Abstract
Background: Rheumatoid arthritis (RA) is a chronic disabling inflammatory disease that causes synovial angiogenesis in an invasive manner and leads to joint destruction. Currently available pharmacotherapy for RA has unwanted side effects and limitations. Although anti-angiogenic therapy is regarded as a new potential treatment for RA, only a few anti-angiogenic drugs are available. An increasing number of studies have shown that β-sitosterol (BSS) may exert inhibitory effects against angiogenesis. However, the mechanisms involved are still unclear. Methods: Based on the results of the gene set enrichment analysis (GSEA) of the transcriptome data of endothelial cells from RA patients, we evaluated the pharmacological effects of BSS on the tube formation, cell proliferation, and migration of human umbilical vein endothelial cells (HUVECs). Furthermore, the effects of BSS treatment on vascular endothelial growth factor receptor 2 (VEGFR2) were determined using molecular docking and Western blotting. Additionally, in the presence or absence of BSS, synovial angiogenesis and joint destruction of the ankle were investigated in collagen-induced arthritis (CIA) mice. The effect of BSS treatment on VEGFR2/p-VEGFR2 expression was verified through immunohistochemical staining. Results: The immunohistochemistry results revealed that BSS treatment inhibited angiogenesis both in vitro and in vivo. In addition, the results of 5-ethynyl-2′-deoxyuridine and cell cycle analysis showed that BSS treatment suppressed the proliferation of HUVECs, while the Transwell migration and stress fiber assays demonstrated that BSS treatment inhibited the migration of HUVECs. Notably, the inhibitory effect of BSS treatment on VEGFR2/p-VEGFR2 was similar to that of axitinib. In CIA mice, BSS also exerted therapeutic effects on the ankles by reducing the degree of swelling, ameliorating bone and cartilage damage, preventing synovial angiogenesis, and inhibiting VEGFR2 and p-VEGFR2 expression. Conclusion: Therefore, our findings demonstrate that BSS exerts an inhibitory effect on synovial angiogenesis by suppressing the proliferation and migration of endothelial cells, thereby alleviating joint swelling and bone destruction in CIA mice. Furthermore, the underlying therapeutic mechanisms may involve the inhibition of VEGF signaling pathway activation.
Highlights
Rheumatoid arthritis (RA) is a common inflammatory disease with a prevalence of about 1% of people worldwide (O’neil et al, 2020), leading to joint deformity and disability constituting a burden both on individuals and society
RA is characterized by persistent synovitis and developing synovial angiogenesis, which leads to subsequent hyperplasia of the synovium and the erosion of cartilage and bone (Mcinnes and Schett, 2011; Bottini and Firestein, 2013)
Anti-Vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) therapies seem to be beneficial for animal models of RA and have a great therapeutic promise for RA (Le and Kwon, 2021), such as Avastin (Bevacizumab, a VEGF humanized monoclonal antibody) (Wang et al, 2013) and Sorafenib (Wang et al, 2018)
Summary
Rheumatoid arthritis (RA) is a common inflammatory disease with a prevalence of about 1% of people worldwide (O’neil et al, 2020), leading to joint deformity and disability constituting a burden both on individuals and society. RA is characterized by persistent synovitis and developing synovial angiogenesis, which leads to subsequent hyperplasia of the synovium and the erosion of cartilage and bone (Mcinnes and Schett, 2011; Bottini and Firestein, 2013). RA was as well regarded as one of the “angiogenic family of diseases” because of the notably increased number and density of new synovial blood vessels in synovium. What is more, increasing evidence support that angiogenesis appears to be a central part involved in the development and maintenance of RA (Leblond et al, 2017). In the progress of angiogenesis, endothelial cells (ECs) are an indispensable source of new synovial blood vessels (Leblond et al, 2017). Rheumatoid arthritis (RA) is a chronic disabling inflammatory disease that causes synovial angiogenesis in an invasive manner and leads to joint destruction.
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