Combination Therapy of PEG-HM-3 and Methotrexate Retards Adjuvant-Induced Arthritis

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.

Effect of astragalosides on long non-coding RNA expression profiles in rats with adjuvant-induced arthritis

“…From day 16, swelling of the left hind paw was measured and the poly-arthritis index was assessed once every 4 days until the animals were sacrificed. Swelling of the paw was determined by water volume (23): Swelling (∆ml)=paw thickness (ml) tested value-paw thickness (ml) original value. The severity of arthritis was graded on a scale of 0-4 with the following criteria (24): 0=no edema or swelling, 1=slight edema and limited erythema, 2=slight edema and erythema from the ankle to the tarsal bone, 3=moderate edema and erythema from the ankle to the tarsal bone, and 4=edema and erythema from the ankle to the entire leg.…”

Synergistic enhancement and hepatoprotective effect of combination of total phenolic extracts of Citrus aurantium L. and methotrexate for treatment of rheumatoid arthritis

“…Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by joint destruction, bone damage, disability, and premature death, resulting in a considerable economic burden on patients and society (Hao et al, ). Although the etiology of RA has not been completely elucidated, it is known that the inflammatory region is characterized by high infiltration of chemokines and inflammatory cytokines, which are responsible for the damage of the bones and joints (Kuncirova et al, ).…”

Recent Advances in Nanotheranostics for Treat‐to‐Target of Rheumatoid Arthritis

“…Zhou et al recently developed a nanocarrier system translatable lipase‐labile (Sn 2) fumagillin prodrug (Fum‐PD) to deliver Fum, which was anticipated to improve drug retention time in the circulation, enhancing net drug delivery to angiogenic endothelial cells via “contact‐facilitated drug delivery.”110 It was reported that PEG‐HM‐3, an integrin inhibitor, possessed antiangiogenesis and antirheumatic functions. Based on this theory, Hao et al developed a combination of PEG‐HM‐3 and MTX which significantly reduced swelling of hind paws, arthritis index, and bone erosion 60. The activity of nuclear transcription factor (NF‐κB) and expression of inflammatory factors were downregulated via integrin α v β 3 and TLR‐4 signaling pathways.…”