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.

骨关节炎（OA）是最常见的关节炎疾病，软骨细胞的表型修饰是导致软骨稳态丧失的重要机制。这项研究发现肌成束蛋白肌动蛋白捆绑蛋白 1 (FSCN1) 在调节软骨细胞表型和维持软骨稳态方面发挥着关键作用。全蛋白质组筛选显示人类 OA 软骨中 FSCN1 蛋白表达显着上调。 FSCN1 的积累在人类和小鼠的 OA 软骨表层中得到证实，主要是在去分化样软骨细胞中，与肌动蛋白应力纤维形成的增强以及 I 型和 III 型胶原蛋白的上调有关。 FSCN1 诱导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促进肌动蛋白聚合并破坏Decorin对TGF-β1的抑制，导致TGF-β1过量产生和ALK1/Smad1/5信号激活，从而加速软骨细胞去分化。关节内注射 FSCN1 过表达的腺相关病毒会加剧小鼠 OA 的进展，而 ALK1 抑制剂可以缓解这种情况。此外，FSCN1 抑制剂 NP-G2-044 通过抑制 ALK1/Smad1/5 信号传导，有效减少 OA 小鼠、培养的人 OA 软骨细胞和软骨外植体的细胞外基质降解。这些发现表明，靶向 FSCN1 代表了一种有前景的 OA 治疗方法。