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

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.

Circular RNA circARPC1B functions as a stabilisation enhancer of Vimentin to prevent high cholesterol‐induced articular cartilage degeneration

“…As a major post-translational modification, ubiquitylation regulates several physiological processes including chondrocytes metabolism. 15,47,59 CircARPC1B knockdown increased Vimentin ubiquitination, whereas circARPC1B overexpression decreased its ubiquitination. Furthermore, rescue experiments further demonstrated that circARPC1B functions as a Vimentin stabilisation enhancer to prevent chondrocyte degradation.…”

“…CircARPC1B altered the expression level of Vimentin protein but not its mRNA level, implying that circARPC1B can influence post‐translational modifications of Vimentin. As a major post‐translational modification, ubiquitylation regulates several physiological processes including chondrocytes metabolism 15,47,59 . CircARPC1B knockdown increased Vimentin ubiquitination, whereas circARPC1B overexpression decreased its ubiquitination.…”

Cellular senescence: A potential mode of circular RNAs regulating prostate cancer

“…AMPK is an important regulator of cellular energy homeostasis, which can regulate cell growth, differentiation and apoptosis by affecting signaling pathways such as mTOR and p53. 107,135 The classic mechanism by which circRNA functions is the ceRNA network. There have demonstrated that circ_002581 regulated the PTEN-AMPK-mTOR pathway via acting as a sponge for miR-122, 117 circWHSC1 modulated the FASN-AMPK-mTOR axis by sponging miR-195-5p, 118 circ_0057558 acted as a miR-206 sponge to activate the ROCK1/AMPK signaling.…”

“…AMPK is an important regulator of cellular energy homeostasis, which can regulate cell growth, differentiation and apoptosis by affecting signaling pathways such as mTOR and p53 107,135 …”

Circ-Slain2 Alleviates Cartilage Degradation and Inflammation of TMJOA

“…Although the various biological functions and molecular mechanisms of cir-cRNAs remain largely uncharacterized, emerging evidence suggests that they participate in the development of different diseases (Li et al 2019). CircRNAs have recently been shown to be involved in OA (Gong et al 2023), but little is known about the importance and roles of circRNAs in TMJ maintenance and OA pathogenesis.…”