2. Academic Validation
  3. Circular RNA CREBBP modulates cartilage degradation by activating the Smad1/5 pathway through the TGFβ2/ALK1 axis

Circular RNA CREBBP modulates cartilage degradation by activating the Smad1/5 pathway through the TGFβ2/ALK1 axis

  • Exp Mol Med. 2022 Oct 12. doi: 10.1038/s12276-022-00865-2.
Yiyang Xu 1 2 3,  Guping Mao 1 2,  Dianbo Long 1 2,  Zengfa Deng 1 2,  Ruobin Xin 1 2,  Ziji Zhang 1 2,  Ting Xue 4,  Weiming Liao 5 6,  Jie Xu 7,  Yan Kang 8 9
Affiliations

Affiliations

  • 1 Department of Joint Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong Province, China.
  • 2 Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, 510080, Guangzhou, Guangdong Province, China.
  • 3 Department of Orthopaedics, Fujian Provincial Hospital, Shengli Clinical Medical College, Fujian Medical University, 350001, Fuzhou, Fujian Province, China.
  • 4 Fujian Provincial Hospital South Branch, Center of Health Management, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
  • 5 Department of Joint Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong Province, China. liaowm@mail.sysu.edu.cn.
  • 6 Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, 510080, Guangzhou, Guangdong Province, China. liaowm@mail.sysu.edu.cn.
  • 7 Department of Orthopaedics, Fujian Provincial Hospital, Shengli Clinical Medical College, Fujian Medical University, 350001, Fuzhou, Fujian Province, China. jiexud@126.com.
  • 8 Department of Joint Surgery, The First Affiliated Hospital, Sun Yat-sen University, 510080, Guangzhou, Guangdong Province, China. kangyan2@mail.sysu.edu.cn.
  • 9 Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, 510080, Guangzhou, Guangdong Province, China. kangyan2@mail.sysu.edu.cn.
PMID: 36224344 DOI: 10.1038/s12276-022-00865-2
Abstract

Osteoarthritis, characterized by articular cartilage degradation, is the leading cause of chronic disability in older adults. Studies have indicated that circular RNAs are crucial regulators of chondrocyte development and are involved in the progression of osteoarthritis. In this study, we investigated the function and mechanism of a circular RNA and its potential for osteoarthritis therapy. The expression levels of circCREBBP, screened by circular RNA Sequencing during chondrogenic differentiation in adipose tissue-derived stem cells, and TGFβ2 were significantly increased in the cartilage of patients with osteoarthritis and IL-1β-induced chondrocytes. circCREBBP knockdown increased anabolism in the extracellular matrix and inhibited chondrocyte degeneration, whereas circCREBBP overexpression led to the opposite effects. Luciferase reporter assays, rescue experiments, RNA immunoprecipitation, and RNA pulldown assays confirmed that circCREBBP upregulated TGFβ2 expression by sponging miR-1208, resulting in significantly enhanced phosphorylation of Smad1/5 in chondrocytes. Moreover, intra-articular injection of adeno-associated virus-sh-circCrebbp alleviated osteoarthritis in a mouse model of destabilization of the medial meniscus. Our findings reveal a critical role for circCREBBP in the progression of osteoarthritis and provide a potential target for osteoarthritis therapy.

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