Fibroblasts from Mice with Progessive Ankylosis Proliferate Excessively in Response to Transforming Growth Factor-Beta 1

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)134-139
Number of pages6
JournalJournal of Investigative Medicine
Volume46
Issue number4
StatePublished - Apr 1998

Keywords

  • Ankylosis
  • Cell culture
  • Fibroblasts
  • Mice
  • Transforming growth factor-beta

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