Top

27-10-2016 | Osteoarthritis | Article

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

Journal: Arthritis Research & Therapy

Authors: Usman Ahmed, Attia Anwar, Richard S. Savage, Paul J. Thornalley, Naila Rabbani

Publisher: BioMed Central

Abstract

Background

There 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.

Methods

Patients 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.

Results

Glycated, 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.

Conclusions

Oxidized, 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.

Thornalley PJ, Rabbani N. Detection of oxidized and glycated proteins in clinical samples using mass spectrometry - a user’s perspective. Biochim Biophys Acta. 2014;1840(2):818–29.CrossRefPubMed

McCord JM. Free Radicals and Inflammation: Protection of synovial fluid by superoxide dismutase. Science. 1974;185(4150):529–31.CrossRefPubMed

Kaur H, Halliwell B. Evidence for nitric oxide-mediated oxidative damage in chronic inflammation. Nitrotyrosine in serum and synovial fluid from rheumatoid patients. FEBS Lett. 1994;350(1):9–12.CrossRefPubMed

Wright HL, Moots RJ, Bucknall RC, Edwards SW. Neutrophil function in inflammation and inflammatory diseases. Rheumatology. 2010;49(9):1618–31.CrossRefPubMed

Sellam J, Berenbaum F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat Rev Rheumatol. 2010;6(11):625–35.CrossRefPubMed

Fearon U, Canavan M, Biniecka M, Veale DJ. Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nat Rev Rheumatol. 2016;12(7):385–97.CrossRefPubMed

Blanco FJ, Rego I, Ruiz-Romero C. The role of mitochondria in osteoarthritis. Nat Rev Rheumatol. 2011;7(3):161–9.CrossRefPubMed

Miyata T, Ishiguro N, Yasuda Y, Ito T, Nangaku M, Iwata H, Kurokawa K. Increased pentosidine, an advanced glycation end product, in plasma and synovial fluid from patients with rheumatoid arthritis and its relation with inflammatory markers. Biochem Biophys Res Comm. 1998;244:45–9.CrossRefPubMed

Drinda S, Franke S, Canet CC, Petrow P, Brauer R, Huttich C, Stein G, Hein G. Identification of the advanced glycation end products Nε-carboxymethyllysine in the synovial tissue of patients with rheumatoid arthritis. Ann Rheum Dis. 2002;61(6):488–92.CrossRefPubMedPubMedCentral

10.

DeGroot J, Verzijl N, Wenting-van Wijk MJG, Jacobs KMG, Van El B, Van Roermund PM, Bank RA, Bijlsma JWJ, TeKoppele JM, Lafeber F. Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum. 2004;50(4):1207–15.CrossRefPubMed

11.

Hardin JA, Cobelli N, Santambrogio L. Consequences of metabolic and oxidative modifications of cartilage tissue. Nat Rev Rheumatol. 2015;11(9):521–9.CrossRefPubMedPubMedCentral

12.

Isaacs JD. The changing face of rheumatoid arthritis: sustained remission for all? Nature Rev Immunol. 2010;10(8):605–11.CrossRef

13.

Roos EM, Arden NK. Strategies for the prevention of knee osteoarthritis. Nat Rev Rheumatol. 2016;12(2):92–101.CrossRefPubMed

14.

Menashe L, Hirko K, Losina E, Kloppenburg M, Zhang W, Li L, Hunter DJ. The diagnostic performance of MRI in osteoarthritis: a systematic review and meta-analysis. Osteoarthr Cartil. 2012;20(1):13–21.CrossRefPubMed

15.

Van Venrooij WJ, van Beers JJBC, Pruijn GJM. Anti-CCP antibodies: the past, the present and the future. Nat Rev Rheumatol. 2011;7(7):391–8.CrossRefPubMed

16.

Ahmed U, Anwar A, Savage RS, Costa ML, Mackay N, Filer A, Raza K, Watts RA, Winyard PG, Tarr J, et al. Biomarkers of early stage osteoarthritis, rheumatoid arthritis and musculoskeletal health. Sci Rep. 2015;5:9259. 9251-9257.CrossRefPubMedPubMedCentral

17.

Rabbani N, Shaheen F, Anwar A, Masania J, Thornalley PJ. Assay of methylglyoxal-derived protein and nucleotide AGEs. Biochem Soc Trans. 2014;42(2):511–7.CrossRefPubMed

18.

Seibel MJ. Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev. 2005;26(4):97–122.PubMedPubMedCentral

19.

Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–24.CrossRefPubMed

20.

Raza K, Falciani F, Curnow SJ, Ross EJ, Lee C-Y, Akbar AN, Lord JM, Gordon C, Buckley CD, Salmon M. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther. 2005;7(4):1–12.CrossRef

21.

Ryd L, Brittberg M, Eriksson K, Jurvelin JS, Lindahl A, Marlovits S, Möller P, Richardson JB, Steinwachs M, Zenobi-Wong M. Pre-osteoarthritis: definition and diagnosis of an elusive clinical entity. Cartilage. 2015;6(3):156–65.CrossRefPubMedPubMedCentral

22.

Raza K, Buckley CE, Salmon M, Buckley CD. Treating very early rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2006;20(5):849–63.CrossRefPubMedPubMedCentral

23.

Gasser AB, Wootton R, Beyeler S, Celada A, Depierre D. Biological variation in free serum hydroxyproline concentration. Clin Chim Acta. 1980;106(1):39–43.CrossRefPubMed

24.

Thompson DK, Sloane R, Bain JR, Stevens RD, Newgard CB, Pieper CF, Kraus VB. Daily variation of serum acylcarnitines and amino acids. Metabolomics. 2012;8(4):556–65.CrossRefPubMedPubMedCentral

25.

Brunnbauer M, Kuenburg E, Winter F, Muller MM, Prager R. Diurnal variations of fructosamine in patients with type II diabetes mellitus. Wien Klin Wochenschr. 1990;180:72–3.

26.

Blanco RA, Ziegler TR, Carlson BA, Cheng P-Y, Park Y, Cotsonis GA, Accardi CJ, Jones DP. Diurnal variation in glutathione and cysteine redox states in human plasma. Am J Clin Nutr. 2007;86(4):1016–23.PubMed

27.

McLellan AC, Thornalley PJ, Benn J, Sonksen PH. The glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. ClinSci. 1994;87(1):21–9.

28.

Kleinman WA, Richie Jr JP. Status of glutathione and other thiols and disulfides in human plasma. Biochem Pharmacol. 2000;60(1):19–29.CrossRefPubMed

29.

Breier M, Wahl S, Prehn C, Fugmann M, Ferrari U, Weise M, Banning F, Seissler J, Grallert H, Adamski J, et al. Targeted metabolomics identifies reliable and stable metabolites in human serum and plasma samples. PLoS ONE. 2014;9(2):e89728.CrossRefPubMedPubMedCentral

30.

Breiman L. Random forests. Mach Learn. 2001;45(1):5–32.CrossRef

31.

Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Software. 2010;33(1):1–22.CrossRef

32.

Sajda P. Machine learning for detection and diagnosis of disease. Annu Rev Biomed Eng. 2006;8(1):537–65.CrossRefPubMed

33.

Fawcett T. An introduction to ROC analysis. Pattern Recogn Lett. 2006;27(8):861–74.CrossRef

34.

Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, Muller M. pROC: an open-source package for R and S plus to analyze and compare ROC curves. BMC Bioinformatics. 2011;12:77–85.CrossRefPubMedPubMedCentral

35.

Collins GS, Reitsma JB, Altman DG, Moons KGM. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD Statement. Ann Intern Med. 2015;162(1):55–63.CrossRefPubMed

36.

Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y, Eguchi M, Wada Y, Kumagai Y, Yamamoto M. The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Molec Cell Biol. 2009;29(2):493–502.CrossRefPubMed

37.

Xue M, Rabbani N, Momiji H, Imbasi P, Anwar MM, Kitteringham NR, Park BK, Souma T, Moriguchi T, Yamamoto M, et al. Transcriptional control of glyoxalase 1 by Nrf2 provides a stress responsive defence against dicarbonyl glycation. Biochem J. 2012;443(1):213–22.CrossRefPubMed

38.

Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg L-O, Kan YW, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S, et al. Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis. 2011;70:844–50.CrossRefPubMed

39.

Davidson RK, Jupp O, de Ferrars R, Kay CD, Culley KL, Norton R, Driscoll C, Vincent TL, Donell ST, Bao Y, et al. Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo. Arthritis Rheum. 2013;65(12):3130–40.CrossRefPubMedPubMedCentral

40.

Gibson DS, Bustard MJ, McGeough CM, Murray HA, Crockard MA, McDowell A, Blayney JK, Gardiner PV, Bjourson AJ. Current and future trends in biomarker discovery and development of companion diagnostics for arthritis. Expert Rev Mol Diagn. 2015;15(2):219–34.CrossRefPubMed

41.

Misko TP, Radabaugh MR, Highkin M, Abrams M, Friese O, Gallavan R, Bramson C, Le Graverand MPH, Lohmander LS, Roman D. Characterization of nitrotyrosine as a biomarker for arthritis and joint injury. Osteoarthr Cartil. 2013;21(1):151–6.CrossRefPubMed

42.

Guma M, Tiziani S, Firestein GS. Metabolomics in rheumatic diseases: desperately seeking biomarkers. Nat Rev Rheumatol. 2016;12(5):269–81.CrossRefPubMedPubMedCentral

43.

Simkin PA, Bassett JE. Pathways of microvascular permeability in the synovium of normal and diseased human knees. J Rheumatol. 2011;38(12):2635–42.CrossRefPubMed

44.

Levick JR. A method for estimating macromolecular reflection by human synovium, using measurements of intra-articular half lives. Ann Rheum Dis. 1998;57(6):339–44.CrossRefPubMedPubMedCentral

45.

Zabek A, Swierkot J, Malak A, Zawadzka I, Deja S, Bogunia-Kubik K, Mlynarz P. Application of 1H NMR-based serum metabolomic studies for monitoring female patients with rheumatoid arthritis. J Pharm Biomed Anal. 2016;117:544–50.CrossRefPubMed

46.

Zhai G, Wang-Sattler R, Hart DJ, Arden NK, Hakim AJ, Illig T, Spector TD. Serum branched-chain amino acid to histidine ratio: a novel metabolomic biomarker of knee osteoarthritis. Ann Rheum Dis. 2010;69(6):1227–31.CrossRefPubMed

47.

Agalou S, Ahmed N, Babaei-Jadidi R, Dawnay A, Thornalley PJ. Profound mishandling of protein glycation degradation products in uremia and dialysis. J Amer Soc Nephrol. 2005;16(5):1471–85.CrossRef

48.

Ahmed N, Babaei-Jadidi R, Howell SK, Beisswenger PJ, Thornalley PJ. Degradation products of proteins damaged by glycation, oxidation and nitration in clinical type 1 diabetes. Diabetologia. 2005;48(8):1590–603.CrossRefPubMed

49.

Ahmed N, Thornalley PJ, Luthen R, Haussinger D, Sebekova K, Schinzel R, Voelker W, Heidland A. Processing of protein glycation, oxidation and nitrosation adducts in the liver and the effect of cirrhosis. J Hepatol. 2004;41:913–9.CrossRefPubMed

50.

Margarson MP, Soni N. Serum albumin: touchstone or totem? Anaesthesia. 1998;53(8):789–803.CrossRefPubMed

51.

Hachulla E, Perezcousin M, Flipo RM, Houvenagel E, Cardon T, Catteau MH, Duquesnoy B, Devulder B. Increased capillary-permeability in systemic rheumatoid vasculitis - detection by dynamic fluorescence nailfold videomicroscopy. J Rheumatol. 1994;21(7):1197–202.PubMed

52.

Masania J, Malczewska-Malec M, Razny U, Goralska J, Zdzienicka A, Kiec-Wilk B, Gruca A, Stancel-Mozwillo J, Dembinska-Kiec A, Rabbani N, et al. Dicarbonyl stress in clinical obesity. Glycoconj J. 2016;33:581–9.CrossRefPubMedPubMedCentral

53.

Heard BJ, Rosvold JM, Fritzler MJ, El-Gabalawy H, Wiley JP, Krawetz RJ. A computational method to differentiate normal individuals, osteoarthritis and rheumatoid arthritis patients using serum biomarkers. J R Soc Interface. 2014;11(97):20140428.CrossRefPubMedPubMedCentral

54.

Li W, Du C, Wang H, Zhang C. Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages. Genet Mol Res. 2014;13(4):9642–9.CrossRefPubMed

55.

Bay-Jensen AC, Reker D, Kjelgaard-Petersen CF, Mobasheri A, Karsdal MA, Ladel C, Henrotin Y, Thudium CS. Osteoarthritis year in review 2015: soluble biomarkers and the BIPED criteria. Osteoarthr Cartil. 2016;24(1):9–20.CrossRefPubMed

56.

McArdle A, Flatley B, Pennington SR, FitzGerald O. Early biomarkers of joint damage in rheumatoid and psoriatic arthritis. Arthritis Res Ther. 2015;17(1):1–12.CrossRef