CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications

  • Nat Commun. 2023 Aug 28;14(1):5242. doi: 10.1038/s41467-023-40975-7.
Zhe Gong  #  1 ,  Jinjin Zhu  #  1 ,  Junxin Chen  #  1 ,  Fan Feng  #  2 ,  Haitao Zhang  1 ,  Zheyuan Zhang  1 ,  Chenxin Song  1 ,  Kaiyu Liang  1 ,  Shuhui Yang  1 ,  Shunwu Fan  3 ,  Xiangqian Fang  4 ,  Shuying Shen  5
Affiliations
  • 1. Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province Sir Run Run Shaw Institute of Clinical Medicine of Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China.
  • 2. Obstetrics and Gynecology Hospital, Kunpeng Road, Hangzhou, 310016, Zhejiang Province, China.
  • 3. Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province Sir Run Run Shaw Institute of Clinical Medicine of Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China. [email protected].
  • 4. Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province Sir Run Run Shaw Institute of Clinical Medicine of Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China. [email protected].
  • 5. Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University & Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province Sir Run Run Shaw Institute of Clinical Medicine of Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang Province, China. [email protected].
  • # Contributed equally.
PMID: 37640697 DOI: 10.1038/s41467-023-40975-7
Abstract

Osteoarthritis is a prevalent age-related disease characterized by dysregulation of extracellular matrix metabolism, lipid metabolism, and upregulation of senescence-associated secretory phenotypes. Herein, we clarify that CircRREB1 is highly expressed in secondary generation chondrocytes and its deficiency can alleviate FASN related senescent phenotypes and osteoarthritis progression. CircRREB1 impedes proteasome-mediated degradation of FASN by inhibiting acetylation-mediated ubiquitination. Meanwhile, CircRREB1 induces RanBP2-mediated SUMOylation of FASN and enhances its protein stability. CircRREB1-FASN axis inhibits FGF18 and FGFR3 mediated PI3K-AKT signal transduction, then increased p21 expression. Intra-articular injection of adenovirus-CircRreb1 reverses the protective effects in CircRreb1 deficiency mice. Further therapeutic interventions could have beneficial effects in identifying CircRREB1 as a potential prognostic and therapeutic target for age-related OA.

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