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Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 1992 Apr;51(4):516–521. doi: 10.1136/ard.51.4.516

Effect of iron complexes on adjuvant arthritis in rats.

A J Dabbagh 1, D R Blake 1, C J Morris 1
PMCID: PMC1004704  PMID: 1586252

Abstract

When a total dose infusion of iron dextran is given to anaemic rheumatoid patients an exacerbation of inflammatory synovitis in previously affected joints is observed. The adjuvant arthritis model of inflammation in rats has been used to investigate the mechanism of iron promoted synovitis. Either iron dextran (5 mg injected intravenously) with a dextran C control, or iron sorbitol (7.5 mg injected intramuscularly) with a sorbitol citrate complex control was given at the onset of clinical joint inflammation. Iron dextran significantly increased joint inflammation (assessed by joint scoring) at days 12, 13, 14, and 16 after injection. Similarly, iron sorbitol produced a significant increase in the joint score at days 17, 18, 19, and 21. In addition, extensive osteoporosis was observed in the rats treated with iron sorbitol. These pro-inflammatory effects of iron coincide with the presence of positive results for synovial iron (III) using Perl's test and neutrophil infiltration. The results of this study suggest that the iron induced increase in synovitis in adjuvant arthritis is a result of iron promoted oxidative damage and is not likely to be due to the dextran C or the sorbitol citric acid components. It is suggested that a similar mechanism may occur in rheumatoid patients given iron supplements.

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Selected References

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  1. Andrews F. J., Morris C. J., Kondratowicz G., Blake D. R. Effect of iron chelation on inflammatory joint disease. Ann Rheum Dis. 1987 Apr;46(4):327–333. doi: 10.1136/ard.46.4.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andrews F. J., Morris C. J., Lewis E. J., Blake D. R. Effect of nutritional iron deficiency on acute and chronic inflammation. Ann Rheum Dis. 1987 Nov;46(11):859–865. doi: 10.1136/ard.46.11.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. BALL J., CHAPMAN J. A., MUIRDEN K. D. THE UPTAKE OF IRON IN RABBIT SYNOVIAL TISSUE FOLLOWING INTRA-ARTICULAR INJECTION OF IRON DEXTRAN. A LIGHT AND ELECTRON MICROSCOPE STUDY. J Cell Biol. 1964 Aug;22:351–364. doi: 10.1083/jcb.22.2.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bacon B. R., Tavill A. S., Brittenham G. M., Park C. H., Recknagel R. O. Hepatic lipid peroxidation in vivo in rats with chronic iron overload. J Clin Invest. 1983 Mar;71(3):429–439. doi: 10.1172/JCI110787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bennett R. M., Williams E. D., Lewis S. M., Holt P. J. Synovial iron deposition in rheumatoid arthritis. Arthritis Rheum. 1973 May-Jun;16(3):298–304. doi: 10.1002/art.1780160303. [DOI] [PubMed] [Google Scholar]
  6. Blake D. R., Gallagher P. J., Potter A. R., Bell M. J., Bacon P. A. The effect of synovial iron on the progression of rheumatoid disease. A histologic assessment of patients with early rheumatoid synovitis. Arthritis Rheum. 1984 May;27(5):495–501. doi: 10.1002/art.1780270503. [DOI] [PubMed] [Google Scholar]
  7. Blake D. R., Lunec J., Ahern M., Ring E. F., Bradfield J., Gutteridge J. M. Effect of intravenous iron dextran on rheumatoid synovitis. Ann Rheum Dis. 1985 Mar;44(3):183–188. doi: 10.1136/ard.44.3.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Blake D. R., Merry P., Unsworth J., Kidd B. L., Outhwaite J. M., Ballard R., Morris C. J., Gray L., Lunec J. Hypoxic-reperfusion injury in the inflamed human joint. Lancet. 1989 Feb 11;1(8633):289–293. doi: 10.1016/s0140-6736(89)91305-6. [DOI] [PubMed] [Google Scholar]
  9. Breedveld F. C., Dynesius-Trentham R., de Sousa M., Trentham D. E. Collagen arthritis in the rat is initiated by CD4+ T cells and can be amplified by iron. Cell Immunol. 1989 Jun;121(1):1–12. doi: 10.1016/0008-8749(89)90001-4. [DOI] [PubMed] [Google Scholar]
  10. Chambers T. J., Ali N. N. Inhibition of osteoclastic motility by prostaglandins I2, E1, E2 and 6-oxo-E1. J Pathol. 1983 Mar;139(3):383–397. doi: 10.1002/path.1711390313. [DOI] [PubMed] [Google Scholar]
  11. Chambers T. J., McSheehy P. M., Thomson B. M., Fuller K. The effect of calcium-regulating hormones and prostaglandins on bone resorption by osteoclasts disaggregated from neonatal rabbit bones. Endocrinology. 1985 Jan;116(1):234–239. doi: 10.1210/endo-116-1-234. [DOI] [PubMed] [Google Scholar]
  12. Currey H. L., Ziff M. Suppression of adjuvant disease in the rat by heterologous antilymphocyte globulin. J Exp Med. 1968 Jan 1;127(1):185–203. doi: 10.1084/jem.127.1.185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Garrett I. R., Boyce B. F., Oreffo R. O., Bonewald L., Poser J., Mundy G. R. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J Clin Invest. 1990 Mar;85(3):632–639. doi: 10.1172/JCI114485. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Green M. R., Hill H. A., Okolow-Zubkowska M. J., Segal A. W. The production of hydroxyl and superoxide radicals by stimulated human neutrophils- measurements by EPR spectroscopy. FEBS Lett. 1979 Apr 1;100(1):23–26. doi: 10.1016/0014-5793(79)81123-0. [DOI] [PubMed] [Google Scholar]
  15. Kaibara N., Hotokebuchi T., Takagishi K., Katsuki I., Morinaga M., Arita C., Jingushi S. Pathogenetic difference between collagen arthritis and adjuvant arthritis. J Exp Med. 1984 May 1;159(5):1388–1396. doi: 10.1084/jem.159.5.1388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kishore V. Effects of adjuvant arthritis on copper, zinc, and iron metabolism in the rat. Res Commun Chem Pathol Pharmacol. 1989 Jan;63(1):153–156. [PubMed] [Google Scholar]
  17. Ledingham I., Mone J. G. Accidental hypothermia. Lancet. 1978 Feb 18;1(8060):391–391. doi: 10.1016/s0140-6736(78)91116-9. [DOI] [PubMed] [Google Scholar]
  18. Merry P., Grootveld M., Blake D. R. Hypoxic-reperfusion injury in inflamed joints. Lancet. 1989 May 6;1(8645):1023–1023. doi: 10.1016/s0140-6736(89)92668-8. [DOI] [PubMed] [Google Scholar]
  19. Morris C. J., Blake D. R., Wainwright A. C., Steven M. M. Relationship between iron deposits and tissue damage in the synovium: an ultrastructural study. Ann Rheum Dis. 1986 Jan;45(1):21–26. doi: 10.1136/ard.45.1.21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mowat A. G., Garner R. W. Influence of iron dextran on adjuvant arthritis in the rat. Ann Rheum Dis. 1972 Jul;31(4):339–343. doi: 10.1136/ard.31.4.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mowat A. G., Hothersall T. E. Nature of anaemia in rheumatoid arthritis. 8. Iron content of synovial tissue in patients with rheumatoid arthritis and in normal individuals. Ann Rheum Dis. 1968 Jul;27(4):345–351. doi: 10.1136/ard.27.4.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Muirden K. D. Ferritin in synovial cells in patients with rheumatoid arthritis. Ann Rheum Dis. 1966 Sep;25(5):387–401. doi: 10.1136/ard.25.5.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Muirden K. D., Fraser J. R., Clarris B. Ferritin formation by synovial cells exposed to haemoglobin in vitro. Ann Rheum Dis. 1967 May;26(3):251–259. doi: 10.1136/ard.26.3.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Muirden K. D., Peace G. Light and electron microscope studies in carragheenin, adjuvant, and tuberculin-induced arthris. Ann Rheum Dis. 1969 Jul;28(4):392–401. doi: 10.1136/ard.28.4.392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Okazaki I., Brinckerhoff C. E., Sinclair J. F., Sinclair P. R., Bonkowsky H. L., Harris E. D., Jr Iron increases collagenase production by rabbit synovial fibroblasts. J Lab Clin Med. 1981 Mar;97(3):396–402. [PubMed] [Google Scholar]
  26. Robinson D. R., Tashjian A. H., Jr, Levine L. Prostaglandin-stimulated bone resorption by rheumatoid synovia. A possible mechanism for bone destruction in rheumatoid arthritis. J Clin Invest. 1975 Nov;56(5):1181–1188. doi: 10.1172/JCI108195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Robinson H. J., Jr, Granda J. L. Prostaglandins in synovial inflammatory disease. Surg Forum. 1974;25(0):476–477. [PubMed] [Google Scholar]
  28. SCHUMACHER H. R., Jr HEMOCHROMATOSIS AND ARTHRITIS. Arthritis Rheum. 1964 Feb;7:41–50. doi: 10.1002/art.1780070106. [DOI] [PubMed] [Google Scholar]
  29. Schumacher H. R. Articular cartilage in the degenerative arthropathy of hemochromatosis. Arthritis Rheum. 1982 Dec;25(12):1460–1468. doi: 10.1002/art.1780251212. [DOI] [PubMed] [Google Scholar]
  30. Sella E. J., Goodman A. H. Arthropathy secondary to transfusion hemochromatosis. J Bone Joint Surg Am. 1973 Jul;55(5):1077–1081. [PubMed] [Google Scholar]
  31. Wilkins M., Williams P., Cavill I. Transferrin iron uptake by human synovium. Ann Rheum Dis. 1977 Oct;36(5):474–475. doi: 10.1136/ard.36.5.474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Williams H. L., Johnson D. J., Haut M. J. Simultaneous spectrophotometry of Fe2+ and Cu2+ in serum denatured with guanidine hydrochloride. Clin Chem. 1977 Feb;23(2 Pt 1):237–240. [PubMed] [Google Scholar]
  33. Winyard P. G., Blake D. R., Chirico S., Gutteridge J. M., Lunec J. Mechanism of exacerbation of rheumatoid synovitis by total-dose iron-dextran infusion: in-vivo demonstration of iron-promoted oxidant stress. Lancet. 1987 Jan 10;1(8524):69–72. doi: 10.1016/s0140-6736(87)91909-x. [DOI] [PubMed] [Google Scholar]
  34. Woodruff T., Blake D. R., Freeman J., Andrews F. J., Salt P., Lunec J. Is chronic synovitis an example of reperfusion injury? Ann Rheum Dis. 1986 Jul;45(7):608–611. doi: 10.1136/ard.45.7.608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yoshikawa T., Tanaka H., Kondo M. Lipid peroxidation in rat adjuvant arthritis and its inhibition by indomethacin. J Appl Biochem. 1983 Dec;5(6):382–387. [PubMed] [Google Scholar]
  36. Yoshikawa T., Tanaka H., Kondo M. The increase of lipid peroxidation in rat adjuvant arthritis and its inhibition by superoxide dismutase. Biochem Med. 1985 Jun;33(3):320–326. doi: 10.1016/0006-2944(85)90006-7. [DOI] [PubMed] [Google Scholar]

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