Study of the mechanism involved in angiogenesis and synovial cell proliferation in human synovial tissues of patients with rheumatoid arthritis using SCID mice.
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.
Nagashima
Masakazu
M
Department of Joint Disease and Rheumatism, Taiho Pharmaceutical Company Ltd., Tokyo, Japan.
Tanaka
Hidekazu
H
Takahashi
Hiroshi
H
Tachihara
Akitoshi
A
Tanaka
Katsunao
K
Ishiwata
Toshiyuki
T
Asano
Goro
G
Yoshino
Shinichi
S
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D003510:Cyclohexanes; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012717:Sesquiterpenes / Q000494:pharmacology; D013583:Synovial Membrane / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology* / Q000637:transplantation; D014183:Transplantation, Heterologous
D020533:Angiogenesis Inhibitors; D018952:Antigens, CD34; D003510:Cyclohexanes; D018809:Proliferating Cell Nuclear Antigen; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol