o-(chloroacetylcarbamoyl)fumagillol and Arthritis--Rheumatoid

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that occurs two to four times as often in women as in men and increases in incidence with advancing age. It affects synovial-lined joints and can also affect the pulmonary, cardiac, nervous, integumentary, and reticuloendothelial systems. RA is manifested clinically by malaise and fatigue, followed by a symmetric pattern of joint inflammation characterized by pain and stiffness. RA most likely occurs in the setting of a genetically predisposed individual, triggered by infectious agents or endogenous antigens. Many of the newer treatments being studied involve blocking cytokine-mediated interactions between cells of the synovium.

Topics: Aged; Antibodies, Monoclonal; Arthritis, Rheumatoid; Cyclohexanes; Diphtheria Toxin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Herpesvirus 4, Human; Humans; Interferon-gamma; Interleukin 1 Receptor Antagonist Protein; Interleukin-2; Lymphocyte Activation; Male; Methotrexate; Minocycline; Neoplasm Proteins; O-(Chloroacetylcarbamoyl)fumagillol; Parvoviridae; Receptors, Tumor Necrosis Factor, Type II; Recombinant Fusion Proteins; Sesquiterpenes; Sialoglycoproteins; Synovitis; Tumor Necrosis Factor Decoy Receptors

To examine whether synovial cell proliferation is due to angiogenesis, we studied the relationship between the inhibition of synovial cell proliferation and an angiogenesis inhibitor, TNP-470, in human synovial tissues. Human synovial tissues were implanted into the back of SCID mice (SCID-HuAg mice). Sixteen mice were divided into two groups of eight mice each: the untreated group (vehicle group) and the TNP-470-treated group that received a dose of 10 mg/kg body weight by subcutaneous injection. The number of blood vessels and synovial lining cells clearly increased in the vehicle group, but the number of synovial lining cells clearly decreased and the blood vessels were hardly detected in the TNP-470 group. Immunohistochemically, cells that stained positively for the anti-proliferating cell nuclear antigen (PCNA) mAb were abundant in synovial lining cells and endothelial cells in synovial tissues. Cells that stained positively for the anti-CD34 polyclonal antibody were abundant in the endothelial cells in the vehicle group, but these positively stained cells were hardly detected in the TNP-470 group. The PCNA positivity ratio in the vehicle group was 0.64 +/- 0.019, whereas that in the TNP-470 group was 0.199 +/- 0.007. The numbers of cells that stained positively for anti-CD34 polyclonal antibody were 242 +/- 13.4 in the vehicle group and 153 +/- 6.73 in the TNP-470 group per 10 microscopic fields. Cells that stained positively for anti-mouse CD31 mAb were mainly localized in the synovial lining, but invaded the subsynovial lining layer in human synovial tissues. On the other hand, cells that stained positively for anti-human CD31 mAb were mainly localized in the subsynovial lining layer. We found that endothelial cell proliferation is dependent on angiogenesis based on the result that angiogenesis and synovial cell proliferation were inhibited by treatment with TNP-470.

Topics: Angiogenesis Inhibitors; Animals; Antigens, CD34; Arthritis, Rheumatoid; Cell Division; Cyclohexanes; Humans; Male; Mice; Mice, SCID; Middle Aged; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Proliferating Cell Nuclear Antigen; Sesquiterpenes; Synovial Membrane; Transplantation, Heterologous

We assessed the clinical and histologic features of angiogenesis inhibition in a transgenic mouse model of arthritis that closely resembles rheumatoid arthritis (RA) in humans.. KRN/NOD mice, which spontaneously develop arthritis, were treated with TNP-470, an angiogenesis inhibitor. Disease was monitored by use of clinical indices and histologic examinations; circulating blood levels of vascular endothelial growth factor were determined by enzyme-linked immunosorbent assay.. In the preventive protocol, with TNP-470 administration at a dosage of 60 mg/kg of body weight, the onset of arthritis was delayed and its clinical intensity was rather mild; 100% of placebo-treated transgenic mice developed arthritis that led to severe articular destruction. At a dosage of 90 mg/kg of TNP-470, the appearance of clinical signs was delayed for a longer period of time and disease was almost abolished. The therapeutic regimen alleviated clinical signs only when given during the very early stage of disease. Reductions in cartilage and bone destruction by TNP-470 treatment were observed histologically, a feature that was still evident at 30 and 80 days after injections were withdrawn.. Our demonstration that in vivo administration of an angiogenesis inhibitor suppresses arthritis and protects from bone destruction provides new insight into the pathogenesis of the disease and opens new possibilities in the treatment of RA in humans.

Topics: Angiogenesis Inhibitors; Animals; Arthritis, Rheumatoid; Bone Resorption; Cyclohexanes; Disease Models, Animal; Endothelial Growth Factors; Lymphokines; Male; Mice; Mice, Inbred NOD; Mice, Transgenic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Cyclohexanes; Cytokines; Disease Models, Animal; Humans; Inflammation; Integrins; Microcirculation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Synovial Membrane