H. Sun (Hangzhou, CN)

Zhejiang University School of Medicine

Presenter Of 1 Presentation

Podium Presentation Osteoarthritis

23.4.9 - Gefitinib for Epidermal Growth Factor Receptor Activated Osteoarthritis Subpopulation Treatment

Presentation Number
23.4.9
Presentation Topic
Osteoarthritis
Lecture Time
11:33 - 11:42
Session Type
Free Papers
Corresponding Author
Disclosure
No Significant Commercial Relationship

Abstract

Purpose

We sought to investigate the mechanism of epidermal growth factor receptor (EGFR) in regulating osteoarthritis (OA), and identify a drug which could restore the balance between cartilage matrix synthesis and degradation in the corresponding OA subpopulation.

Methods and Materials

Immunohistochemistry was performed to evaluate EGFR activation in the cartilage of OA patients. The conditional gene knockout (Col2a1-creERT2; Egfrf/f) mice were utilized and the destabilization of medial meniscus (DMM) surgery was conducted to induce OA. Gefitinib encapsulated chitosan microspheres or lentivirus were injected into the joints for treatment or gene knockdown. Safranin O and immunostaining were performed to evaluate EGFR activation and OA progression. For in vitro study, qPCR and western blot analysis were utilized for transcriptional and translational change detection respectively. RNA sequencing was also performed for the transcriptome alteration analysis.

Results

The heterogeneous activation of EGFR among the OA patients was discovered, and the subpopulation of OA patients displaying high activation level of EGFR (indicated by phosphorylated EGFR) was identified. With Col2a1-creERT2; Egfrf/fmice, it was found that EGFR inhibition prohibited cartilage matrix degeneration and promoted cartilage regeneration in the mouse OA model. Consistent with the clinical case report, The Food and Drug Administration (FDA)-approved drug gefitinib could efficiently inhibit EGFR functions to restore chondrocyte phenotype in vitro and preserve OA joints in vivo. Mechanism study showed that gefitinib exerts its protective effect through re-activating autophagy in the chondrocytes.

Conclusion

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.

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