Fibroblast growth factor 21 (FGF21) alleviates senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the SIRT1-mTOR signaling pathway

Hongwei Lu,Xiucui Li,Wei Wang,Dengying Wu,Jun Pan,Chao Jia,Zeng Lin,Haidong Jin

doi:10.1038/s41419-021-04157-x

Abstract

Osteoarthritis (OA) is a complex condition that involves both apoptosis and senescence and currently cannot be cured. Fibroblast growth factor 21 (FGF21), known for its role as a potent regulator of glucose and energy metabolism, protects from various diseases, possibly by mediating autophagy. In the present study, the role of FGF21 in the progression of OA was investigated in both in vitro and in vivo experiments. In vitro, the results revealed that FGF21 administration alleviated apoptosis, senescence, and extracellular matrix (ECM) catabolism of the chondrocytes induced by tert-butyl hydroperoxide (TBHP) by mediating autophagy flux. Furthermore, CQ, an autophagy flux inhibitor, could reverse the protective effect of FGF21. It was observed that the FGF21-induced autophagy flux enhancement was mediated by the nuclear translocation of TFEB, which occurs due to the activation of the SIRT1-mTOR signaling pathway. The in vivo experiments demonstrated that FGF21 treatment could reduce OA in the DMM model. Taken together, these findings suggest that FGF21 protects chondrocytes from apoptosis, senescence, and ECM catabolism via autophagy flux upregulation and also reduces OA development in vivo, demonstrating its potential as a therapeutic agent in OA.

Highlights

Osteoarthritis (OA) is a degenerative disease of the joints that occurs in the elderly [1]
We found and senescence induced by tert-butyl hydroperoxide (TBHP) in chondrocytes that Fibroblast growth factor 21 (FGF21) might suppress apoptosis, senescence, and extracellular matrix (ECM) Chloroquine (CQ), a lysosomal cavity alkalizer, was found to block catabolism induced by TBHP in chondrocytes
The results demonstrated compared to their levels in the FGF21 group, indicating that that Collagen II and aggrecan were reduced in the TBHP group, autophagy flux was involved in the protective effect of FGF21 on while MMP-13 and ADAMTS-5 were enhanced in this group. the catabolism of ECM in the chondrocytes (Fig. 5A, B)

Summary

INTRODUCTION

Osteoarthritis (OA) is a degenerative disease of the joints that occurs in the elderly [1]. Assay further demonstrated that FGF21 could reduce the incidence of senescence in the chondrocytes induced by TBHP CQ reversed the protective effects of FGF21 on the ECM (Fig. 1F, H). The results demonstrated compared to their levels in the FGF21 group, indicating that that Collagen II and aggrecan were reduced in the TBHP group, autophagy flux was involved in the protective effect of FGF21 on while MMP-13 and ADAMTS-5 were enhanced in this group. These results demonstrated that FGF21 inhibited the FGF21 upregulated autophagy flux by enhancing TFEB catabolism of the ECM induced in the chondrocytes by TBHP. There were more autophagy bodies and autophagy lysosomes in the cytoplasm of chondrocytes treated with FGF21 con-siRNA group, the number of autophagosomes and autophagolysosomes was significantly reduced in the TFEB-siRNA3 group, indicating impaired autophagic flux with lysosomal dysfunction (Fig. 3E) These results collectively suggested that FGF21 promoted (Fig. 6F, G).

Lu et al 3

DISCUSSION

MATERIALS AND METHODS

Findings

ETHICS STATEMENT