SIRT1 Restoration Enhances Chondrocyte Autophagy in Osteoarthritis Through PTEN-Mediated EGFR Ubiquitination

The pharmacological interventions aimed at activating pathways inducing chondrocyte autophagy or reversing extracellular matrix degradation may be a promising approach for the management of OA. Evidence exists suggesting that sirtuin 1 (SIRT1) is involved in the pathogenesis of osteoarthritis (OA). The present study aimed to explore the regulatory role of SIRT1 in OA. Bioinformatic predictions identified downstream factors phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) in OA. We found poorly expressed SIRT1 and EGFR and highly expressed PTEN in cartilage tissues of OA patients. OA was induced in vitro by exposing human primary chondrocytes to IL-1β and in vivo by destabilization of the medial meniscus (DMM) in a mouse model. SIRT1 knockdown was found to augment IL-1β-stimulated inflammation and chondrocyte metabolic imbalance. Knockdown of SIRT1 diminished PTEN acetylation and then enhanced PTEN expression. PTEN inactivation decreased EGFR ubiquitination and promoted EGFR expression by destabilizing the EGFR-Cbl complex, which in turn inhibited extracellular matrix degradation in cartilage tissue and activated chondrocyte autophagy. In the DMM mouse model, knockdown of SIRT1 inhibited chondrocyte autophagy, increased metabolic imbalance, thus accelerating osteoarthritic process. In conclusion, SIRT1 represses the ubiquitination of EGFR by down-regulating PTEN, thereby inhibiting extracellular matrix degradation and activating chondrocyte autophagy, thereby playing a role in alleviating OA. Funding Information: This study was supported by Youth Foundation of National Natural Science Foundation of China (No. 82002343); General Projects of Shandong Natural Science Foundation (No. ZR2020MH147 & No. ZR2020MH278). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: This study was approved by the Ethics Committee of Qilu Hospital of Shandong University and written informed consent of the patients or caregivers were obtained. The study was performed in accordance with the Declaration of Helsinki. All animal experiments were performed under a protocol approved by the Laboratory Animal Care and Use Committee of Qilu Hospital of Shandong University.