1. Academic Validation
  2. Acid-sensitive ion channel 1a mediates osteoarthritis chondrocyte senescence by promoting Lamin B1 degradation

Acid-sensitive ion channel 1a mediates osteoarthritis chondrocyte senescence by promoting Lamin B1 degradation

  • Biochem Pharmacol. 2022 Aug;202:115107. doi: 10.1016/j.bcp.2022.115107.
Jie Ding 1 Yong Chen 1 Ying-Jie Zhao 1 Fan Chen 1 Lei Dong 1 Hai-Lin Zhang 1 Wei-Rong Hu 2 Shu-Fang Li 1 Ren-Peng Zhou 3 Wei Hu 4
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China.
  • 2 The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Medical University, Ministry of Education, Hefei 230032, China.
  • 3 Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China; Anhui Provincial Institute of Translational Medicine, Hefei 230032, China. Electronic address: zhourenpeng@ahmu.edu.cn.
  • 4 Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China; Anhui Provincial Institute of Translational Medicine, Hefei 230032, China. Electronic address: huwei@ahmu.edu.cn.
Abstract

Osteoarthritis (OA) is a common and debilitating chronic joint disease, which is characterized by degeneration of articular cartilage and the aging of chondrocytes. Acid-sensitive ion channel 1a (ASIC1a) is a proton-activated cationic channel abundant in chondrocytes, which senses and regulates joint cavity pH. Our previous study demonstrated that ASIC1a was involved in acid-induced rat articular chondrocyte senescence, but the mechanistic basis remained unclear. In this study, we explored the mechanism of ASIC1a in chondrocyte senescence and OA. The results showed that senescence-related-β-galactosidase, senescence-related markers (p53 and p21) and the autophagy-related protein Beclin-1 were found to be increased, but Lamin B1 was found to be reduced with acid (pH 6.0) treatment. These effects were inhibited by ASIC1a-specific blocker psalmotoxin-1 or ASIC1a-short hairpin RNA respectively in chondrocytes. Moreover, Silencing of Lamin B1 enhanced ASIC1a-mediated chondrocyte senescence, this effect was reversed by overexpression of Lamin B1, indicating that Lamin B1 was involved in ASIC1a-mediated chondrocyte senescence. Further, blockade of ASIC1a inhibits acid-induced autophagosomes and Beclin-1 protein expression, suggesting that ASIC1a is involved in acid-induced chondrocyte Autophagy. Blocking Autophagy with chloroquine inhibited Beclin-1 and increased Lamin B1 in acid-induced chondrocyte senescence. We further demonstrated that ASIC1a-mediated reduction of Lamin B1 expression was caused by Autophagy pathway-dependent protein degradation. Finally, blocking ASIC1a protected cartilage tissue, restored Lamin B1 levels and inhibited chondrocyte senescence in a rat OA model. In summary, these findings suggest that ASIC1a may promote Lamin B1 degradation to mediate osteoarthritis chondrocyte senescence through the Autophagy pathway.

Keywords

ASIC1a; Acid; Autophagy; Lamin B1; Osteoarthritis; Senescence.

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