Abstract
Background
Murine progressive ankylosis (MPA) is a spontaneous arthropathy that produces ankylosis of peripheral and spinal joints in mice homozygous for the gene ank. This animal model bears a striking resemblance clinically, radiographically, and histologically to ankylosing spondylitis. Phosphocitrate (PC) is the only treatment known to significantly delay disease progression in MPA. Transforming growth factor-beta (TGF-β) is important for both developmental bone formation and fracture healing, and has been detected in biopsy specimens from sacroiliac joints of patient with ankylosing spondylitis. We hypothesized that TGF-β might be involved in the pathogenesis of MPA.
Methods
We compared the proliferative response of resting fibroblasts from normal and MPA mice to TGF-β1 as measured by 3H-thymidine incorporation and the effect of PC on that response. Cells were cultured with 10% serum 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 significantly better in TGF-β1 than the poorly responsive normal mouse fibroblasts. PC, at 10-3 mol/L, inhibited the TGF-β1-induced proliferation of MPA and 3T3 cells, but had no effect on normal fibroblasts.
Conclusions
MPA fibroblasts proliferate excessively to TGFβ1 in vitro. This effect could be caused by altered TGF receptors, changes in signal transduction, or impaired inhibition of the TGF-β signal. This excessive response is blocked by PC. These results give further clues as to how PC inhibits the progression of ankylosis in MPA.
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