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.

Arthritis: Protein protects against cartilage damage

A protein called epidermal growth factor receptor (EGFR) helps protect against cartilage destruction in mouse models of osteoarthritis. Ling Qin, from the University of Pennsylvania Perelman School of Medicine, USA, and colleagues in China and Canada induced the degenerative joint disease osteoarthritis by surgically destabilizing the meniscus in mouse joints. They reduced the levels of EGFR in mice either through genetic modification or with gefitinib, a cancer drug. Tissue analyses conducted three months after surgery revealed that chondrocytes, the cells that maintain healthy cartilage, were more severely damaged in mice with reduced levels of EGFR than in mice with normal levels. Elevated amounts of destructive proteinase enzymes contributed to the cartilage degradation, resulting in accelerated progression of osteoarthritis. The findings point to EGFR as a potential therapeutic target for osteoarthritis drug development.

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