Rspo2 exacerbates rheumatoid arthritis by targeting aggressive phenotype of fibroblast-like synoviocytes and disrupting chondrocyte homeostasis via Wnt/β-catenin pathway.
Rspo2 exacerbates rheumatoid arthritis by targeting aggressive phenotype of fibroblast-like synoviocytes and disrupting chondrocyte homeostasis via Wnt/β-catenin pathway.
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RSPO2通过靶向成纤维细胞样的滑膜细胞的侵袭性表型来加剧类风湿关节炎，并通过Wnt/β-catenin途径破坏软骨细胞稳态。
DOI：
10.1186/s13075-023-03198-1
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发表时间：
2023-11-09
影响因子：
4.9
通讯作者：
中科院分区：
文献类型：
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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性关节炎（RA）恶化的促成因素。遗憾的是，目前没有有效的治疗干预措施来解决这个问题。最近的研究揭示了R-spondin-2（Rspo 2）在细胞增殖、软骨降解和肿瘤发生中的关键调节作用。然而，Rspo 2对RA的具体影响仍然知之甚少。我们的目的是研究Rspo 2在调节FLS的侵袭性表型和维持RA背景下软骨细胞稳态中的功能和机制。采用免疫组织化学方法检测Rspo 2在RA小鼠、RA患者膝关节滑膜和软骨中的表达。本研究采用重组小鼠Rspo 2（rmRspo 2）、Rspo 2中和抗体（Rspo 2-NAb）和重组小鼠DKK 1（rmDKK 1，一种有效的Wnt信号通路抑制剂），在体内外研究Rspo 2在RA进展中的作用和机制，特别是与FLS侵袭性表型和软骨细胞稳态的关系。我们发现，在RA小鼠和RA患者中，随着RA的进展，滑膜和关节软骨中Rspo 2的表达上调。Rspo 2增加上调FLS和软骨细胞中富含亮氨酸重复序列的G蛋白偶联受体5（LGR 5）（作为Rspo 2的配体）和β-连环蛋白的表达。随后的研究显示，关节内施用rmRspo 2引起显著的进行性滑膜炎和关节软骨破坏，从而加剧小鼠的RA进展。相反，Rspo 2的中和或Wnt/β-catenin通路的抑制有效地减轻了实验性RA的发展。此外，Rspo 2主要通过激活Wnt/β-catenin通路促进FLS侵袭表型，破坏软骨细胞的稳态，而Rspo 2-NAb或rmDKK 1可有效缓解这种作用。我们的数据证实了Rspo 2在增强FLS的侵袭性表型和在RA背景下通过Wnt/β-catenin途径破坏软骨细胞稳态中的关键作用。此外，结果表明，关节内施用Rspo 2中和抗体或重组DKK 1可能代表治疗RA的有希望的治疗策略。在线版本包含补充材料，可通过10.1186/s13075-023-03198-1获得。
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. The online version contains supplementary material available at 10.1186/s13075-023-03198-1.
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影响因子：
12.7
作者：
Guo, Dong;Lin, Chuangxin;Lu, Yuheng;Guan, Hong;Qi, Weizhong;Zhang, Hongbo;Shao, Yan;Zeng, Chun;Zhang, Rongkai;Zhang, Haiyan;Bai, Xiaochun;Cai, Daozhang
通讯作者：
Cai, Daozhang
DOI：
10.1084/jem.20070906
发表时间：
2008-02-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Armaka M;Apostolaki M;Jacques P;Kontoyiannis DL;Elewaut D;Kollias G
通讯作者：
Kollias G
影响因子：
4.3
作者：
Kim, KA;Zhao, JS;Funk, WD
通讯作者：
Funk, WD
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
--
作者：
Izquierdo, Elena;Canete, Juan D.;Pablos, Jose L.
通讯作者：
Pablos, Jose L.