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Research ArticleArticle

An Angiogenesis Inhibitor, 2-Methoxyestradiol, Involutes Rat Collagen-Induced Arthritis and Suppresses Gene Expression of Synovial Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor

ERNEST BRAHN, MONA L. BANQUERIGO, JOHN K. LEE, EUN J. PARK, WILLIAM E. FOGLER and STACY M. PLUM
The Journal of Rheumatology November 2008, 35 (11) 2119-2128; DOI: https://doi.org/10.3899/jrheum.080302
ERNEST BRAHN
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  • For correspondence: ebrahn@mednet.ucla.edu
MONA L. BANQUERIGO
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JOHN K. LEE
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EUN J. PARK
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WILLIAM E. FOGLER
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STACY M. PLUM
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Abstract

Objective

Rheumatoid arthritis (RA) pannus may be dependent on angiogenesis and several critical growth factors including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). 2-Methoxyestradiol (2ME2), an endogenous metabolite with low estrogen receptor affinity, has both antiangiogenic and antiproliferative activity. 2ME2 was assessed in the rat collagen- induced arthritis (CIA) model to determine if it could prevent or involute established synovitis.

Methods

Rats were immunized on Day 0 with collagen and randomized to a vehicle control or two 2ME2 prevention arms. In additional studies, multiple parallel treatment arms were initiated at Day 10 after arthritis onset.

Results

2ME2 in preventive protocols at 30 or 100 mg/kg significantly delayed the onset and reduced the severity of clinical and radiographic CIA. In established CIA, oral 2ME2 at 50 mg/kg/bid, 100 mg/kg/day, and 300 mg/kg/day reduced severity compared to vehicle controls. Efficacy of 2ME2 delivery by osmotic pumps at 60 mg/kg/day was equivalent to 300 mg/kg/day by daily gavage. The 3 oral treatment protocols all significantly reduced radiographic scores in a dose-dependent fashion, with the greatest benefit at 300 mg/kg. 2ME2 showed marked suppression of synovial gene expression of proangiogenic bFGF and VEGF, with parallel reduction of synovial blood vessels. Serum antibody levels to native type II collagen were not reduced, suggesting that 2ME2 did not influence humoral immunity.

Conclusion

Our results indicate that 2ME2 may represent a novel agent for the treatment of inflammatory autoimmune diseases such as RA.

Key Indexing Terms:
  • ANIMAL DISEASE MODELS
  • ENDOTHELIAL CELLS
  • 2-METHOXYESTRADIOL
  • VASCULAR ENDOTHELIAL GROWTH FACTOR
  • ANGIOGENESIS INHIBITION

Footnotes

  • E. Brahn, MD; M.L. Banquerigo, MD; J.K. Lee, BA, Division of Rheumatology, UCLA School of Medicine; E.J. Park, PhD; W.E. Fogler, PhD; S.M. Plum, PhD, Translational Research, EntreMed, Inc.

  • Supported in part by NIH Grant AR-42200 and EntreMed, Rockville, Maryland.

    • Accepted for publication June 6, 2008.
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The Journal of Rheumatology
Vol. 35, Issue 11
1 Nov 2008
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An Angiogenesis Inhibitor, 2-Methoxyestradiol, Involutes Rat Collagen-Induced Arthritis and Suppresses Gene Expression of Synovial Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor
ERNEST BRAHN, MONA L. BANQUERIGO, JOHN K. LEE, EUN J. PARK, WILLIAM E. FOGLER, STACY M. PLUM
The Journal of Rheumatology Nov 2008, 35 (11) 2119-2128; DOI: 10.3899/jrheum.080302

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An Angiogenesis Inhibitor, 2-Methoxyestradiol, Involutes Rat Collagen-Induced Arthritis and Suppresses Gene Expression of Synovial Vascular Endothelial Growth Factor and Basic Fibroblast Growth Factor
ERNEST BRAHN, MONA L. BANQUERIGO, JOHN K. LEE, EUN J. PARK, WILLIAM E. FOGLER, STACY M. PLUM
The Journal of Rheumatology Nov 2008, 35 (11) 2119-2128; DOI: 10.3899/jrheum.080302
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