Abstract
Objectives
The cytokines play critical roles in the complex pathogenesis of rheumatoid arthritis (RA), but the specific cytokines are still in need of being discovered. This multi-stage study was performed to identify novel RA cytokines in plasma and further understand the pathological mechanism of the identified cytokines.
Method
The plasma cytokine protein profile was evaluated by using Human Cytokine Antibody Array 440 in 18 subjects (RA: healthy control = 9:9). Then, enzyme-linked immunosorbent assay (ELISA) was used to validate the highlighted cytokines in 80 subjects (RA: healthy control = 40:40). Further functional experiments on fibroblast-like synoviocytes were performed to identify the pathological mechanisms of the highlighted cytokines for RA.
Results
A total of seven significant cytokines have differential expressions between RA patients and controls (fold change (FC) > 2, P value < 0.05). The difference in plasma for the highlighted platelet-derived growth factor (PDGF)-BB was validated in an independent validation sample (P = 0.005). Further, the PDGF-BB obviously promotes cell proliferation of MH7A cell, probably by inhibiting cell apoptosis and accelerating the cell cycle. The PDGF-BB can also promote MH7A cell migration.
Conclusions
This study evaluated the plasma cytokine protein array profile associated with RA and highlighted the importance of PDGF-BB. PDGF-BB has an important role in RA-FLS proliferation and migration. These results suggest that PDGF-BB might contribute to occurrence and development of RA.
Key Points • The levels of plasma cytokines were systemically tested using Human Cytokine Antibody Arrays. • The expression difference of PDGF-BB was validated in an independent sample. • PDGF-BB obviously promotes cell proliferation and migration in RA-FLS. |
Similar content being viewed by others
References
Scott DL, Wolfe F, Huizinga TW (2010) Rheumatoid arthritis. Lancet 24:1094–1108
Robinson WH, Lindstrom TM, Cheung RK, Sokolove J (2013) Mechanistic biomarkers for clinical decision making in rheumatic diseases. Nat Rev Rheumatol 9:267–276
Krabben A, Huizinga TW, Mil AH (2015) Biomarkers for radiographic progression in rheumatoid arthritis. Curr Pharm Des 21:147–169
Jansen AL, van der Horst-Bruinsma I, van Schaardenburg D et al (2002) Rheumatoid factor and antibodies to cyclic citrullinated peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis. J Rheumatol 29:2074–2076
Gizinski AM, Fox DA (2014) T cell subsets and their role in the pathogenesis of rheumatic disease. Curr Opin Rheumatol 26:204–210
Bartok B, Firestein GS (2010) Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 233:233–255
Chang SK, Gu Z, Brenner MB (2010) Fibroblast-like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin-11. Immunol Rev 233:256–266
Bustamante MF, Garcia-Carbonell R, Whisenant KD, Guma M (2017) Fibroblast-like synoviocyte metabolism in the pathogenesis of rheumatoid arthritis. Arthritis Res Ther 19:110
Verheul MK, Fearon U, Trouw LA, Veale DJ (2015) Biomarkers for rheumatoid and psoriatic arthritis. Clin Immunol 161:2–10
Meyer PW, Hodkinson B, Ally M et al (2010) Circulating cytokine profiles and their relationships with autoantibodies, acute phase reactants, and disease activity in patients with rheumatoid arthritis. Mediat Inflamm 2010:158514
Niu X, Chen G (2014) Clinical biomarkers and pathogenic-related cytokines in rheumatoid arthritis. J Immunol Res 2014:698192
Burska A, Boissinot M, Ponchel F (2014) Cytokines as biomarkers in rheumatoid arthritis. Mediat Inflamm 2014:54549
van Steensel L, Paridaens D, van Meurs M, van Hagen PM, van den Bosch WA, Kuijpers RWAM, Drexhage HA, Hooijkaas H, Dik WA (2012) Orbit-infiltrating mast cells, monocytes, and macrophages produce PDGF isoforms that orchestrate orbital fibroblast activation in Graves' ophthalmopathy. J Clin Endocrinol Metab 97:E400–E408
Siegfried G, Basak A, Prichett-Pejic W, Scamuffa N, Ma L, Benjannet S, Veinot JP, Calvo F, Seidah N, Khatib AM (2005) Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases. Oncogene 24:6925–6935
Neogi T, Aletaha D, Silman AJ, Naden RL, Felson DT, Aggarwal R, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Khanna D, Kvien TK, Laing T, Liao K, Mease P, Ménard HA, Moreland LW, Nair R, Pincus T, Ringold S, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G, American College of Rheumatology, European League Against Rheumatism (2010) The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: phase 2 methodological report. Arthritis Rheum 62:2582–2591
Hosaka K, Yang Y, Seki T, Nakamura M, Andersson P, Rouhi P, Yang X, Jensen L, Lim S, Feng N, Xue Y, Li X, Larsson O, Ohhashi T, Cao Y (2013) Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis. Nat Commun 4:2129
Xie H, Cui Z, Wang L, Xia Z, Hu Y, Xian L, Li C, Xie L, Crane J, Wan M, Zhen G, Bian Q, Yu B, Chang W, Qiu T, Pickarski M, Duong LT, Windle JJ, Luo X, Liao E, Cao X (2014) PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat Med 20:1270–1278
Pierce GF, Mustoe TA, Altrock BW, Deuel TF, Thomason A (1991) Role of platelet-derived growth factor in wound healing. J Cell Biochem 45:319–326
Mokuda S, Miyazaki T, Ito Y, Yamasaki S, Inoue H, Guo Y, Kong WS, Kanno M, Takasugi K, Sugiyama E, Masumoto J (2015) The proto-oncogene survivin splice variant 2B is induced by PDGF and leads to cell proliferation in rheumatoid arthritis fibroblast-like synoviocytes. Sci Rep 5:9795
Wang H, Yin Y, Li W, Zhao X, Yu Y, Zhu J, Qin Z, Wang Q, Wang K, Lu W, Liu J, Huang L (2012) Over-expression of PDGFR-beta promotes PDGF-induced proliferation, migration, and angiogenesis of EPCs through PI3K/Akt signaling pathway. PLoS One 7:e30503
Fiedler J, Etzel N, Brenner RE (2004) To go or not to go: migration of human mesenchymal progenitor cells stimulated by isoforms of PDGF. J Cell Biochem 93:990–998
Xue Y, Lim S, Yang Y, Wang Z, Jensen LD, Hedlund EM, Andersson P, Sasahara M, Larsson O, Galter D, Cao R, Hosaka K, Cao Y (2011) PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells. Nat Med 18:100–110
Presciutti SM, Paglia DN, Karukonda T, Soung DY, Guzzo R, Drissi H, Moss IL (2014) PDGF-BB inhibits intervertebral disc cell apoptosis in vitro. J Orthop Res 32:1181–1188
Chen CF, Feng X, Liao HY et al (2014) Regulation of T cell proliferation by JMJD6 and PDGF-BB during chronic hepatitis B infection. Sci Rep 4:6359
Lafyatis R, Thompson NL, Remmers EF, Flanders KC, Roche NS, Kim SJ, Case JP, Sporn MB, Roberts AB, Wilder RL (1989) Transforming growth factor-beta production by synovial tissues from rheumatoid patients and streptococcal cell wall arthritic rats. Studies on secretion by synovial fibroblast-like cells and immunohistologic localization. J Immunol 143:1142–1148
Sano H, Engleka K, Mathern P, Hla T, Crofford LJ, Remmers EF, Jelsema CL, Goldmuntz E, Maciag T, Wilder RL (1993) Coexpression of phosphotyrosine-containing proteins, platelet-derived growth factor-B, and fibroblast growth factor-1 in situ in synovial tissues of patients with rheumatoid arthritis and Lewis rats with adjuvant or streptococcal cell wall arthritis. J Clin Invest 91:553–565
Li R, Sun J, Ren LM, Wang HY, Liu WH, Zhang XW, Chen S, Mu R, He J, Zhao Y, Long L, Liu YY, Liu X, Lu XL, Li YH, Wang SY, Pan SS, Li C, Wang HY, Li ZG (2012) Epidemiology of eight common rheumatic diseases in China: a large-scale cross-sectional survey in Beijing. Rheumatology (Oxford) 51:721–729
Sonomoto K, Yamaoka K, Tanaka Y (2014) An approach to bone and cartilage repair of rheumatoid arthritis by mesenchymal stem cells. J UOEH 36:141–146
Rosengren S, Corr M, Boyle DL (2010) Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes. Arthritis Res Ther 12:R65
Pepys MB, Hirschfield GM (2003) C-reactive protein: a critical update. J Clin Invest 111:1805–1812
Funding
This work was supported by National Natural Science Foundation of China (81473046 and 81502868).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Disclosures
None.
Ethical standards
All human studies have been approved by the Soochow University’s committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Wang, BH., Lu, YH., Wu, LF. et al. Evaluation of plasma cytokine protein array profile: the highlighted PDGF-BB in rheumatoid arthritis. Clin Rheumatol 39, 3323–3330 (2020). https://doi.org/10.1007/s10067-020-05109-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10067-020-05109-0