Laboratorio de Reumatología Experimental y Observacional, y Servicio de Reumatología, Instituto de Investigación Sanitaria de Santiago (IDIS), Hospital Clínico Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saude (SERGAS), Travesía da Choupana s/n, Santiago de Compostela, Spain (N.M., A.R.-T., A.G., C.C.); Servicio de Reumatología, Instituto de Investigacion Biomedica de A Coruña (INIBIC)-Hospital Universitario A Coruña, A Xubias 84, A Coruña, Spain (F.J.B.); and Servicio de Reumatología, Instituto de Investigación Sanitaria de Santiago (IDIS), Hospital Clínico Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saude (SERGAS), Travesía da Choupana s/n, Santiago de Compostela, Spain (A.M.-V.).
Laboratorio de Reumatología Experimental y Observacional, y Servicio de Reumatología, Instituto de Investigación Sanitaria de Santiago (IDIS), Hospital Clínico Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saude (SERGAS), Travesía da Choupana s/n, Santiago de Compostela, Spain (N.M., A.R.-T., A.G., C.C.); Servicio de Reumatología, Instituto de Investigacion Biomedica de A Coruña (INIBIC)-Hospital Universitario A Coruña, A Xubias 84, A Coruña, Spain (F.J.B.); and Servicio de Reumatología, Instituto de Investigación Sanitaria de Santiago (IDIS), Hospital Clínico Universitario de Santiago de Compostela (CHUS), Servizo Galego de Saude (SERGAS), Travesía da Choupana s/n, Santiago de Compostela, Spain (A.M.-V.)
J Pharmacol Exp Ther. 2020 Feb;372(2):185-192. doi: 10.1124/jpet.119.261370. Epub 2019 Dec 4.
Fibroblast-like synoviocytes (FLSs) are pivotal in inflammation and joint damage of rheumatoid arthritis (RA). They acquire an active and aggressive phenotype, displaying increased migration and invasiveness and contributing to perpetuate synovial inflammation and destruction of cartilage and bone. The main current therapies of RA are focused against inflammatory factors and immune cells; however, a significant percentage of patients do not successfully respond. Combined treatments with drugs that control inflammation and that reverse the pathogenic phenotype of FLS could improve the prognosis of these patients. An unexplored area includes the retinoic acid, the main biologic retinoid, which is a candidate drug for many diseases but has reached clinical use only for a few. Here, we explored the effect of all- retinoic acid (ATRA) on the aggressive phenotype of FLS from patients with RA. RA FLSs were treated with ATRA, tumor necrosis factor (TNF), or TNF+ATRA, and cell migration and invasion were analyzed. In addition, a microarray analysis of expression, followed by gene-set analysis and quantitative polymerase chain reaction validation, was performed. We showed that ATRA induced a notable decrease in FLS migration and invasion that was accompanied by complex changes in gene expression. At supraphysiological doses, many of these effects were overridden or reverted by the concomitant presence of TNF. In conclusion, these results have demonstrated the therapeutic potential of retinoic acid on RA FLS provided TNF could be counterbalanced, either with high ATRA doses or with TNF inhibitors. SIGNIFICANCE STATEMENT: All- retinoic acid (ATRA) reduced the rheumatoid arthritis (RA) fibroblast-like synoviocyte migration and invasiveness and down-regulated gene expression of cell motility and migration genes. At supraphysiological doses, some of these effects were reverted by tumor necrosis factor. Therefore, ATRA could be an RA drug candidate that would require high doses or combined treatment with anti-inflammatory drugs.
成纤维样滑膜细胞（FLS）在类风湿关节炎（RA）的炎症和关节损伤中起着关键作用。它们获得了活跃和侵袭性的表型，表现出增加的迁移和侵袭能力，并有助于持续滑膜炎症和软骨及骨破坏。目前 RA 的主要治疗方法是针对炎症因子和免疫细胞；然而，仍有相当一部分患者治疗效果不佳。联合使用控制炎症和逆转 FLS 致病表型的药物可能会改善这些患者的预后。一个尚未探索的领域包括视黄酸，它是主要的生物视黄醇，是许多疾病的候选药物，但仅用于少数几种疾病的临床应用。在这里，我们研究了全反式视黄酸（ATRA）对 RA 患者 FLS 侵袭表型的影响。用 ATRA、肿瘤坏死因子（TNF）或 TNF+ATRA 处理 RA FLS，分析细胞迁移和侵袭。此外，进行了表达的微阵列分析，随后进行基因集分析和定量聚合酶链反应验证。我们发现 ATRA 诱导 FLS 迁移和侵袭明显减少，同时伴随基因表达的复杂变化。在生理超剂量下，许多这些作用被 TNF 的同时存在所掩盖或逆转。总之，这些结果表明视黄酸对 RA FLS 具有治疗潜力，前提是可以平衡 TNF，要么使用高剂量的 ATRA，要么使用 TNF 抑制剂。意义陈述：全反式视黄酸（ATRA）降低了类风湿关节炎（RA）成纤维样滑膜细胞的迁移和侵袭能力，并下调了细胞迁移和迁移基因的表达。在生理超剂量下，一些这些作用被肿瘤坏死因子所逆转。因此，ATRA 可能是一种 RA 候选药物，需要高剂量或与抗炎药物联合治疗。
