FIBROBLASTS FROM MICE WITH PROGRESSIVE ANKYLOSIS PROLIFERATE EXCESSIVELY IN RESPONSE TO TRANSFORMING-GROWTH-FACTOR-BETA-1

Background: Murine progressive ankylosis (MPA) is a spontaneous arthro pathy that produces ankylosis of peripheral and spinal joints in mice homozygous for the gene ank. This animal model bears a striking resemb lance clinically, radiographically, and histologically to ankylosing s pondylitis, Phosphocitrate (PC) is the only treatment known to signifi cantly delay disease progression in MPA, Transforming growth factor-be ta (TGF-beta) is important for both developmental bone formation and f racture healing, and has been detected in biopsy specimens from sacroi liac joints of patient with ankylosing spondylitis. We hypothesized th at TGF-beta might be involved in the pathogenesis of MPA. Methods: We compared the proliferative response of resting fibroblasts from normal and MPA mice to TGF-beta 1 as measured by H-3-thymidine incorporation and the effect of PC on that response. Cells were cultured with 10% s erum as a positive control. The mouse fibroblast cell line, BALB/3T3, controlled for culture conditions. Results: MPA and normal fibroblasts responded similarly to serum. MPA fibroblasts proliferated significan tly better in TGF-beta 1 than the poorly responsive normal mouse fibro blasts. PC, at 10(-3) mol/L, inhibited the TGF-beta-induced proliferat ion of MPA and 3T3 cells, but had no effect on normal fibroblasts. Con clusions: MPA fibroblasts proliferate excessively to TGF beta 1 in vit ro. This effect could be caused by altered TGF receptors, changes in s ignal transduction, or impaired inhibition of the TGF-beta signal. Thi s excessive response is blocked by PC. These results give further clue s as to how PC inhibits the progression of ankylosis in MPA.