EGFR Signaling Is Required for Maintaining Adult Cartilage Homeostasis and Attenuating Osteoarthritis Progression

Abstract

The uppermost superficial zone of articular cartilage is the first line of defense against the initiation of osteoarthritis (OA). We previously used Col2-Cre to demonstrate that epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, plays an essential role in maintaining superficial chondrocytes during articular cartilage development. Here, we showed that EGFR activity in the articular cartilage decreased as mice age. In mouse and human OA samples, EGFR activity was initially reduced at the superficial layer and then resurged in cell clusters within the middle and deep zone in late OA. To investigate the role of EGFR signaling in postnatal and adult cartilage, we constructed an inducible mouse model with cartilage-specific EGFR inactivation (Aggrecan-CreER Egfr Wa5/flox , Egfr iCKO). EdU incorporation revealed that postnatal Egfr iCKO mice contained fewer slow-cycling cells than controls. EGFR deficiency induced at 3 months of age reduced cartilage thickness and diminished superficial chondrocytes, in parallel to alterations in lubricin production, cell proliferation, and survival. Furthermore, male Egfr iCKO mice developed much more severe OA phenotypes, including cartilage erosion, subchondral bone plate thickening, cartilage degeneration at the lateral site, and mechanical allodynia, after receiving destabilization of the medial meniscus (DMM) surgery. Similar OA phenotypes were also observed in female iCKO mice. Moreover, tamoxifen injections of iCKO mice at 1 month post-surgery accelerated OA development 2 months later. In summary, our data demonstrated that chondrogenic EGFR signaling maintains postnatal slow-cycling cells and plays a critical role in adult cartilage homeostasis and OA progression.

Unbiased comparison and modularization identify time-related transcriptomic reprogramming in exercised rat cartilage: Integrated data mining and experimental validation

“…EGFR is a trans-membrane receptor tyrosine kinase ( Dutta and Maity, 2007 ). EGFR signaling is critical for maintaining adult cartilage homeostasis and attenuating osteoarthritis progression ( Jia et al, 2016 ; Mchugh, 2021 ; Wei et al, 2022 ). Genetic or pharmacologic activation of EGFR attenuates surgery-induced OA cartilage degeneration, subchondral bone plate sclerosis, and joint pain ( Wei et al, 2021 ).…”

Activating EGFR Signaling Attenuates Osteoarthritis Development Following Loading Injury in Mice

“…These data complement our previous reports showing that EGFR signaling attenuates OA development in a surgical DMM model. (5,11,13) A single loading episode of mouse tibia induced lesions, indicated by cell death, in articular cartilage. Mechanistically, we found that activating EGFR signaling promoted the survival and lubrication of chondrocytes at the lesion site, thereby mitigating the loading impact on cartilage.…”

“…(5) A subsequent study using inducible chondrocyte-specific Aggrecan-CreER demonstrated that EGFR activity is also required for the normal structure and function of articular cartilage and preventing OA initiation after DMM surgery. (11) In contrast, EGFR overactivation in mice by overexpressing EGFR ligand, HBEGF, in chondrocytes using Col2a1-Cre leads to articular cartilage expansion in young mice and resistance to DMM-induced OA progression in adult mice. (13) Interestingly, HBEGF overexpression stimulates the proliferation and survival of chondrocytes at the top layer of articular cartilage but does not affect the production of cartilage matrix proteins and the synthesis of cartilage degradation proteases.…”

“…Although EGFR is expressed ubiquitously by articular cartilage chondrocytes, EGFR activity, indicated by phosphorylated EGFR (p-EGFR) and phosphorylated ERK (p-ERK), is mainly located at the superficial layer of human and mouse articular cartilage. (11) This activity is drastically reduced during aging and OA initiation, indicating an essential role in OA progression. Previous cell culture studies showed that EGFR had both anabolic and catabolic actions.…”

“…( 5 ) A subsequent study using inducible chondrocyte‐specific Aggrecan‐CreER demonstrated that EGFR activity is also required for the normal structure and function of articular cartilage and preventing OA initiation after DMM surgery. ( 11 )…”