EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation

Abstract

<p id="d1764964e427">The uppermost superficial zone of articular cartilage plays multifaceted roles in maintaining cartilage structure, function, and mechanical properties and in preventing cartilage degeneration during osteoarthritis initiation. However, its regulation by growth factors and hormones is still largely unknown. Here we report that EGFR signaling is an important growth factor pathway that maintains superficial chondrocyte number, promotes boundary lubricant secretion and cartilage surface lubrication, and stimulates mechanical strength of articular cartilage. Reduction in EGFR activity leads to structurally, functionally, and mechanically compromised articular cartilage during development and drastically accelerates cartilage degeneration under normal and surgically induced osteoarthritis conditions. Thus, our studies strongly suggest that targeting cartilage surface EGFR signaling should be considered as a novel direction for osteoarthritis treatment. </p><p class="first" id="d1764964e430">Osteoarthritis (OA) is the most common joint disease, characterized by progressive destruction of the articular cartilage. The surface of joint cartilage is the first defensive and affected site of OA, but our knowledge of genesis and homeostasis of this superficial zone is scarce. EGFR signaling is important for tissue homeostasis. Immunostaining revealed that its activity is mostly dominant in the superficial layer of healthy cartilage but greatly diminished when OA initiates. To evaluate the role of EGFR signaling in the articular cartilage, we studied a cartilage-specific <i>Egfr</i>-deficient ( <i>CKO</i>) mouse model ( <i>Col2-Cre EgfrWa5/flox</i>). These mice developed early cartilage degeneration at 6 mo of age. By 2 mo of age, although their gross cartilage morphology appears normal, <i>CKO</i> mice had a drastically reduced number of superficial chondrocytes and decreased lubricant secretion at the surface. Using superficial chondrocyte and cartilage explant cultures, we demonstrated that EGFR signaling is critical for maintaining the number and properties of superficial chondrocytes, promoting chondrogenic proteoglycan 4 (Prg4) expression, and stimulating the lubrication function of the cartilage surface. In addition, EGFR deficiency greatly disorganized collagen fibrils in articular cartilage and strikingly reduced cartilage surface modulus. After surgical induction of OA at 3 mo of age, <i>CKO</i> mice quickly developed the most severe OA phenotype, including a complete loss of cartilage, extremely high surface modulus, subchondral bone plate thickening, and elevated joint pain. Taken together, our studies establish EGFR signaling as an important regulator of the superficial layer during articular cartilage development and OA initiation. </p>