Study On The Effects And Mechanism Of Epidermal Growth Factor Receptor Inhibition On Cartilage Homeostasis Restoration In Osteoarthritis

Osteoarthritis(OA)is the most widely spread degenerative arthritic disease affecting millions of people worldwide,bringing heavy burden to family and society.Currently,there are still no etiological treatments for OA due to our limited understanding of the disease mechanism.Previous studies revealed that the epidermal growth factor receptor(EGFR)signaling pathway plays an important role during cartilage development and pathogenesis,but the direct impact of EGFR on OA development still remains elusive.Additionally,OA has not been accurately classified into subpopulations,thus hindering the development of personalized precision medicine.The aim of our research was to clarify the exact mechanism of EGFR in OA development,and to identify subpopulations associated with EGFR that could be targeted with the existing EGFR inhibiting drug.This study utilized a conditional knockout system,a small molecule inhibitor,a controlled-release system and high-throughput sequencing method.Moreover,the EGFR activation level was examined in multiple human patients,taking research from the"bench-to-bedside".We discovered that the activation of EGFR,indicated by EGFR phosphorylation(pEGFR),led to an inhibition of the cartilage extracellular matrix(ECM)components biosynthesis,and an up-regulation of the matrix-degrading enzyme matrix expression to destruct joints.In contrast,EGFR inhibition prohibited cartilage matrix degeneration and promoted cartilage regeneration.The Food and Drug Administration(FDA)-approved drug gefitinib could efficiently inhibit EGFR functions in OA joints and restore cartilage homeostasis of OA with high EGFR activity.In order to avoid the side effects from direct systemically administered gefitinib,chitosan microspheres were employed for intra-articular controlled-release of the drug;results showed promising therapeutic effect of gefitinib-encapsulated chitosan microspheres with minimal unexpected side effects.Furthermore,in the mechanical study,chromotin immunoprecipitation followed by sequencing(ChIP-seq)and RNA sequencing(RNA-seq)were performed and illustrated that autophagy was involved in the connection between EGFR activation and cartilage homeostasis.At last,we examined 59 OA patients and identified an OA subpopulation displaying high activation level of EGFR(pEGFRhigh).This subpopulation of OA patients was also found to share similar characteristics to what we previously described in the mouse OA model.Overall,our findings supported the concept of OA subpopulation with high EGFR activity and illustrated the mechanism of EGFR signaling in cartilage homeostasis regulation.Gefitinib could be a promising disease-modifying drug for pEGFRhigh OA subpopulation treatment.The concept of targeting a specific subpopulation,together with the application of FDA-approved drug gefitinib,shed new light upon OA treatment and precision medicine.