2. Academic Validation
  3. CircZSWIM6 mediates dysregulation of ECM and energy homeostasis in ageing chondrocytes through RPS14 post-translational modification

CircZSWIM6 mediates dysregulation of ECM and energy homeostasis in ageing chondrocytes through RPS14 post-translational modification

  • Clin Transl Med. 2023 Jan;13(1):e1158. doi: 10.1002/ctm2.1158.
Zhe Gong 1 2 3,  Kefan Wang 1 2 3,  Junxin Chen 1 2 3,  Jinjin Zhu 1 2 3,  Zhenhua Feng 1 2 3,  Chenxin Song 1 2 3,  Zheyuan Zhang 1 2 3,  Haoming Wang 1 2 3,  Shunwu Fan 1 2 3,  Shuying Shen 1 2 3,  Xiangqian Fang 1 2 3
Affiliations

Affiliations

  • 1 Department, of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, Zhejiang, China.
  • 2 Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 3 Sir Run Run Shaw Institute of Clinical Medicine of Zhejiang University, Hangzhou, Zhejiang, China.
PMID: 36604982 DOI: 10.1002/ctm2.1158
Abstract

Background: Circular RNAs (CircRNAs) are important and have different roles in disease progression. Herein, we aim to elucidate the roles of a novel CircRNA (CircZSWIM6) which is upregulated in ageing chondrocytes.

Methods: We verified the roles of CircZSWIM6 in senescent and osteoarthritis (OA) development in vitro through CircZSWIM6 knockdown and overexpression. RNA pulldown assay and RNA binding protein immunoprecipitation were performed to identify the interaction between CircZSWIM6 and Ribosomal protein S14 (RPS14). The roles of CircZSWIM6 in ageing-related OA were also confirmed in non-traumatic and traumatic model respectively.

Results: CircZSWIM6 regulates extracellular matrix (ECM) and energy metabolism in ageing chondrocyte. Mechanistically, CircZSWIM6 competitively bound to the E3 Ligase STUB1 binding site on RPS14 (K125) to inhibit proteasomal degradation of RPS14 to maintain RPS14 function. CircZSWIM6-RPS14 axis is highly associated with AMPK signaling transduction, which keeps energy metabolism in chondrocyte. Furthermore, CircZSWIM6 AAV Infection leads to senescent and OA phenotypes in a non-traumatic model and accelerates OA progression in a traumatic model.

Conclusion: Our results revealed a significant role of CircZSWIM6 in age-related OA by regulating ECM metabolism and AMPK-associated energy metabolism. We highlight the CircZSWIM6-RPS14-PCK1-AMPK axis is a potential biomarker for OA.

Keywords

AMPK; CircZSWIM6; RPS14; metabolism; osteoarthritis; senescence.

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