Signals from VEGFR-1 TK contribute to the onset and progression of arthritis. (A) The incidence of arthritis was significantly lower in pX Vegfr-1 tk^–/– mice than pX mice. In addition, the incidence of arthritis in pX Vegfr-1 tk^+/– heterozygotes was slightly lower in the early stages. (B) Clinical grades of arthritis were reduced depending on the deficiency of the VEGFR-1 TK domain from 2 to 6 months after birth. pX Vegfr-1 tk^+/– mice showed mild clinical scores between those of pX and pX Vegfr-1 tk^–/– mice. The data (A-B) represent the mean ± SEM obtained from 33 to 122 mice. *P < .05 versus pX; **P < .01 versus pX. (C-E) Cross-sections of ankle joints in control and RA mice. Joints of wild-type mice (C) show no remarkable change. Joints of pX mice (D) show synovial hyperplasia (*), inflammatory cell infiltration (▵), pannus formation (▴), and loss of cartilage and bone (□). These findings are milder in pX Vegfr-1 tk^–/– mice (E). Sections are taken from average cases in these mice. Scale bars, 200 μm. Images in panels C-E were taken with a Nikon Eclipse TE600 microscope (Nikon, Tokyo, Japan) using AxioVision 3.0 software (Carl Zeiss, Jena, Germany) and a 10×/0.30 NA objective lens, then processed with Photoshop CS (Adobe Systems, San Jose, CA). (F) Histologic scores of the degree of pathology in paws and ankles. Scores of pX Vegfr-1 tk^–/– mice were about half those of the pX mice. The data represent the mean ± SEM. *P < .05 versus pX; **P <.01 versus pX.