Gefitinib for Epidermal Growth Factor Receptor Activated Osteoarthritis Subpopulation Treatment

Abstract

Osteoarthritis (OA) is a leading cause of physical disability among aging populations, with no available drugs able to efficiently restore the balance between cartilage matrix synthesis and degradation. Also, OA has not been accurately classified into subpopulations, hindering the development toward personalized precision medicine.In the present study, we identified a subpopulation of OA patients displaying high activation level of epidermal growth factor receptor (EGFR). With Col2a1-creERT2; Egfrf/f mice, it was found that the activation of EGFR, indicated by EGFR phosphorylation (pEGFR), led to the destruction of joints. Excitingly, 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 structure and function in the mouse model as well as the clinical case report.Overall, our findings suggested the concept of the EGFR activated OA subpopulation and illustrated the mechanism of EGFR signaling in regulating cartilage homeostasis. Gefitinib could be a promising disease-modifying drug for this OA subpopulation treatment.

EGFR Signaling: Friend or Foe for Cartilage?

“…Since early studies have demonstrated that OA initiation in dog and cyclic impact loading on cartilage explants significantly elevate Mig‐6 mRNA level in chondrocytes, we reason that the downregulation of EGFR activity during early OA is potentially due to the abnormal loading‐induced Mig6 action and therefore could occur without changes in ligand availability. At the late stage of OA, it was reported that human OA samples (between 3 and 4 in the Kellgren and Lawrence grading system), as well as rat samples after OA surgery, contain significantly more activated EGFR than controls. These temporal changes of EGF‐like ligands and EGFR activity during OA progression strongly implicate that EGFR signaling is involved in OA pathology but possibly in a stage‐dependent manner.…”

Inhibition of Osteoarthritis-Related Molecules by Isomucronulatol 7-O-β-d-glucoside and Ecliptasaponin A in IL-1β-Stimulated Chondrosarcoma Cell Model

“…Ageing, obesity, gender, increased biomechanical loading of joints, and genetics or low-grade systemic inflammation have been known as risk factors for OA [ 9 , 10 ]. Although the mechanistic details of OA pathogenesis remain to be elucidated, the cartilage degradation and inflammation is the most predominant pathological feature that inevitably leads to joint dysfunction [ 11 , 12 ]. The articular cartilage is composed of water and extracellular matrix (ECM), which mainly composed of Type II collagen, aggrecan, proteoglycans and other collagen subtypes [ 10 ].…”

“…The articular cartilage is composed of water and extracellular matrix (ECM), which mainly composed of Type II collagen, aggrecan, proteoglycans and other collagen subtypes [ 10 ]. Thus, the cartilage homeostasis is maintained by the balance between ECM synthesis and degradation [ 12 ]. Disturbances of this balance are one of the main characteristics of OA cartilage, and the restoration of balance is the key factor for cartilage regeneration in OA.…”

Overexpression of Mig-6 in Cartilage Induces an Osteoarthritis-Like Phenotype in Mice

“…Mig-6 overexpression has been demonstrated in OA cartilage in dogs (38), suggesting that the same could occur in human OA. More generally, the EGFR pathway, through which Mig-6 primarily acts, has been shown to be deregulated in human OA in several studies (21,34,72).Thus, the current study is highly relevant to the pathogenesis of human OA.…”

“…In addition, the role of Mig-6 in human OA will require further studies. While there is plenty of evidence for crucial roles of the EGFR pathway in human OA, and Mig-6 is a crucial regulator of this pathway, more direct analyses of this role in human cartilage is required (21,71,72).…”