Characterization of nitrotyrosine as a biomarker for arthritis and joint injury

Misko, Thomas P.; Radabaugh, Melissa R.; Highkin, Maureen; Abrams, M.; Friese, Olga; Gallavan, Robert H.; Bramson, Candace; Graverand, M.-P. Hellio Le; Lohmander, L. Stefan; Roman, D.

doi:10.1016/j.joca.2012.09.005

Cited by 42 publications

(29 citation statements)

References 27 publications

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“…Plasma CRP levels were previously found to be associated with NTyr levels 38 . We found that CRP levels were also independent predictors of higher NT-apoAI/apoAI ratio.…”

Section: Discussionmentioning

confidence: 95%

Nitrated apolipoprotein AI/apolipoprotein AI ratio is increased in diabetic patients with coronary artery disease

et al. 2016

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Aims/Hypothesis Recent studies have suggested that determination of HDL function may be more informative than its concentration in predicting its protective role in coronary artery disease (CAD). Apolipoprotein AI (apoAI), the major protein of HDL, is nitrosylated in vivo to nitrated apoAI (NT-apoAI) that might cause dysfunction. We hypothesized that NT-apoAI/apoAI ratio might be associated with diabetes mellitus (DM) in CAD patients. Methods We measured plasma NT-apoAI and apoAI levels in 777 patients with coronary artery disease (CAD) by ELISA. Further, we measured plasma cholesterol efflux potential in subjects with similar apoAI but different NT-apoAI levels. Results We found that median NT-apoAI/apoAI ratio was significantly higher in diabetes mellitus (DM) (n=327) versus non-diabetic patients (n=450). Further analysis indicated that DM, thiobarbituric acid-reactive substances and C-reactive protein levels were independent predictors of higher NT-apoAI/apoAI ratio. There was negative correlation between NT-apoAI/apoAI and use of anti-platelet and lipid lowering drugs. The cholesterol efflux capacity of plasma from 67 individuals with differing NT-apoAI but similar apoAI levels from macrophages in vitro was negatively correlated with NT-apoAI/apoAI ratio. Conclusions Higher NT-apoAI/apoAI ratio is significantly associated with DM in this relatively large German cohort with CAD and may contribute to associated complications by reducing cholesterol efflux capacity.

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“…Plasma CRP levels were previously found to be associated with NTyr levels 38 . We found that CRP levels were also independent predictors of higher NT-apoAI/apoAI ratio.…”

Section: Discussionmentioning

confidence: 95%

Nitrated apolipoprotein AI/apolipoprotein AI ratio is increased in diabetic patients with coronary artery disease

et al. 2016

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“…Even for eRA, however, the anti-CPP antibody test has relatively low sensitivity [15]; indeed, we observed sensitivity of 56 % herein with patients recruited within 5 months of the onset of symptoms [16]. Hitherto, biomarkers of protein oxidation, nitration and glycation have not been developed for clinical diagnostic application in arthritis, excepting studies on plasma 3-NT [41]; the trace-level of these biomarkers leads to them often being overlooked in untargeted approaches to biomarkers in arthritis [42]. …”

Section: Discussionmentioning

confidence: 99%

Protein oxidation, nitration and glycation biomarkers for early-stage diagnosis of osteoarthritis of the knee and typing and progression of arthritic disease

et al. 2016

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BackgroundThere is currently no blood-based test for detection of early-stage osteoarthritis (OA) and the anti-cyclic citrullinated peptide (CCP) antibody test for rheumatoid arthritis (RA) has relatively low sensitivity for early-stage disease. Morbidity in arthritis could be markedly decreased if early-stage arthritis could be routinely detected and classified by clinical chemistry test. We hypothesised that damage to proteins of the joint by oxidation, nitration and glycation, and with signatures released in plasma as oxidized, nitrated and glycated amino acids may facilitate early-stage diagnosis and typing of arthritis.MethodsPatients with knee joint early-stage and advanced OA and RA or other inflammatory joint disease (non-RA) and healthy subjects with good skeletal health were recruited for the study (n = 225). Plasma/serum and synovial fluid was analysed for oxidized, nitrated and glycated proteins and amino acids by quantitative liquid chromatography-tandem mass spectrometry. Data-driven machine learning methods were employed to explore diagnostic utility of the measurements for detection and classifying early-stage OA and RA, non-RA and good skeletal health with training set and independent test set cohorts.ResultsGlycated, oxidized and nitrated proteins and amino acids were detected in synovial fluid and plasma of arthritic patients with characteristic patterns found in early and advanced OA and RA, and non-RA, with respect to healthy controls. In early-stage disease, two algorithms for consecutive use in diagnosis were developed: (1) disease versus healthy control, and (2) classification as OA, RA and non-RA. The algorithms featured 10 damaged amino acids in plasma, hydroxyproline and anti-CCP antibody status. Sensitivities/specificities were: (1) good skeletal health, 0.92/0.91; (2) early-stage OA, 0.92/0.90; early-stage RA, 0.80/0.78; and non-RA, 0.70/0.65 (training set). These were confirmed in independent test set validation. Damaged amino acids increased further in severe and advanced OA and RA.ConclusionsOxidized, nitrated and glycated amino acids combined with hydroxyproline and anti-CCP antibody status provided a plasma-based biochemical test of relatively high sensitivity and specificity for early-stage diagnosis and typing of arthritic disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1154-3) contains supplementary material, which is available to authorized users.

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“…MMP-13 has been shown to be five times to 10 times more active in digesting Type II collagen than other collagenases, and MMP-13 overexpression in mice has been associated with advanced joint degeneration [3,17,25,31]. Prior human studies have demonstrated elevated MMP concentrations in arthritic joint synovial fluid [4,21,23,28,34]. However, there were no prior studies evaluating for the presence of MMPs after articular fracture, which is the clinical setting with the most articular damage and the highest rates of posttraumatic OA.…”

Section: Discussionmentioning

confidence: 99%

“…A variety of animal OA models with ACL transection have shown upregulation of genes coding for aggrecanases and MMPs as well as increased concentrations of these destructive proteases [1,10,20,47]. Most human studies demonstrate elevated MMPs and aggrecan degradation in patients with OA as compared with healthy control subjects and that these proteases are more elevated in patients with end-stage OA compared with early OA [4,21,23,28,34]. In an effort to look specifically at the presence of proteolytic enzymes after traumatic injury, several authors have shown elevated MMPs and aggrecan degradation after ACL tear.…”

Section: Introductionmentioning

confidence: 99%

Intraarticular Matrix Metalloproteinases and Aggrecan Degradation Are Elevated After Articular Fracture

Haller

Swearingen

Partridge

et al. 2015

Clin Orthop Relat Res

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Background Posttraumatic osteoarthritis (OA) is a variant of OA that can develop after articular injury. Although the mechanism(s) of posttraumatic OA are uncertain, the presence and impact of postinjury proteolytic enzymes on articular cartilage remain unknown. To our knowledge, there are no studies that evaluate the presence of matrix metalloproteinases (MMPs) or aggrecan degradation after articular fracture.Questions/purposes (1) Are MMP concentrations and aggrecan degradation elevated after intraarticular fracture? (2) Are MMP concentrations and aggrecan degradation greater in high-energy injuries compared with low-energy injuries? (3) Do the concentrations of these biomarkers remain elevated at a secondary aspiration? Methods Between December 2011 and June 2013, we prospectively enrolled patients older than 18 years of age with acute tibial plateau fracture. Exclusion criteria included age older than 60 years, preexisting knee OA, injury greater than 24 hours before evaluation, contralateral knee injury, history of autoimmune disease, open fracture, and non-English-speaking patients. During the enrollment period, we enrolled 45 of the 91 (49%) tibial plateau fractures treated at our facility. Knee synovial fluid aspirations were obtained from both the injured and uninjured knees; two patients received aspirations in the emergency department and the remaining patients received aspirations in the operating room. Twenty patients who underwent spanning external fixator followed by definitive fixation were aspirated during both surgical procedures. MMP-1, -2, -3, -7, -9, -10, -12, and -13 concentrations were quantified using multiplex assays. Aggrecan degradation was quantified using sandwich enzyme-linked immunosorbent assay. Results There were higher concentrations of MMP-1 (3.89 ng/mL [95% confidence interval {CI}, 2.37-6.37] versus 0.37 ng/mL [95% CI, 0.23-0.61], p \ 0.001), MMP-3The institution of one or more of the authors (JMH, TFH) has received peer-reviewed research grant funding from the Orthopedic Trauma Association, LS Peery Foundation, and AO North America for this project. One of the authors certifies that he (TFH), or a member of his immediate family, has signed an agreement with DePuy Synthes (Warsaw, IN, USA) for consulting activities not related to the current study, and has not received payments or benefits, during the study period. One or more of the authors (CAS, KT) are employed at Eli Lilly (Indianapolis, IN, USA). All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research1 editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research1 neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDAapproval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved or waived approval for the reporting of this investigation and that all inves...

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Characterization of nitrotyrosine as a biomarker for arthritis and joint injury

Abstract: NT may serve as a useful biomarker for arthritis and joint injury. In RA, NT is highly correlated with several biomarkers and clinical correlates of disease activity and responds to anti-TNF therapy.

Cited by 42 publications

References 27 publications

Nitrated apolipoprotein AI/apolipoprotein AI ratio is increased in diabetic patients with coronary artery disease

Nitrated apolipoprotein AI/apolipoprotein AI ratio is increased in diabetic patients with coronary artery disease

Protein oxidation, nitration and glycation biomarkers for early-stage diagnosis of osteoarthritis of the knee and typing and progression of arthritic disease

Intraarticular Matrix Metalloproteinases and Aggrecan Degradation Are Elevated After Articular Fracture

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