靶向 Fascin1 可维持软骨细胞表型并减轻骨关节炎的发展

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2024-09-04 DOI:10.1038/s41413-024-00357-1
Panpan Yang, Yun Xiao, Liangyu Chen, Chengliang Yang, Qinwei Cheng, Honghao Li, Dalin Chen, Junfeng Wu, Zhengquan Liao, Changsheng Yang, Chong Wang, Hong Wang, Bin Huang, Ee Ke, Xiaochun Bai, Kai Li
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引用次数: 0

摘要

骨关节炎(OA)是最常见的关节炎疾病,而软骨细胞的表型改变是导致软骨失去平衡的重要机制。本研究发现,Fascin肌动蛋白束缚蛋白1(FSCN1)在调控软骨细胞表型和维持软骨稳态方面发挥着关键作用。全蛋白质组筛选发现,在人类 OA 软骨中,FSCN1 蛋白表达明显上调。FSCN1在人和小鼠OA软骨表层的积聚得到证实,主要是在已分化的类软骨细胞中,与肌动蛋白应力纤维形成的增强以及I型和III型胶原的上调有关。FSCN1 诱导的基因敲除小鼠在实验性 OA 手术后表现出延迟的软骨退化。从机制上讲,FSCN1促进了肌动蛋白聚合,破坏了Decorin对TGF-β1的抑制作用,导致TGF-β1产生过多和ALK1/Smad1/5信号激活,从而加速了软骨细胞的去分化。关节内注射FSCN1表达的腺相关病毒会加剧小鼠的OA进展,而ALK1抑制剂可减轻这种情况。此外,FSCN1抑制剂NP-G2-044通过抑制ALK1/Smad1/5信号传导,有效减少了OA小鼠、培养的人类OA软骨细胞和软骨外植体的细胞外基质降解。这些研究结果表明,靶向 FSCN1 是治疗 OA 的一种很有前景的方法。
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Targeting Fascin1 maintains chondrocytes phenotype and attenuates osteoarthritis development

Osteoarthritis (OA) is the most common form of arthritic disease, and phenotypic modification of chondrocytes is an important mechanism that contributes to the loss of cartilage homeostasis. This study identified that Fascin actin-bundling protein 1 (FSCN1) plays a pivotal role in regulating chondrocytes phenotype and maintaining cartilage homeostasis. Proteome-wide screening revealed markedly upregulated FSCN1 protein expression in human OA cartilage. FSCN1 accumulation was confirmed in the superficial layer of OA cartilage from humans and mice, primarily in dedifferentiated-like chondrocytes, associated with enhanced actin stress fiber formation and upregulated type I and III collagens. FSCN1-inducible knockout mice exhibited delayed cartilage degeneration following experimental OA surgery. Mechanistically, FSCN1 promoted actin polymerization and disrupted the inhibition of Decorin on TGF-β1, leading to excessive TGF-β1 production and ALK1/Smad1/5 signaling activation, thus, accelerated chondrocyte dedifferentiation. Intra-articular injection of FSCN1-overexpressing adeno-associated virus exacerbated OA progression in mice, which was mitigated by an ALK1 inhibitor. Moreover, FSCN1 inhibitor NP-G2-044 effectively reduced extracellular matrix degradation in OA mice, cultured human OA chondrocytes, and cartilage explants by suppressing ALK1/Smad1/5 signaling. These findings suggest that targeting FSCN1 represents a promising therapeutic approach for OA.

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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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