Stimulation of human synovial cell DNA synthesis by iron

To determine the effect of iron and cytokines on proliferation of synovial cells (SC), we isolated SC obtained at the time of total knee replacement from 11 patients with rheumatoid arthritis (RA) and 2 with osteoarthritis (OA) following enzymatic treatment of synovial tissue.

SC were cultured in the presence of ferric citrate or sodium citrate at concentrations of 0, 0.01, 0.1, and 1 mM for 72 h. In vitro synthesis of DNA by SC was measured by intracellular 3H-thymidine uptake.

Synthesis of DNA by SC was significantly enhanced by ferric citrate but not sodium citrate. The maximum synthesis was observed following stimulation with 0.1 mM ferric citrate and was obtained after 3 days of culture, thereafter declining until Day 7. This stimulatory effect of ferric citrate was observed in all specimens of SC tested. In our examination of the concomitant addition of each of 8 different recombinant human cytokines with 0.1 mM ferric citrate on SC DNA synthesis, 4 of them, i.e., interleukin-1 beta (IL-1 beta), IL-7, tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN-gamma) each enhanced the synthesis of SC DNA at concentrations ranging from 1 to 100 u/ml, while IL-1 beta, IL-7, TNF alpha or IFN-gamma together showed an additive effect. No significant effect was shown by IL-2, IL-6, and IL-8, or granulocyte colony stimulating factor (G-CSF).

Iron stimulated in vitro SC DNA synthesis and had an additive effect on the activity of human cytokines for SC proliferation. Iron may play a role in the proliferation of synovial cells in patients with RA synovitis.