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Link to original content: https://www.ncbi.nlm.nih.gov/pubmed/15535839?dopt=Abstract
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Review
. 2004;6(6):265-78.
doi: 10.1186/ar1447. Epub 2004 Oct 13.

Oxidation in rheumatoid arthritis

Carol A Hitchon  1 , Hani S El-Gabalawy
Affiliations
Review

Oxidation in rheumatoid arthritis

Carol A Hitchon et al. Arthritis Res Ther. 2004.

Abstract

Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis. Reactive oxygen species (ROS) produced in the course of cellular oxidative phosphorylation, and by activated phagocytic cells during oxidative bursts, exceed the physiological buffering capacity and result in oxidative stress. The excessive production of ROS can damage protein, lipids, nucleic acids, and matrix components. They also serve as important intracellular signaling molecules that amplify the synovial inflammatory-proliferative response. Repetitive cycles of hypoxia and reoxygenation associated with changes in synovial perfusion are postulated to activate hypoxia-inducible factor-1alpha and nuclear factor-kappaB, two key transcription factors that are regulated by changes in cellular oxygenation and cytokine stimulation, and that in turn orchestrate the expression of a spectrum of genes critical to the persistence of synovitis. An understanding of the complex interactions involved in these pathways might allow the development of novel therapeutic strategies for rheumatoid arthritis.

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Figures

Figure 1
Figure 1
Hypoxic regulation of the hypoxia-inducible factor-1α (HIF-1α) transcription factor is primarily through inhibition of degradation. Under normoxic conditions, HIF-1α undergoes rapid proteosomal degradation once it forms a complex with von Hippel–Landau tumor suppressor factor (VHL) and E3 ligase complex. This requires the hydroxylation of critical proline residues by a family of HIF-1α-specific prolyl hydroxylases (PHD-1,2,3), which requires O2 and several cofactors, including iron. Under hypoxic conditions, or when iron is chelated or competitively inhibited, proline hydroxylation does not occur, thus stabilizing HIF-1α and allowing it to interact with the constitutively expressed HIF-1β (aryl hydrocarbon nuclear translocator; ARNT). The HIF-1 complex then translocates to the nucleus and activates genes with hypoxia-responsive elements in their promoters. bHLH, basic helix-loop-helix; CBP, cAMP response element binding protein; FIH, factor inhibiting HIF-1α; PAS, PER-ARNT-SIM; TAD, transactivation domain.
Figure 2
Figure 2
Genes that have been shown to be directly regulated by hypoxia-inducible factor-1α through hypoxia-responsive elements in their promoter regions. The genes are classified on the basis on their best known functional properties. A full listing of the gene annotations is presented in the Additional file.
Figure 3
Figure 3
Expression of hypoxia-inducible factor-1α (HIF-1α) in RA synovium and fibroblast-like synoviocytes under normoxic and hypoxic conditions. (a) Under normoxic conditions, HIF-1α expression in fresh synovial explants was patchy and confined to some cells in the lining layer. (b) When fresh RA tissue explants were cultured in hypoxic conditions (1% O2), nuclear staining for HIF-1α was readily detected in the lining cells. (c, d) A similar pattern of expression was seen in fibroblast-like synoviocytes where under normoxic conditions no HIF-1α staining was detected (c), whereas under hypoxic conditions intense nuclear staining was seen maximally at 4–6 hours (d). Reproduced, with permission, from [91].
Figure 4
Figure 4
Regulation of the hypoxia-inducible factor-1α (HIF-1α) and nuclear factor-κB (NF-κB) pathways by reactive oxygen species (ROS) and cytokine stimulation. The complex and interrelated activation of these two critical transcription factors is central to most of the processes that sustain synovitis in rheumatoid arthritis, such as endothelial activation, leukocyte recruitment, angiogenesis, and enhanced cell survival. IL, interleukin; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; TNF, tumor necrosis factor.
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References

    1. Babior BM. Phagocytes and oxidative stress. Am J Med. 2000;109:33–44. doi: 10.1016/S0002-9343(00)00481-2. - DOI - PubMed
    1. Lotz M. Neuropeptides, free radicals and nitric oxide. Rheumatology. 2003:135–146. - PubMed
    1. Olofsson P, Holmberg J, Tordsson J, Lu S, Akerstrom B, Holmdahl R. Positional identification of Ncf1 as a gene that regulates arthritis severity in rats. Nat Genet. 2003;33:25–32. doi: 10.1038/ng1058. - DOI - PubMed
    1. van de Loo FA, Bennink MB, Arntz OJ, Smeets RL, Lubberts E, Joosten LA, van Lent PL, Coenen-de Roo CJ, Cuzzocrea S, Segal BH, et al. Deficiency of NADPH oxidase components p47phox and gp91phox caused granulomatous synovitis and increased connective tissue destruction in experimental arthritis models. Am J Pathol. 2003;163:1525–1537. - PMC - PubMed
    1. van der Veen RC, Dietlin TA, Hofman FM, Pen L, Segal BH, Holland SM. Superoxide prevents nitric oxide-mediated suppression of helper T lymphocytes: decreased autoimmune encephalomyelitis in nicotinamide adenine dinucleotide phosphate oxidase knockout mice. J Immunol. 2000;164:5177–5183. - PubMed

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