Iron has long been suspected to be the culprit

Ann Rheum Dis 1989 May;48(5):382-8



Investigation of the anti-inflammatory properties of hydroxypyridinones.

Hewitt SD, Hider RC, Sarpong P, Morris CJ, Blake DR
Cancer Research Unit, University of York, Heslington.

Synovial iron deposition associated with rheumatoid disease may result in the
production of highly reactive oxygen free radicals, leading to tissue damage.
This chain of events can be interrupted by iron chelation. Families of strong
iron (III) chelators have been tested for their iron scavenging properties in
vitro and their effects assessed in vivo using a rat model of inflammation. All
the chelators competed successfully for iron with apotransferrin, and some
removed up to 34% of iron from ferritin. The best anti-inflammatory effects
were achieved with the most hydrophilic chelators and those which chelated iron
most avidly. Activity was dependent on dose. The route of administration was
also an important factor with lower affinity chelators. This work introduces a
range of simple bidentate iron chelators, which under certain conditions exceed
desferrioxamine in their iron scavenging abilities, and some of which, in this
simple animal model, approach indomethacin in their anti-inflammatory
capabilities.

PMID: 2730166, UI: 89272259


Annals of the Rheumatic Diseases 2002;61:741-744

Iron deposits may damage joint tissue in RA

Our understanding of the role of iron in rheumatoid arthritis (RA) has improved
with a recent study showing where iron accumulates in the synovial membranes of
affected joints. The researchers speculate how iron might build up to toxic
amounts.
Ferritin, both light and heavy subunits , was found in the lining layer and
subintimal zone of the synovium and in synovial macrophages and fibroblasts.
Transferrin receptor appeared only in the lining layer .
Non-specific resistance associated macrophage proteins (Nramp) were also found
. These are proteins that span membranes and transport divalent cations. Nramp
2 occurred in the macrophages and fibroblasts. Nramp 1 was present in
macrophages and neutrophils, in the synovial lining layer and the subintimal
zone, and in infiltrating inflammatory cells, but not in fibroblasts.
The study used synovial membranes from arthroplasties of 20 patients with RA.
Thin sections were stained cytochemically for ferritin, transferrin receptor ,
and Nramp 1 with monoclonal or polyclonal antibodies. Macrophages and
fibroblasts were isolated from collaginase digests of synovial membranes.
Neutrophils were isolated from synovial fluid aspirated routinely from the
joints . These cell types were stained for ferritin and transferrin receptor
immunocytochemically. Nramp 1 and Nramp 2 were identified by reverse
transcriptase polymerase chain reaction.
A high iron content has been noted in synovial membraines in RA , but the
uptake and storage of iron and its potential relation to imflammation of the
joints has been unknown until now.
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