Serum levels of 14‑3‑3η are associated with increased disease risk, activity and duration of rheumatoid arthritis in Chinese patients

Tu,Jianxin; Chen,Xiaowei; Dai,Meijie; Pan,Axiao; Liu,Cailong; Zhou,Yan; Xia,Xiaoru; Sun,Li

doi:10.3892/etm.2020.8761

Serum levels of 14‑3‑3η are associated with increased disease risk, activity and duration of rheumatoid arthritis in Chinese patients

Authors:
- Jianxin Tu
- Xiaowei Chen
- Meijie Dai
- Axiao Pan
- Cailong Liu
- Yan Zhou
- Xiaoru Xia
- Li Sun
View Affiliations

Affiliations: Department of Rheumatology and Immunology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Laboratory Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Orthopaedic Sports Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: May 17, 2020 https://doi.org/10.3892/etm.2020.8761
Pages: 754-761
Copyright: © Tu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to determine the association between serum 14-3-3η expression levels and disease risk, inflammation level and disease duration in Chinese patients with rheumatoid arthritis (RA). A total of 45 Chinese patients with RA, 45 patients with osteoarthritis (OA) and 44 age‑ and sex‑matched (with the RA group) healthy control (HC) subjects were consecutively recruited for the present case‑controlled study. In addition, the demographic and clinicopathological characteristics of the patients with RA were collected. Serum samples were obtained from patients with RA, patients with OA and the HCs, and the serum levels of 14‑3‑3η were determined by ELISA. Compared with that in the OA patients (P=0.006) and HCs (P<0.001), 14‑3‑3η expression was significantly increased in RA patients, and receiver operating characteristics (ROC) analysis indicated that it served as a potential predictive marker for the risk of RA. In patients with RA, serum levels of 14‑3‑3η were positively correlated with disease duration (P=0.003), erythrocyte sedimentation rate (P=0.006) and disease activity score in 28 joints (P=0.025). The proportion of rheumatoid factor (RF)‑positive patients (P=0.023) and anti‑citrullinated protein antibody (ACPA)‑positive patients (P=0.002) with RA was increased (when 14‑3‑3η expression was increased) compared with RF‑negative patients or ACPA‑negative patients, respectively. Of note, 14‑3‑3η serum levels were able to distinguish patients with established RA (disease duration, >2 years) from patients with early RA (disease duration, ≤2 years) with an AUC of 0.759 (95% CI, 0.612‑0.905), and the sensitivity and the specificity at the best cut‑off point (14‑3‑3η=0.613 ng/ml) were 79.3 and 75.0%, respectively. Furthermore, 14‑3‑3η was able to differentiate between RF‑positive RA patients and RF‑negative patients or HCs. In conclusion, circulating 14‑3‑3η expression may serve as a novel biomarker for disease risk and activity of RA in Chinese patients.

View Figures

View References

1	Malmstrom V, Catrina AI and Klareskog L: The immunopathogenesis of seropositive rheumatoid arthritis: From triggering to targeting. Nat Rev Immunol. 17:60–75. 2017.PubMed/NCBI View Article : Google Scholar
2	Smolen JS, Aletaha D and McInnes IB: Rheumatoid arthritis. Lancet. 388:2023–2038. 2016.PubMed/NCBI View Article : Google Scholar
3	McInnes IB and Schett G: The pathogenesis of rheumatoid arthritis. N Engl J Med. 365:2205–2219. 2011.PubMed/NCBI View Article : Google Scholar
4	Scott DL, Wolfe F and Huizinga TW: Rheumatoid arthritis. Lancet. 376:1094–1108. 2010.PubMed/NCBI View Article : Google Scholar
5	Isaacs JD: The changing face of rheumatoid arthritis: Sustained remission for all? Nat Rev Immunol. 10:605–611. 2010.PubMed/NCBI View Article : Google Scholar
6	McInnes IB and Schett G: Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 389:2328–2337. 2017.PubMed/NCBI View Article : Google Scholar
7	Burmester GR and Pope JE: Novel treatment strategies in rheumatoid arthritis. Lancet. 389:2338–2348. 2017.PubMed/NCBI View Article : Google Scholar
8	Obsil T, Ghirlando R, Klein DC, Ganguly S and Dyda F: Crystal structure of the 14-3-3zeta:serotonin N-acetyltransferase complex. A role for scaffolding in enzyme regulation. Cell. 105:257–267. 2001.PubMed/NCBI View Article : Google Scholar
9	Cau Y, Valensin D, Mori M, Draghi S and Botta M: Structure, function, involvement in diseases and targeting of 14-3-3 proteins: An update. Curr Med Chem. 25:5–21. 2018.PubMed/NCBI View Article : Google Scholar
10	Sluchanko NN and Gusev NB: Moonlighting chaperone-like activity of the universal regulatory 14-3-3 proteins. FEBS J. 284:1279–1295. 2017.PubMed/NCBI View Article : Google Scholar
11	de Boer AH, van Kleeff PJ and Gao J: Plant 14-3-3 proteins as spiders in a web of phosphorylation. Protoplasma. 250:425–440. 2013.PubMed/NCBI View Article : Google Scholar
12	Jia H, Liang Z, Zhang X, Wang J, Xu W and Qian H: 14-3-3 proteins: An important regulator of autophagy in diseases. Am J Transl Res. 9:4738–4746. 2017.PubMed/NCBI
13	Cornell B and Toyo-Oka K: 14-3-3 Proteins in brain development: neurogenesis, neuronal migration and neuromorphogenesis. Front Mol Neurosci. 10(318)2017.PubMed/NCBI View Article : Google Scholar
14	Zhao J, Meyerkord CL, Du Y, Khuri FR and Fu H: 14-3-3 proteins as potential therapeutic targets. Semin Cell Dev Biol. 22:705–712. 2011.PubMed/NCBI View Article : Google Scholar
15	Kilani RT, Maksymowych WP, Aitken A, Boire G, St-Pierre Y, Li Y and Ghahary A: Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation. J Rheumatol. 34:1650–1657. 2007.PubMed/NCBI
16	Maksymowych WP and Marotta A: 14-3-3eta: A novel biomarker platform for rheumatoid arthritis. Clin Exp Rheumatol. 32 (Suppl 85)(S35-S39)2014.PubMed/NCBI
17	Hirata S, Marotta A, Gui Y, Hanami K and Tanaka Y: Serum 14-3-3η level is associated with severity and clinical outcomes of rheumatoid arthritis, and its pretreatment level is predictive of DAS28 remission with tocilizumab. Arthritis Res Ther. 17(280)2015.PubMed/NCBI View Article : Google Scholar
18	Maksymowych WP, Naides SJ, Bykerk V, Siminovitch KA, van Schaardenburg D, Boers M, Landewe R, van der Heijde D, Tak PP, Genovese MC, et al: Serum 14-3-3η is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis. J Rheumatol. 41:2104–2113. 2014.PubMed/NCBI View Article : Google Scholar
19	Gong X, Xu SQ, Wu Y, Ma CC, Qi S, Liu W and Xu JH: Elevated serum 14-3-3eta protein may be helpful for diagnosis of early rheumatoid arthritis associated with secondary osteoporosis in Chinese population. Clin Rheumatol. 36:2581–2587. 2017.PubMed/NCBI View Article : Google Scholar
20	Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31:315–324. 1988.PubMed/NCBI View Article : Google Scholar
21	Sreedhar R, Arumugam S, Thandavarayan RA, Giridharan VV, Karuppagounder V, Pitchaimani V, Afrin R, Miyashita S, Nomoto M, Harima M, et al: Myocardial 14-3-3eta protein protects against mitochondria mediated apoptosis. Cell Signal. 27:770–776. 2015.PubMed/NCBI View Article : Google Scholar
22	Sreedhar R, Arumugam S, Thandavarayan RA, Giridharan VV, Karuppagounder V, Pitchaimani V, Afrin R, Harima M, Nakamura M, Suzuki K, et al: Depletion of cardiac 14-3-3η protein adversely influences pathologic cardiac remodeling during myocardial infarction after coronary artery ligation in mice. Int J Cardiol. 202:146–153. 2016.PubMed/NCBI View Article : Google Scholar
23	Plotegher N, Kumar D, Tessari I, Brucale M, Munari F, Tosatto L, Belluzzi E, Greggio E, Bisaglia M, Capaldi S, et al: The chaperone-like protein 14-3-3η interacts with human α-synuclein aggregation intermediates rerouting the amyloidogenic pathway and reducing alpha-synuclein cellular toxicity. Hum Mol Genet. 23:5615–5629. 2014.PubMed/NCBI View Article : Google Scholar
24	Maksymowych WP, van der Heijde D, Allaart CF, Landewe R, Boire G, Tak PP, Gui Y, Ghahary A, Kilani R and Marotta A: 14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage. Arthritis Res Ther. 16(R99)2014.PubMed/NCBI View Article : Google Scholar
25	Carrier N, Marotta A, de Brum-Fernandes AJ, Liang P, Masetto A, Menard HA, Maksymowych WP and Boire G: Serum levels of 14-3-3η protein supplement C-reactive protein and rheumatoid arthritis-associated antibodies to predict clinical and radiographic outcomes in a prospective cohort of patients with recent-onset inflammatory polyarthritis. Arthritis Res Ther. 18(37)2016.PubMed/NCBI View Article : Google Scholar
26	Garg N, Syngle A and Krishan P: Nitric Oxide: Link between inflammation and endothelial dysfunction in rheumatoid arthritis. Int J Angiol. 26:165–169. 2017.PubMed/NCBI View Article : Google Scholar
27	Alam J, Jantan I and Bukhari SNA: Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy. Biomed Pharmacother. 92:615–633. 2017.PubMed/NCBI View Article : Google Scholar
28	Noack M and Miossec P: Selected cytokine pathways in rheumatoid arthritis. Semin Immunopathol. 39:365–383. 2017.PubMed/NCBI View Article : Google Scholar
29	Siebuhr AS, Bay-Jensen AC, Leeming DJ, Plat A, Byrjalsen I, Christiansen C, van de Heijde D and Karsdal MA: Serological identification of fast progressors of structural damage with rheumatoid arthritis. Arthritis Res Ther. 15(R86)2013.PubMed/NCBI View Article : Google Scholar
30	Pap T, Shigeyama Y, Kuchen S, Fernihough JK, Simmen B, Gay RE, Billingham M and Gay S: Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis. Arthritis Rheum. 43:1226–1232. 2000.PubMed/NCBI View Article : Google Scholar
31	Tchetverikov I, Lard LR, DeGroot J, Verzijl N, TeKoppele JM, Breedveld FC, Huizinga TW and Hanemaaijer R: Matrix metalloproteinases-3, -8, -9 as markers of disease activity and joint damage progression in early rheumatoid arthritis. Ann Rheum Dis. 62:1094–1099. 2003.PubMed/NCBI
32	Green MJ, Gough AK, Devlin J, Smith J, Astin P, Taylor D and Emery P: Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis. Rheumatology (Oxford). 42:83–88. 2003.PubMed/NCBI View Article : Google Scholar
33	van Beers-Tas MH, Marotta A, Boers M, Maksymowych WP and van Schaardenburg D: A prospective cohort study of 14-3-3η in ACPA and/or RF-positive patients with arthralgia. Arthritis Res Ther. 18(76)2016.PubMed/NCBI View Article : Google Scholar
34	Tsukamoto M, Suzuki K, Seta N and Takeuchi T: Increased circulating CD14brightCD16⁺ intermediate monocytes are regulated by TNF-α and IL-6 axis in accordance with disease activity in patients with rheumatoid arthritis. Clin Exp Rheumatol. 36:540–544. 2018.PubMed/NCBI
35	Dulic S, Vasarhelyi Z, Sava F, Berta L, Szalay B, Toldi G, Kovacs L and Balog A: T-Cell subsets in rheumatoid arthritis patients on long-term anti-TNF or IL-6 receptor blocker therapy. Mediators Inflamm. 2017(6894374)2017.PubMed/NCBI View Article : Google Scholar
36	Hong H, Zeng Y, Jian W, Li L, Lin L, Mo Y, Liu M, Fang S and Xia Y: CDK7 inhibition suppresses rheumatoid arthritis inflammation via blockage of NF-κB activation and IL-1β/IL-6 secretion. J Cell Mol Med. 22:1292–1301. 2018.PubMed/NCBI View Article : Google Scholar
37	Shovman O, Gilburd B, Zandman-Goddard G, Sherer Y, Orbach H, Gerli R and Shoenfeld Y: The diagnostic utility of anti-cyclic citrullinated peptide antibodies, matrix metalloproteinase-3, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein in patients with erosive and non-erosive rheumatoid arthritis. Clin Dev Immunol. 12:197–202. 2005.PubMed/NCBI View Article : Google Scholar
38	Wu JF, Yang YH, Wang LC, Lee JH, Shen EY and Chiang BL: Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in juvenile rheumatoid arthritis. Clin Exp Rheumatol. 25:782–785. 2007.PubMed/NCBI
39	Otterness IG: The value of C-reactive protein measurement in rheumatoid arthritis. Semin Arthritis Rheum. 24:91–104. 1994.PubMed/NCBI View Article : Google Scholar
40	Ward MM: Relative sensitivity to change of the erythrocyte sedimentation rate and serum C-reactive protein concentration in rheumatoid arthritis. J Rheumatol. 31:884–895. 2004.PubMed/NCBI
41	Galeazzi M, Morozzi G, Veronesi M, Ronconi S, Magi B, Bini L and Marcolongo R: Usefulness of the determination of C reactive protein and other acute phase proteins in rheumatoid arthritis. Recenti Prog Med. 86:456–462. 1995.9 (In Italian). PubMed/NCBI