PA, USA ; Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine , Shanghai, China.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Chandra
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: L Scott
authors.initials: LS
authors.lastname: Levin
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario , London, ON, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania , Philadelphia, PA, USA ; Department of Surgery, The Children's Hospital of Philadelphia , Philadelphia, PA, USA.
authors.forename: Motomi
authors.initials: M
authors.lastname: Enomoto-Iwamoto
authors.affiliation: Department of Orthopaedic Surgery, School of Medicine, University of Pennsylvania , Philadelphia, PA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Qin