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

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 TGF beta 2 were significantly increased in the cartilage of patients with osteoarthritis and IL-1 beta-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 TGF beta 2 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. Osteoarthritis: Circular RNA linked to cartilage degeneration A circular RNA implicated in cartilage degeneration could offer a new therapeutic target for treating osteoarthritis. Yan Kang from Sun Yat-sen University, Jie Xu from Fujian Provincial Hospital, and colleagues in China found that a circular RNA called circCREBBP is highly expressed in cartilage samples taken from the knee joints of individuals with osteoarthritis. Working with cartilage precursor cells, the researchers showed that the circular RNA induces destruction of the surrounding extracellular matrix through its inhibitory effects on a microRNA. This microRNA normally blocks expression of a growth factor involved in matrix degradation. When bound to circCREBBP, the microRNA can no longer keep the growth factor in check and osteoarthritis results. Inhibiting circCREBBP activity prevented cartilage breakdown and alleviated osteoarthritis in mouse models, suggesting that a similar therapeutic strategy could work in humans.

Automated summary

This study found that a circular RNA called circCREBBP is highly expressed in cartilage samples taken from individuals with osteoarthritis, and it induces destruction of the surrounding extracellular matrix through its inhibitory effects on a microRNA. Inhibiting circCREBBP activity prevented cartilage breakdown and alleviated osteoarthritis in mouse models, suggesting that it could be a potential therapeutic target for treating osteoarthritis.