ASIC1a Promotes Acid-Induced Autophagy in Rat Articular Chondrocytes through the AMPK/FoxO3a Pathway.

Beibei Dai,Zhisen Wang,Feihu Chen,Jinfang Ge,Shengqin Zu,Xiaoshan Wu,Yaya Xie,Ge Li,Yong Chen,Renpeng Zhou,Fei Zhu

doi:10.3390/ijms18102125

Beibei Dai, Zhisen Wang + Show 9 more

Open Access

https://doi.org/10.3390/ijms18102125

Copy DOI

Abstract

Acid-sensing ion channel 1a (ASIC1a) is a member of the extracellular H+-activated cation channels family. Our previous studies suggested that ASIC1a contributed to acid-induced rat articular chondrocytes autophagy. However, its potential mechanisms remain unclear. The present study demonstrated the effect of ASIC1a on rat articular chondrocytes autophagy and explored the underlying molecular mechanisms. The results demonstrated that ASIC1a contributed to acid-induced autophagy in rat articular chondrocytes, and which was associated with an increase in (Ca2+)i, as indicated that acid-induced increases in mRNA and protein expression of LC3B-II and other autophagy-related markers were inhibited by ASIC1a-specific blocker, PcTx1 and calcium chelating agent, BAPTA-AM. Furthermore, the results showed that extracellular acid increased level of Forkhead box O (FoxO) 3a, but was reversed by inhibition of ASIC1a and Ca2+ influx. Moreover, gene ablation of FoxO3a prevented acid-induced increases in mRNA and protein expression of LC3B-II, Beclin1 and the formation of autophagosome. Finally, it also showed that ASIC1a activated adenine nucleotide (AMP)-activated protein kinase (AMPK). In addition, suppression of AMPK by Compound C and its small interfering RNA (siRNA) prevented acid-induced upregulation of total and nuclear FoxO3a and increases in mRNA and protein expression of LC3B-II, Beclin1, and ATG5. Taken together, these findings suggested that AMPK/FoxO3a axis plays an important role in ASIC1a-mediated autophagy in rat articular chondrocytes, which may provide novel mechanistic insight into ASIC1a effects on autophagy.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disorder that affects 1% of the population in the world and characterized by chronic, multi arthritis synovial inflammation, leading to extra articular lesion [1]
Our previous studies indicated that the activation of acid-sensing ion channel 1a (ASIC1a) contributed to the acid-induced articular chondrocytes damage which was associated with an increase in (Ca2+)i and blockade of ASIC1a protected articular cartilage from the destruction [11,12,13,14]
Our results showed that ASIC1a promoted autophagy in acid-induced articular chondrocytes by increasing intracellular calcium concentrations, which was consistent with the results in our previous study

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disorder that affects 1% of the population in the world and characterized by chronic, multi arthritis synovial inflammation, leading to extra articular lesion [1]. Acid-sensing ion channels (ASICs), known as voltage-independent cationic channels that belong to the epithelial sodium channel/degenerin family, can be transiently activated by extracellular acidification [3]. A decrease in extracellular pH activates ASICs, and leads to the extracellular Na+, Ca2+ influx, which regulates cell behaviors such as apoptosis, differentiation, and autophagy [4,5,6,7,8]. Our previous studies indicated that the activation of acid-sensing ion channel 1a (ASIC1a) contributed to the acid-induced articular chondrocytes damage which was associated with an increase in (Ca2+)i and blockade of ASIC1a protected articular cartilage from the destruction [11,12,13,14].

Methods

Results

Discussion

Conclusion