Synovial Iron Deposition in Rheumatoid Arthritis

Bennett, Robert M.; Williams, E. D.; Lewis, S. M.; Holt, P. J.

doi:10.1002/art.1780160303

Cited by 26 publications

(9 citation statements)

References 10 publications

(4 reference statements)

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“…Iron deposition is found in haemochromatosis joints but this is an unspecific phenomenon 6 7 14. One significant finding is premature chrondrocalcinosis of wrists and knee joints, although pseudogout attacks are uncommon in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

VCAM-1 serum levels are associated with arthropathy in hereditary haemochromatosis

et al. 2013

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ObjectivesThe aim of this study was to assess the role of vascular adhesion molecule 1 (VCAM-1) in patients with hereditary haemochromatosis (HH) with or without arthropathy.MethodsSera from a large cross-sectional cohort of unselected HH patients (n=147) were obtained and compared to an age-matched and sex-matched control group. Serum levels of VCAM-1 were measured by ELISA and were correlated with clinical measures.ResultsVCAM-1 serum levels were elevated in HH patients as compared to matched controls (mean 913±456 vs 654±451 ng/ml, p<0.0001). Within the HH patient group, VCAM-1 levels were much higher in patients with arthropathy and joint replacement surgery. VCAM-1 levels correlated well with radiographic measures of HH arthropathy (r=0.36, p<0.0001). Multivariate regression analysis confirmed a highly significant association of VCAM-1 serum levels and the presence of HH arthropathy, independent from diabetes, body mass index and age.ConclusionsVCAM-1 serum levels emerge as a biomarker for haemochromatosis arthropathy.

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Section: Discussionmentioning

confidence: 99%

VCAM-1 serum levels are associated with arthropathy in hereditary haemochromatosis

et al. 2013

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“…18,22,23 In both processes, microbleeding is well described and iron deposition correlates closely with the extent of erosive disease and is associated with a poor prognosis. 23,24 Aberrantly activated gene sequences, proto-oncogenes, have been suggested to play a role in the invasive behavior of rheumatoid synovial fibroblasts. 12 Increased expression of oncogenes and their gene products have been detected in human synovial tissues from patients with rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 99%

c-myc proto-oncogene expression in hemophilic synovitis: in vitro studies of the effects of iron and ceramide

Wen

Jabbar

Chen

et al. 2002

Blood

123

120

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Hemophilia is a rare congenital bleeding disorder that is due to the deficiency of blood coagulation factor VIII or IX. Recurrent musculoskeletal bleeding is common and bleeding into joints results in a chronic inflammatory condition termed hemophilic synovitis. This destructive process is characterized by hemosiderin deposition in the superficial and deeper layers of the synovial membrane as well as a proliferation of synovial fibroblasts and vascular cells. The hyperplastic synovium and neovascular changes are reminiscent of the histopathologic appearance observed in malignant tissues. Indeed, the benign hyperplastic synovium in patients with hemophilia displays similar invasive and destructive behaviors suggesting the possibility of analogous disturbances in growth control and locally invasive mechanisms. Iron plays a role in malignant cell growth, local invasion, and tumor progression, possibly due to changes in the expression of the proto-oncogene, c-myc. We hypothesized that iron plays a similar role in hemophilic synovitis. To explore this hypothesis, we investigated the in vitro effects of iron on the proliferation of a primary, human synovial fibroblast cell (HSFC) line and the involvement of c-myc in this process. We also examined the role of ceramide, a sphingolipid capable of inducing apoptosis in this model system. HSFC proliferation was increased in a dose-dependent fashion and c-myc expression was enhanced by ferric citrate compared to sodium citrate control. Ceramide prevented both the iron-induced increases in HSFC proliferation and c-myc expression. These results indicate that iron probably plays a role in the proliferative changes observed in hemophilic joint disease and that aberrant expression of c-myc may underlie the iron effects. Furthermore, these results suggest that there may be a therapeutic role for ceramide in reversing these changes. IntroductionRecurrent musculoskeletal bleeding is the most frequent manifestation of severe hemophilia. Bleeding into a joint results in a complex arthritis known as "hemophilic arthropathy" that in time evolves into a chronic, persistent inflammatory disorder termed "hemophilic synovitis." It has been speculated that the persistent presence of blood in the joint space is involved in the pathogenesis of this disorder. 1 Iron deposition in synovial tissues is one of the hallmarks of hemophilic arthropathy. [2][3][4] In vitro, DNA synthesis by synovial fibroblast cells exposed to ferric citrate at concentrations up to 1 mM for 72 hours is increased compared to cells cultured with sodium citrate. 5 Iron, in combination with interleukin-1␤ (IL-␤), IL-7, tumor necrosis factor ␣ (TNF-␣), or interferon ␥ (IFN-␥) exerts an additive effect on DNA synthesis suggesting that iron increases cell proliferation by a mechanism distinct from inflammatory cytokines. 5 In vitro, cells isolated from hemophilic synovial tissue produce more IL-1␤, IL-6, and TNF-␣ compared to cells from normal synovial tissue. 4 Monocytes and synovial fibroblasts are capable of generating m...

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“…The literature discloses evidence that iron deposits in synovial fluid in numerous inflammatory and degenerative joint disorders, e.g. rheumatoid arthritis, osteoarthritis, hemophilic synovitis, and seronegative arthritis [79–86]. In these joint diseases, just as in inflammatory disorders of the bowel, accumulating iron seemingly takes on a part as a villain to maintain and exacerbate chronic inflammation.…”

Section: Iron-mediated Pathology In Neurodegeneration As Interplay Bementioning

confidence: 99%

Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration

Andersen

Johnsen

Moos

2013

Cell. Mol. Life Sci.

133

111

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Neurodegenerative disorders are characterized by the presence of inflammation in areas with neuronal cell death and a regional increase in iron that exceeds what occurs during normal aging. The inflammatory process accompanying the neuronal degeneration involves glial cells of the central nervous system (CNS) and monocytes of the circulation that migrate into the CNS while transforming into phagocytic macrophages. This review outlines the possible mechanisms responsible for deposition of iron in neurodegenerative disorders with a main emphasis on how iron-containing monocytes may migrate into the CNS, transform into macrophages, and die out subsequently to their phagocytosis of damaged and dying neuronal cells. The dying macrophages may in turn release their iron, which enters the pool of labile iron to catalytically promote formation of free-radical-mediated stress and oxidative damage to adjacent cells, including neurons. Healthy neurons may also chronically acquire iron from the extracellular space as another principle mechanism for oxidative stress-mediated damage. Pharmacological handling of monocyte migration into the CNS combined with chelators that neutralize the effects of extracellular iron occurring due to the release from dying macrophages as well as intraneuronal chelation may denote good possibilities for reducing the deleterious consequences of iron deposition in the CNS.

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Synovial Iron Deposition in Rheumatoid Arthritis

Cited by 26 publications

References 10 publications

VCAM-1 serum levels are associated with arthropathy in hereditary haemochromatosis

VCAM-1 serum levels are associated with arthropathy in hereditary haemochromatosis

c-myc proto-oncogene expression in hemophilic synovitis: in vitro studies of the effects of iron and ceramide

Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration

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