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.
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环状 RNA CREBBP 通过 TGFβ2/ALK1 轴激活 Smad1/5 途径来调节软骨退化
DOI：
10.1038/s12276-022-00865-2
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发表时间：
2022-10
影响因子：
12.8
通讯作者：
Kang, Yan
中科院分区：
文献类型：
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作者：
Xu, Yiyang;Mao, Guping;Long, Dianbo;Deng, Zengfa;Xin, Ruobin;Zhang, Ziji;Xue, Ting;Liao, Weiming;Xu, Jie;Kang, Yan
以关节软骨退化为特征的骨关节炎是老年人慢性残疾的主要原因。研究表明，环状rna是软骨细胞发育的关键调节因子，并参与骨关节炎的进展。在这项研究中，我们研究了环状RNA的功能和机制及其在骨关节炎治疗中的潜力。通过环状RNA测序筛选脂肪组织源性干细胞成软骨分化过程中circCREBBP和tgf - β2的表达水平在骨关节炎患者软骨和il -1β诱导的软骨细胞中显著升高。circCREBBP敲低会增加细胞外基质的合成代谢，抑制软骨细胞变性，而circCREBBP过表达则会导致相反的效果。荧光素酶报告基因测定、救援实验、RNA免疫沉淀和RNA拉下实验证实circrebbp通过海绵miR-1208上调tgf - β2的表达，导致软骨细胞中Smad1/5的磷酸化显著增强。此外，在内侧半月板失稳小鼠模型中，关节内注射腺相关病毒sh- circcrebbp可减轻骨关节炎。我们的研究结果揭示了circrebbp在骨关节炎进展中的关键作用，并为骨关节炎治疗提供了一个潜在的靶点。与软骨变性有关的环状RNA可能为治疗骨关节炎提供新的治疗靶点。中山大学的康岩、福建省医院的徐洁和中国的同事们发现，一种叫做circCREBBP的环状RNA在骨关节炎患者膝关节软骨样本中高度表达。通过对软骨前体细胞的研究，研究人员发现环状RNA通过对microRNA的抑制作用诱导周围细胞外基质的破坏。这种microRNA通常会阻断一种参与基质降解的生长因子的表达。当与circrebbp结合时，microRNA不能再控制生长因子和骨关节炎的结果。在小鼠模型中，抑制circrebbp活性可防止软骨破裂并减轻骨关节炎，这表明类似的治疗策略可能在人类中起作用。
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. 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.
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影响因子：
4.6
作者：
Barrett, Steven P.;Salzman, Julia
通讯作者：
Salzman, Julia
影响因子：
7
作者：
Finnson, K. W.;Parker, W. L.;Philip, A.
通讯作者：
Philip, A.
影响因子：
11.4
作者：
Goumans, MJ;Valdimarsdottir, G;ten Dijke, P
通讯作者：
ten Dijke, P
从受体到 Smads 的 TGF-β 信号传导
影响因子：
7.2
作者：
Hata A;Chen YG
通讯作者：
Chen YG
TGFβ 信号的背景
DOI：
10.1038/nrm3434
发表时间：
2012-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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