成纤维细胞样滑膜细胞（FLS）的侵袭性表型已被确定为通过促进滑膜炎和软骨损伤而导致类风湿关节炎（RA）恶化的一个因素。遗憾的是，目前没有有效的治疗干预措施可以解决这个问题。最近的研究揭示了 R-spondin-2 (Rspo2) 在细胞增殖、软骨退化和肿瘤发生中的关键调节作用。然而，Rspo2 对 RA 的具体影响仍知之甚少。我们的目的是研究Rspo2在RA背景下调节FLS侵袭性表型和维持软骨细胞稳态的功能和机制。在抗原诱导性关节炎（AIA）的RA小鼠中检测到Rspo2在膝关节滑膜和软骨中的表达和 RA 患者。使用重组小鼠Rspo2（rmRspo2）、Rspo2中和抗体（Rspo2-NAb）和重组小鼠DKK1（rmDKK1，Wnt信号通路的有效抑制剂）来探讨Rspo2在RA进展中的作用和机制，特别是与RA进展的关系。我们发现，随着 RA 小鼠和 RA 患者的 RA 进展，滑膜和关节软骨中的 Rspo2 表达均上调。 Rspo2 的增加上调了富含亮氨酸重复序列的 G 蛋白偶联受体 5 (LGR5)（作为 Rspo2 的配体）以及 FLS 和软骨细胞中的 β-连环蛋白的表达。随后的研究表明，关节内注射 rmRspo2 会引起显着的进行性滑膜炎和关节软骨破坏，从而加剧小鼠 RA 的进展。相反，中和 Rspo2 或抑制 Wnt/β-catenin 通路可有效缓解实验性 RA 的发展。此外，Rspo2 主要通过激活 Wnt/β-catenin 通路促进 FLS 侵袭性表型并破坏软骨细胞稳态，而 Rspo2-NAb 或 rmDKK1 可以有效缓解这种情况。我们的数据证实了 Rspo2 在增强 FLS 侵袭性表型和破坏软骨细胞中的关键作用RA 中通过 Wnt/β-连环蛋白途径实现稳态。此外，结果表明，关节内施用 Rspo2 中和抗体或重组 DKK1 可能是治疗 RA 的一种有前景的治疗策略。© 2023。作者。

The aggressive phenotype of fibroblast-like synoviocytes (FLS) has been identified as a contributing factor to the exacerbation of rheumatoid arthritis (RA) through the promotion of synovitis and cartilage damage. Regrettably, there is currently no effective therapeutic intervention available to address this issue. Recent research has shed light on the crucial regulatory role of R-spondin-2 (Rspo2) in cellular proliferation, cartilage degradation, and tumorigenesis. However, the specific impact of Rspo2 on RA remains poorly understood. We aim to investigate the function and mechanism of Rspo2 in regulating the aggressive phenotype of FLS and maintaining chondrocyte homeostasis in the context of RA.The expression of Rspo2 in knee joint synovium and cartilage were detected in RA mice with antigen-induced arthritis (AIA) and RA patients. Recombinant mouse Rspo2 (rmRspo2), Rspo2 neutralizing antibody (Rspo2-NAb), and recombinant mouse DKK1 (rmDKK1, a potent inhibitor of Wnt signaling pathway) were used to explore the role and mechanism of Rspo2 in the progression of RA, specifically in relation to the aggressive phenotype of FLS and chondrocyte homeostasis, both in vivo and in vitro.We indicated that Rspo2 expression was upregulated both in synovium and articular cartilage as RA progressed in RA mice and RA patients. Increased Rspo2 upregulated the expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), as the ligand for Rspo2, and β-catenin in FLS and chondrocytes. Subsequent investigations revealed that intra-articular administration of rmRspo2 caused striking progressive synovitis and articular cartilage destruction to exacerbate RA progress in mice. Conversely, neutralization of Rspo2 or inhibition of the Wnt/β-catenin pathway effectively alleviated experimental RA development. Moreover, Rspo2 facilitated FLS aggressive phenotype and disrupted chondrocyte homeostasis primarily through activating Wnt/β-catenin pathway, which were effectively alleviated by Rspo2-NAb or rmDKK1.Our data confirmed a critical role of Rspo2 in enhancing the aggressive phenotype of FLS and disrupting chondrocyte homeostasis through the Wnt/β-catenin pathway in the context of RA. Furthermore, the results indicated that intra-articular administration of Rspo2 neutralizing antibody or recombinant DKK1 might represent a promising therapeutic strategy for the treatment of RA.© 2023. The Author(s).