EGFR Signaling Is Critical For Maintaining The Superficial Layer Of Articular Cartilage And Preventing Osteoarthritis Progression

Background/Object: To investigate the function of epidermal growth factor receptor(EGFR) in articular cartilage development and osteoarthritis(OA) progression in genetically modified and surgical mouse models.Methods: Cartilage-specific Egfr knockout(CKO) mice were generated. Their knee joints as well as controls were examined by histology, immunohistochemistry, nanoindentation, and micro CT with or without destabilization of the medial meniscus(DMM) surgery. Primary chondrocytes were used to study the direct effects of activating EGFR on chondrocytes. Computational simulation was built to calculate the loading on cartilage and subchondral bone plate(SBP) after DMM.Results: EGFR is expressed in both human and mouse articular cartilage and its activity is more dominant in the superficial layer. Compared to controls, adult CKO mice had fewer superficial chondrocytes, lower cartilage surface stiffness, and less boundary lubricant secretion and developed early OA symptoms and phenotypes. In culture, activating EGFR is critical for maintaining chondrocyte number, preventing hypertrophy, and promoting Prg4 expression. After DMM, CKO mice quickly developed the most severe OA phenotype including a complete loss of cartilage at the medial side and an increase in joint pain. They also developed subchondral bone sclerosis only under the cartilage damage area, which is caused by elevated mechanical loading, reduced sclerostin amount, and increased bone formation in SBP.Conclusion: EGFR signaling is critical for articular cartilage homeostasis and OA development. Local crosstalk between damaged cartilage and SBP in OA is mediated by mechanical loading.