Khodadust Fatemeh, Philippon Eva M L, Steinz Maarten M, van Hamburg Jan Piet, van Meerloo Johan, van Beijnum Judy R, Jansen Gerrit, Tas Sander W, van der Laken Conny J
Department of Rheumatology & Clinical Immunology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Department of Experimental Immunology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Cells. 2025 Jan 11;14(2):102. doi: 10.3390/cells14020102.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation leading to joint damage and systemic complications. Angiogenesis promotes inflammation and contributes to RA progression. This study evaluated potential anti-angiogenic effects of several compounds including small-molecule kinase inhibitors, such as sunitinib (pan-kinase inhibitor), tofacitinib (JAK-inhibitor), NIKi (NF-κB-inducing kinase inhibitor), and the integrin-targeting peptide fluciclatide, using a scratch assay and 3D spheroid-based models of angiogenesis. For all drugs tested in the low micromolar range (1-25 μM), sunitinib (as positive anti-angiogenetic control) showed marked inhibition of endothelial cell (EC) migration and sprouting, effectively reducing both scratch closure and sprout formation. Tofacitinib exhibited marginal effectiveness in the scratch assay, but performed better in the 3D models (55% inhibition), whereas NIKi showed around 50% anti-angiogenic effects in both models. Fluciclatide changed EC morphology rather than migration, and only when stimulated with synovial fluid in spheroid model did it show inhibitory effects (at ≥2.5 µM), with none below this dosage. These results highlight the potential of NIKi and tofacitinib for angiogenesis inhibition and of fluciclatide for safe diagnostic targeting of microdose in RA, as well as the need for advanced screening models that mimic RA's complex inflammatory pro-angiogenic environment.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征是炎症导致关节损伤和全身并发症。血管生成促进炎症并推动RA的进展。本研究使用划痕试验和基于三维球体的血管生成模型，评估了几种化合物的潜在抗血管生成作用，这些化合物包括小分子激酶抑制剂，如舒尼替尼（泛激酶抑制剂）、托法替布（JAK抑制剂）、NIKi（NF-κB诱导激酶抑制剂）以及整合素靶向肽氟西拉肽。对于在低微摩尔范围（1-25μM）内测试的所有药物，舒尼替尼（作为阳性抗血管生成对照）显示出对内皮细胞（EC）迁移和芽生的显著抑制，有效减少了划痕闭合和芽生形成。托法替布在划痕试验中表现出微弱的效果，但在三维模型中表现更好（抑制率为55%），而NIKi在两种模型中均显示出约50%的抗血管生成作用。氟西拉肽改变了EC的形态而非迁移，并且仅在球体模型中用滑液刺激时才显示出抑制作用（≥2.5μM时），低于此剂量则无作用。这些结果突出了NIKi和托法替布在抑制血管生成方面的潜力，以及氟西拉肽在RA中安全诊断微剂量靶向方面的潜力，同时也凸显了需要能够模拟RA复杂炎症促血管生成环境的先进筛选模型。
