Oxidative damage in synovial tissue is associated with in vivo hypoxic status in the arthritic joint

Biniecka, Monika; Kennedy, A. D.; Fearon, Ursula; Ng, Chin Teck; Veale, Douglas J.; O'Sullivan, Jacintha

doi:10.1136/ard.2009.111211

Cited by 91 publications

(95 citation statements)

References 68 publications

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“…Using a novel technique, we have recently demonstrated the hypoxic nature of synovial tissue in inflammatory arthritis, and we reported that in vivo synovial tissue partial oxygen pressure (tPO 2 ) measurements were strongly associated with levels of joint inflammation, vascularity, blood vessel stability, and disease activity (16,17). Furthermore, our studies showed that levels of oxidative damage in patients with inflammatory arthritis were strongly associated with tPO 2 in vivo, disease activity, and secretion of angiogenic markers (18).…”

mentioning

confidence: 70%

“…We have previously observed synovial tissue lipid peroxidation (4-HNE) in patients with inflammatory arthritides and found no significant differences in 4-HNE levels between RA patients and PsA patients (18), which may suggest that oxidative stress mechanisms are similar in the two diseases. We demonstrated that in vivo PO 2 levels were inversely correlated with lipid peroxidation in synovial tissue and synovial fluid but not in matched serum, suggesting that local levels of hypoxia and oxidative stress may be early markers of disease progression.…”

Section: Discussionmentioning

confidence: 92%

“…Under local anesthesia, each patient underwent arthroscopy of the inflamed knee, performed using a Wolf 2.7-mm needle arthroscope. A Licox combined PO 2 and temperature probe (Integra Life Sciences) was used to determine oxygen partial pressure as previously described (18). Synovial membrane biopsy samples were obtained from the site of the oxygen tension measurement and immediately embedded in mounting media for immunohistochemical analysis or snap frozen in liquid nitrogen for mitochondrial mutagenesis analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Levels of 8-oxodG and 4-HNE were also examined in cell culture supernatants after stimulation with SOD, NAC, or DMOG. Competitive enzyme-linked immunosorbent assays (Gentaur) were used to measure 8-oxodG and 4-HNE, as previously described (18).…”

Section: Mitochondrial Random Mutation Capture Assaymentioning

confidence: 99%

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Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Biniecka¹,

Fox²,

Gao³

et al. 2011

Arthritis & Rheumatism

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Objective. To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels.Methods. Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO 2 ) were measured at arthroscopy using a Results. The median tPO 2 level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P ‫؍‬ 0.05) and with higher synovial 4-HNE cytoplasmic expression (P ‫؍‬ 0.04). Synovial expression of CytcO II correlated with in vivo tPO 2 levels (P ‫؍‬ 0.03), and levels were lower in patients with tPO 2 <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC.Conclusion. These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.

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mentioning

confidence: 70%

Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Mitochondrial Random Mutation Capture Assaymentioning

confidence: 99%

See 2 more Smart Citations

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Biniecka¹,

Fox²,

Gao³

et al. 2011

Arthritis & Rheumatism

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“…This amino acid motif matches the consensus sequence for the basophilic AGC kinases (such as protein kinase B), which regulate cell migration and whose activity is stimulated by integrin binding and interaction with T-cell receptors (21). C5orf30 sequences also contains a motif matching closely the consensus for CDK1 phosphorylation (amino acids [20][21][22][23][24][25][26][27][28][29][30], which coupled to recognition sequences for cyclins (amino acids 139-170) is a strong indication of a roles for C5orf30 in the cell cycle. C5orf30 encodes a basic polypeptide (pI 9.5), a feature typical of proteins interacting with phospholipids, membranes, and/or nucleic acid interactions.…”

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confidence: 99%

C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

Muthana

Hawtree

Wilshaw

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The variant rs26232, in the first intron of the chromosome 5 open reading frame 30 (C5orf30) locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation, implying a central function in these organisms. Here, we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro, and gene profiling following C5orf30 inhibition confirmed up-regulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, because inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a previously unidentified negative regulator of tissue damage in RA, and this protein may act by modulating the autoaggressive phenotype that is characteristic of RASFs.

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Tumor necrosis factor blocking therapy alters joint inflammation and hypoxia

Kennedy¹,

Ng²,

Chang³

et al. 2011

Arthritis & Rheumatism

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Objective. To examine the effect of tumor necrosis factor (TNF) blocking therapy on hypoxia in vivo, macroscopic and microscopic inflammation, and magnetic resonance imaging (MRI) results in patients with inflammatory arthritis.Methods. Patients with inflammatory arthritis (n ‫؍‬ 20) underwent full clinical assessment, arthroscopy, synovial biopsy, and MRI before and after initiation of biologic therapy. Macroscopic synovitis/vascularity was assessed with a visual analog scale, and tissue PO 2 (tPO 2 ) was measured at arthroscopy using a Licox probe. Cell-specific markers (CD4, CD8, CD68, CD20, and CD19) and blood vessel maturity were quantified by immunohistologic analysis and dual-immunofluorescence factor VIII/␣-smooth muscle actin staining, respectively. Contiguous gadoteric acid-enhanced MRI of the target knee was used to assess synovial enhancement.Results. Biologic therapy responders showed a significant increase of tPO 2 in vivo (P < 0.05). This response was associated with significant reductions in 28-joint Disease Activity Score using the C-reactive protein level (DAS28-CRP) (P ‫؍‬ 0.012), macroscopic synovitis (P ‫؍‬ 0.017), macroscopic vascularity (P ‫؍‬ 0.05), CD4؉ T cells (P < 0.041), and CD68؉ macrophages (P < 0.011). Blood vessel numbers were also reduced in responders; however, this did not reach statistical significance. Strong inverse correlations were demonstrated between changes in tPo 2 levels and changes in DAS28-CRP (r ‫؍‬ ؊0.53, P < 0.001), CD4 (r ‫؍‬ ؊0.44, P < 0.026), CD68 (r ‫؍‬ ؊0.46, P < 0.003), and macroscopic vascularity (r ‫؍‬ ؊0.314, P ‫؍‬ 0.049) after therapy. Furthermore, changes in inflammation as measured by MRI showed a strong inverse correlation with tPO 2 levels (r ‫؍‬ ؊0.688, P < 0.002) and positive correlations with CRP levels (r ‫؍‬ 0.707, P ‫؍‬ 0.001), macroscopic synovitis (r ‫؍‬ 0.457, P ‫؍‬ 0.056), macroscopic vascularity (r ‫؍‬ 0.528, P‫؍‬ 0.017), CD4 (r ‫؍‬ 0.553, P < 0.032), and CD68 (r ‫؍‬ 0.670, P < 0.002) after therapy.Conclusion. This is the first study to show that successful biologic therapy significantly improves in vivo synovial hypoxia. Changes are strongly associated with changes in macroscopic and microscopic measures of joint inflammation and MRI improvement. These data further strengthen the concept that hypoxia is an important event driving synovial inflammation.

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Oxidative damage in synovial tissue is associated with in vivo hypoxic status in the arthritic joint

Abstract: Lipid peroxidation is associated with low oxygen tension in vivo, disease activity and angiogenic marker expression in inflammatory arthritis.

Cited by 91 publications

References 68 publications

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

C5orf30 is a negative regulator of tissue damage in rheumatoid arthritis

Tumor necrosis factor blocking therapy alters joint inflammation and hypoxia

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