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Synergistic effect of antiangiogenic nanotherapy combined with methotrexate in the treatment of experimental inflammatory arthritis.

ABSTRACT: This study examines the effect of combining the antiangiogenic effect of ?vß?-targeted fumagillin nanoparticles with the conventional antirheumatic drug methotrexate for the treatment of inflammatory arthritis.Arthritis was induced in mice by K/BxN serum transfer, and disease activity was monitored by clinical score and change in ankle thickness. Groups of mice received nanoparticles or methotrexate as single therapy or nanoparticles and methotrexate as combination therapy.We found that animals treated with a pulse dose of fumagillin nanoparticles followed by methotrexate had significantly improved and sustained clinical response compared with those treated with either agent alone. Histological analysis confirmed a significant decrease in inflammatory cell influx, bone erosions, cartilage damage and angiogenesis with the combination therapy.Analysis of plasma cytokine levels suggests that fumagillin nanoparticles enhanced the systemic anti-inflammatory effects of methotrexate. Antiangiogenic nanotherapy may represent a promising approach for the treatment of inflammatory arthritis when combined with a conventional antirheumatic drug.

SUBMITTER: Zhou HF

PROVIDER: S-EPMC3035945 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Synergistic effect of antiangiogenic nanotherapy combined with methotrexate in the treatment of experimental inflammatory arthritis.

Zhou Hui-Fang HF Hu Grace G Wickline Samuel A SA Lanza Gregory M GM Pham Christine T N CT

Nanomedicine (London, England) 20100901 7

<h4>Aim</h4>This study examines the effect of combining the antiangiogenic effect of αvß₃-targeted fumagillin nanoparticles with the conventional antirheumatic drug methotrexate for the treatment of inflammatory arthritis.<h4>Method</h4>Arthritis was induced in mice by K/BxN serum transfer, and disease activity was monitored by clinical score and change in ankle thickness. Groups of mice received nanoparticles or methotrexate as single therapy or nanoparticles and methotrexate as combination the ...[more]

PMID: 20874021

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Project description:Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by chronic synovitis, bone erosion, and bone loss. Erzhi Pill (EZP), a classic Chinese patent medicine, is often used to treat osteoporosis and shows a capacity for bone metabolism regulation. Methotrexate (MTX), an essential drug for RA treatment, has been reported to inhibit generalized bone loss in RA patients. However, the combined therapeutic effects and mechanism of EZP and MTX in RA have not been fully elucidated. The aim of this study was to investigate the synergistic effect of EZP and MTX on RA and to explore the underlying mechanism through network pharmacological prediction and experimental verification. Chemical compounds of EZP, human target proteins of EZP and MTX, and RA-related human genes were identified in the Encyclopedia of Traditional Chinese Medicine database, PubChem database, and NCBI database, respectively. The molecular network of EZP and MTX in RA was generated and analyzed with Ingenuity Pathway Analysis software according to the datasets. Then, MTX monotherapy, EZP monotherapy, and combined MTX and EZP therapy were administered to collagen-induced arthritis rats, followed by assessment of pathological score, bone damage, bone alkaline phosphatases (BALP), and tartrate-resistant acid phosphatase (TRACP), and of gene levels related to the Wnt1/LRP5/?-catenin pathway according to network pharmacological analysis. Finally, serum samples from MTX-, EZP- and MTX+EZP-treated rats were used to treat the rat osteoblast (OB)-like UMR-106 cell line to evaluate gene levels related to Wnt1/LRP5/?-catenin. Network pharmacological analysis showed that the Wnt/?-catenin signaling pathway was the top signaling pathway shared among MTX, EZP, and RA. The results from in vivo experiments indicated that EZP combined with MTX reduced arthritis severity, alleviated ankle bone damage, increased BALP and decreased TRACP serum levels, and regulated the mRNA expression of Wnt1, LRP5, ?-catenin, Runx2, BALP, and BGP in the ankles. In vitro experiments showed that EZP combined with MTX could also improve the expression of genes related to the Wnt1/LRP5/?-catenin pathway. This study demonstrated that EZP in combination with MTX played a synergistic role in regulating OBs in RA, which was connected to the modulatory effect of EZP and MTX on the Wnt1/LRP5/?-catenin signaling pathway.

Dataset Information

Synergistic effect of antiangiogenic nanotherapy combined with methotrexate in the treatment of experimental inflammatory arthritis.

Publications

Synergistic effect of antiangiogenic nanotherapy combined with methotrexate in the treatment of experimental inflammatory arthritis.

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