Abstract
At present, the early phenomenon of inflammatory angiogenesis is rarely studied in Rheumatoid arthritis (RA). Previous research found that PEG-HM-3, an integrin inhibitor, possessed anti-angiogenesis and anti-rheumatic activity. In this study, the advantages of inhibiting angiogenesis and immune cell adhesion and migration, as well as the benefits of anti-arthritis effects, were evaluated using a combination of PEG-HM-3 and methotrexate (MTX). In vitro, spleen cell proliferation and the levels of tumor necrosis factor α (TNF-α) in macrophage supernatant were assessed. Hind paw edema, arthritis index, clinical score, body weight and immunohistochemistry (IHC) of the spleen, thymus, and joint cavity were evaluated in vivo in adjuvant-induced arthritis rats. Joints of the left hind paws were imaged by X-ray. The expression of the toll-like receptor 4 (TLR-4) protein was assessed in lipopolysaccharide (LPS)-induced synoviocytes. PEG-HM-3 combined with MTX significantly reduced primary and secondary swelling of the hind paws, the arthritis index, the clinical score and bone erosion. The results of IHC showed that the levels of interleukin-6 (IL-6) in spleens and the levels of TNF-α, CD31 (cluster of differentiation 31), and CD105 in the joint cavity were decreased. The body weight of rats was maintained during combination therapy. Ankle cavity integrity, and bone erosion and deformity were improved in combination treatment. The expression of TLR-4 was significantly reduced with combination treatment in rat synoviocytes. Co-suppression of both inflammation and angiogenesis in arthritis was achieved in this design with combination therapy. The activity of nuclear transcription factor (NF-κB) and the expression of inflammatory factors were down regulated via integrin αvβ3 and TLR-4 signaling pathways. In the future, the application of this combination can be a candidate in early and mid-term RA therapy.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disease characterized by a persistent chronic inflammation of synovium, leading to various degrees of cartilage destruction, bone erosion with subsequent joint deformity, and loss of joint function [1]
If an accurate combination therapy on inhibition of angiogenesis and primary and secondary arthritis is given during this course, patients can get a high response rate
It is earnestly suggested that the application of2PEG-HM-3 in combination with MTX is most suitable for resisting inflammatory angiogenesis for early and mid-stage therapy
Summary
Rheumatoid arthritis (RA) is an autoimmune disease characterized by a persistent chronic inflammation of synovium, leading to various degrees of cartilage destruction, bone erosion with subsequent joint deformity, and loss of joint function [1]. Decades of studies have shown that synovial inflammatory angiogenesis is closely related to RA [2]. These cytokines can directly or indirectly promote angiogenesis through the vascular endothelial growth factor (VEGF) signaling pathway [3], resulting in synovial hyperplasia, bone destruction, and pannus. Adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) are chronic arthritis animal models which can simulate the clinical symptoms of RA patients. The inflammatory reaction happens in the early stage of immune response followed by the formation of blood vessels
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