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Open Access 01-12-2022 | Ankylosing Spondylitis | Research

A_2A adenosine receptor agonist reduced MMP8 expression in healthy M2-like macrophages but not in macrophages from ankylosing spondylitis patients

Authors: Omid Sadatpour, Mohammad Taha Ebrahimi, Maryam Akhtari, Nooshin Ahmadzadeh, Mahdi Vojdanian, Ahmadreza Jamshidi, Elham Farhadi, Mahdi Mahmoudi

Published in: BMC Musculoskeletal Disorders | Issue 1/2022

Abstract

Background

Ankylosing spondylitis (AS) is an inflammatory autoimmune disease that mostly affects different joints of the body. Macrophages are the predominant cells that mediate disease progression by secreting several pro-inflammatory mediators. Different receptors are involved in macrophages’ function including the adenosine receptors (AR). Our main objective in this study was to assess the effect of applying A_2A adenosine receptor agonist (CGS-21,680) on the gene expression of inflammatory mediators including bone morphogenetic proteins (BMP)-2, 4 and matrix metalloproteinases (MMP)-3, 8, 9, and 13 on the macrophages from AS patients compared to healthy macrophages.

Methods

Monocytes were isolated from the whole blood of 28 individuals (AS patients and healthy controls in a 1:1 ratio). Macrophages were differentiated using macrophage colony-stimulating factor (M-CSF), and flow cytometry was performed to confirm surface markers. CGS-21,680 was used to treat cells that had been differentiated. Using SYBR green real-time PCR, relative gene expression was determined.

Results

Activating A_2AAR diminished MMP8 expression in healthy macrophages while it cannot reduce MMP8 expression in patients’ macrophages. The effect of A_2AAR activation on the expression of BMP2 and MMP9 reached statistical significance neither in healthy macrophages nor in the patients’ group. We also discovered a significant positive connection between MMP8 expression and patient scores on the Bath ankylosing spondylitis functional index (BASFI).

Conclusion

Due to the disability of A_2AAR activation in the reduction of MMP8 expression in patients’ macrophages and the correlation of MMP8 expression with BASFI index in patients, these results represent defects and dysregulations in the related signaling pathway in patients’ macrophages.

Gao S, Zhang J, Xu T, Xun C, Cao R, Guo H, Liang W, Sheng W. Associations of toll-like receptor 4 and 2 gene polymorphisms with susceptibility to ankylosing spondylitis: A meta-analysis. Int J Immunogenet. 2021;48(2):219–28. https://doi.org/10.1111/iji.12524CrossRefPubMed

Hwang MC, Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021;40(8):3079–93. https://doi.org/10.1007/s10067-021-05679-7CrossRefPubMedPubMedCentral

Chen S, Deng L. Risk factors for radiological hip involvement in patients with ankylosing spondylitis. Rev Assoc Med Bras (1992). 2021;67(9):1293-8. https://doi.org/10.1590/1806-9282.20210585

Akhtari M, Vojdanian M, Javinani A, Ashraf-Ganjouei A, Jamshidi A, Mahmoudi M. Activation of adenosine A(2A) receptor induced interleukin-23 mRNA expression in macrophages of ankylosing spondylitis patients. Cytokine. 2020;128:154997. https://doi.org/10.1016/j.cyto.2020.154997CrossRefPubMed

Sharip A, Kunz J. Understanding the Pathogenesis of Spondyloarthritis. Biomolecules. 2020;10(10). https://doi.org/10.3390/biom10101461

Dong K, Gao ZW, Zhang HZ. The role of adenosinergic pathway in human autoimmune diseases. Immunol Res. 2016;64(5–6):1133–41. https://doi.org/10.1007/s12026-016-8870-2CrossRefPubMedPubMedCentral

Antonioli L, Pacher P, Vizi ES, Haskó G. CD39 and CD73 in immunity and inflammation. Trends Mol Med. 2013;19(6):355–67. https://doi.org/10.1016/j.molmed.2013.03.005CrossRefPubMedPubMedCentral

Di Virgilio F, Vuerich M. Purinergic signaling in the immune system. Auton Neurosci. 2015;191:117–23. https://doi.org/10.1016/j.autneu.2015.04.011CrossRefPubMed

Akhtari M, Zargar SJ, Mahmoudi M, Vojdanian M, Rezaeimanesh A, Jamshidi A. Ankylosing spondylitis monocyte-derived macrophages express increased level of A(2A) adenosine receptor and decreased level of ectonucleoside triphosphate diphosphohydrolase-1 (CD39), A(1) and A(2B) adenosine receptors. Clin Rheumatol. 2018;37(6):1589–95. https://doi.org/10.1007/s10067-018-4055-9CrossRefPubMed

10.

Yang J, Xu S, Chen M, Yuan Y, Zhang X, Ma Y, Wu M, Han R, Hu X, Liu R, Deng J, Guan S, Gao X, Pan M, Xu S, Shuai Z, Jiang S, Guan S, Chen L, Pan F. Serum Sclerostin and Bone Morphogenetic Protein-2 Levels in Patients with Ankylosing Spondylitis: A Meta-Analysis. Calcif Tissue Int. 2019;105(1):37–50. https://doi.org/10.1007/s00223-019-00542-zCrossRefPubMed

11.

Joo YB, Bang SY, Kim TH, Shim SC, Lee S, Joo KB, Kim JH, Min HJ, Rahman P, Inman RD. Bone morphogenetic protein 6 polymorphisms are associated with radiographic progression in ankylosing spondylitis. PLoS ONE. 2014;9(8):e104966. https://doi.org/10.1371/journal.pone.0104966CrossRefPubMedPubMedCentral

12.

Chen MH, Chen HA, Chen WS, Chen MH, Tsai CY, Chou CT. Upregulation of BMP-2 expression in peripheral blood mononuclear cells by proinflammatory cytokines and radiographic progression in ankylosing spondylitis. Mod Rheumatol. 2015;25(6):913–8. https://doi.org/10.3109/14397595.2015.1029221CrossRefPubMed

13.

Mahmoud A, Fayez D, Gabal MM, Hamza SM, Badr T. Insight on Bone Morphogenetic Protein 7 in Ankylosing Spondylitis and its association with disease activity and radiographic damage. Electron Physician. 2016;8(7):2670–8. https://doi.org/10.19082/2670CrossRefPubMedPubMedCentral

14.

Malemud CJ. Matrix Metalloproteinases and Synovial Joint Pathology. Prog Mol Biol Transl Sci. 2017;148:305–25. https://doi.org/10.1016/bs.pmbts.2017.03.003CrossRefPubMed

15.

Moz S, Aita A, Basso D, Ramonda R, Plebani M, Punzi L. Spondyloarthritis: Matrix Metalloproteinasesas Biomarkers of Pathogenesis and Response to Tumor Necrosis Factor (TNF) Inhibitors. Int J Mol Sci. 2017;18(4). https://doi.org/10.3390/ijms18040830

16.

Vandooren B, Kruithof E, Yu DT, Rihl M, Gu J, De Rycke L, Van Den Bosch F, Veys EM, De Keyser F, Baeten D. Involvement of matrix metalloproteinases and their inhibitors in peripheral synovitis and down-regulation by tumor necrosis factor alpha blockade in spondylarthropathy. Arthritis Rheum. 2004;50(9):2942–53. https://doi.org/10.1002/art.20477CrossRefPubMed

17.

Zhu Y, Li S, Huang Z, Xing W, Li F, Da Y, Xue J, Li M, Sun K, Jia H, Yang X. Association study between matrix metalloproteinase-3 gene (MMP3) polymorphisms and ankylosing spondylitis susceptibility. Mol Genet Genomic Med. 2019;7(7):e00752. https://doi.org/10.1002/mgg3.752CrossRefPubMedPubMedCentral

18.

Mattey DL, Packham JC, Nixon NB, Coates L, Creamer P, Hailwood S, Taylor GJ, Bhalla AK. Association of cytokine and matrix metalloproteinase profiles with disease activity and function in ankylosing spondylitis. Arthritis Res Ther. 2012;14(3):R127. https://doi.org/10.1186/ar3857CrossRefPubMedPubMedCentral

19.

Meng C, Bai R, Zhao Z, Huang G, Jin T, Feng W, Liu W. MMP-8 single-nucleotide polymorphisms are related to ankylosing spondylitis in Chinese Han population. Med (Baltim). 2018;97(35):e12136. https://doi.org/10.1097/md.0000000000012136CrossRef

20.

Akhtari M, Zargar SJ, Vojdanian M, Jamshidi A, Mahmoudi M. Monocyte-derived and M1 macrophages from ankylosing spondylitis patients released higher TNF-α and expressed more IL1B in response to BzATP than macrophages from healthy subjects. Sci Rep. 2021;11(1):17842. https://doi.org/10.1038/s41598-021-96262-2CrossRefPubMedPubMedCentral

21.

Lari A, Gholami Pourbadie H, Jafari M, Sharifi-Zarchi A, Akhtari M, Nejatbakhsh Samimi L, Jamshidi A, Mahmoudi M. Downregulation of ITM2A Gene Expression in Macrophages of Patients with Ankylosing Spondylitis. Int Arch Allergy Immunol. 2021;182(11):1113–21. https://doi.org/10.1159/000516179CrossRefPubMed

22.

van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27(4):361–8. https://doi.org/10.1002/art.1780270401CrossRefPubMed

23.

Stamp LK, Hazlett J, Roberts RL, Frampton C, Highton J, Hessian PA. Adenosine receptor expression in rheumatoid synovium: a basis for methotrexate action. Arthritis Res Ther. 2012;14(3):R138. https://doi.org/10.1186/ar3871CrossRefPubMedPubMedCentral

24.

Mia S, Warnecke A, Zhang XM, Malmström V, Harris RA. An optimized protocol for human M2 macrophages using M-CSF and IL-4/IL-10/TGF-β yields a dominant immunosuppressive phenotype. Scand J Immunol. 2014;79(5):305–14. https://doi.org/10.1111/sji.12162CrossRefPubMedPubMedCentral

25.

Rőszer T. Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms. Mediators Inflamm. 2015;2015:816460. https://doi.org/10.1155/2015/816460CrossRefPubMedPubMedCentral

26.

Ravani A, Vincenzi F, Bortoluzzi A, Padovan M, Pasquini S, Gessi S, Merighi S, Borea PA, Govoni M, Varani K. Role and Function of A(2A) and A₃ Adenosine Receptors in Patients with Ankylosing Spondylitis, Psoriatic Arthritis and Rheumatoid Arthritis. Int J Mol Sci. 2017;18(4). https://doi.org/10.3390/ijms18040697

27.

Ågren MS. Auf dem Keller U. Matrix Metalloproteinases: How Much Can They Do? Int J Mol Sci. 2020;21(8). https://doi.org/10.3390/ijms21082678

28.

Huang WC, Sala-Newby GB, Susana A, Johnson JL, Newby AC. Classical macrophage activation up-regulates several matrix metalloproteinases through mitogen activated protein kinases and nuclear factor-κB. PLoS ONE. 2012;7(8):e42507. https://doi.org/10.1371/journal.pone.0042507CrossRefPubMedPubMedCentral

29.

Ho HH, Antoniv TT, Ji JD, Ivashkiv LB. Lipopolysaccharide-induced expression of matrix metalloproteinases in human monocytes is suppressed by IFN-gamma via superinduction of ATF-3 and suppression of AP-1. J Immunol. 2008;181(7):5089–97. https://doi.org/10.4049/jimmunol.181.7.5089CrossRefPubMed

30.

Alexander JS, Harris MK, Wells SR, Mills G, Chalamidas K, Ganta VC, McGee J, Jennings MH, Gonzalez-Toledo E, Minagar A. Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b. Mult Scler. 2010;16(7):801–9. https://doi.org/10.1177/1352458510370791CrossRefPubMed

31.

Schmalz G, Davarpanah I, Jäger J, Mausberg RF, Krohn-Grimberghe B, Schmidt J, Haak R, Sack U, Ziebolz D. MMP-8 and TIMP-1 are associated to periodontal inflammation in patients with rheumatoid arthritis under methotrexate immunosuppression - First results of a cross-sectional study. J Microbiol Immunol Infect. 2019;52(3):386–94. https://doi.org/10.1016/j.jmii.2017.07.016CrossRefPubMed

32.

Reveille JD. Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis. Clin Rheumatol. 2015;34(6):1009–18. https://doi.org/10.1007/s10067-015-2949-3CrossRefPubMedPubMedCentral

33.

Faber-Elmann A, Sthoeger Z, Tcherniack A, Dayan M, Mozes E. Activity of matrix metalloproteinase-9 is elevated in sera of patients with systemic lupus erythematosus. Clin Exp Immunol. 2002;127(2):393–8. https://doi.org/10.1046/j.1365-2249.2002.01758.xCrossRefPubMedPubMedCentral

34.

Ram M, Sherer Y, Shoenfeld Y. Matrix metalloproteinase-9 and autoimmune diseases. J Clin Immunol. 2006;26(4):299–307. https://doi.org/10.1007/s10875-006-9022-6CrossRefPubMed

35.

Ernens I, Rouy D, Velot E, Devaux Y, Wagner DR. Adenosine Inhibits Matrix Metalloproteinase-9 Secretion By Neutrophils. Circ Res. 2006;99(6):590–7. https://doi.org/10.1161/01.RES.0000241428.82502.d4CrossRefPubMed

36.

Chen H, Koupenova M, Yang D, Sume SS, Trackman PC, Ravid K. Regulation of MMP-9 expression by the A2b adenosine receptor and its dependency on TNF-α signaling. Exp Hematol. 2011;39(5):525–30. https://doi.org/10.1016/j.exphem.2011.02.004CrossRefPubMedPubMedCentral

37.

Shubayev VI, Angert M, Dolkas J, Campana WM, Palenscar K, Myers RR. TNFalpha-induced MMP-9 promotes macrophage recruitment into injured peripheral nerve. Mol Cell Neurosci. 2006;31(3):407–15. https://doi.org/10.1016/j.mcn.2005.10.011CrossRefPubMed

38.

Xiong W, MacTaggart J, Knispel R, Worth J, Persidsky Y, Baxter BT. Blocking TNF-alpha attenuates aneurysm formation in a murine model. J Immunol. 2009;183(4):2741–6. https://doi.org/10.4049/jimmunol.0803164CrossRefPubMed

39.

Carter S, Braem K, Lories RJ. The role of bone morphogenetic proteins in ankylosing spondylitis. Ther Adv Musculoskelet Dis. 2012;4(4):293–9. https://doi.org/10.1177/1759720x12444175CrossRefPubMedPubMedCentral

40.

Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA. Novel regulators of bone formation: molecular clones and activities. Science. 1988;242(4885):1528–34. https://doi.org/10.1126/science.3201241CrossRefPubMed

41.

Champagne CM, Takebe J, Offenbacher S, Cooper LF. Macrophage cell lines produce osteoinductive signals that include bone morphogenetic protein-2. Bone. 2002;30(1):26–31. https://doi.org/10.1016/s8756-3282(01)00638-xCrossRefPubMed

42.

Li B, Cao H, Zhao Y, Cheng M, Qin H, Cheng T, Hu Y, Zhang X, Liu X. Retraction Note: In vitro and in vivo responses of macrophages to magnesium-doped titanium. Sci Rep. 2021;11(1):8959. https://doi.org/10.1038/s41598-021-88664-zCrossRefPubMedPubMedCentral

43.

Xie Z, Wang P, Li Y, Deng W, Zhang X, Su H, Li D, Wu Y, Shen H. Imbalance Between Bone Morphogenetic Protein 2 and Noggin Induces Abnormal Osteogenic Differentiation of Mesenchymal Stem Cells in Ankylosing Spondylitis. Arthritis Rheumatol. 2016;68(2):430–40. https://doi.org/10.1002/art.39433CrossRefPubMed

44.

Kwan YH, Tan JJ, Phang JK, Fong W, Lim KK, Koh HL, Lui NL, Tan CS, Østbye T, Thumboo J, Leung YY. Validity and reliability of the Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with axial spondyloarthritis (axSpA) in Singapore. Int J Rheum Dis. 2019;22(12):2206–12. https://doi.org/10.1111/1756-185x.13735CrossRefPubMed

45.

https://pga.mgh.harvard.edu/primerbank/index.html.

46.

Lin J, Yu Y, Wang X, Ke Y, Sun C, Yue L, Xu G, Xu B, Xu L, Cao H, Xu D, Olsen N, Chen W. Iguratimod Inhibits the Aggressiveness of Rheumatoid Fibroblast-Like Synoviocytes. J Immunol Res. 2019;2019:6929286. https://doi.org/10.1155/2019/6929286CrossRefPubMedPubMedCentral

47.

Toegel S, Wu SQ, Otero M, Goldring MB, Leelapornpisid P, Chiari C, Kolb A, Unger FM, Windhager R, Viernstein H. Caesalpinia sappan extract inhibits IL1β-mediated overexpression of matrix metalloproteinases in human chondrocytes. Genes Nutr. 2012;7(2):307–18. https://doi.org/10.1007/s12263-011-0244-8CrossRefPubMed

48.

Mousavi MJ, Farhadi E, Vodjgani M, Karami J, Tahmasebi MN, Sharafat Vaziri A, Asgari M, Rezaei N, Mostafaei S, Jamshidi A, Mahmoudi M. Role of Fibroblast Activation Protein Alpha in Fibroblast-like Synoviocytes of Rheumatoid Arthritis. Iran J Allergy Asthma Immunol. 2021;20(3):338–49. https://doi.org/10.18502/ijaai.v20i3.6335CrossRefPubMed

Title: A2A adenosine receptor agonist reduced MMP8 expression in healthy M2-like macrophages but not in macrophages from ankylosing spondylitis patients
Authors: Omid Sadatpour
Mohammad Taha Ebrahimi
Maryam Akhtari
Nooshin Ahmadzadeh
Mahdi Vojdanian
Ahmadreza Jamshidi
Elham Farhadi
Mahdi Mahmoudi
Publication date: 01-12-2022
Publisher: BioMed Central
Keyword: Ankylosing Spondylitis
Published in: BMC Musculoskeletal Disorders / Issue 1/2022
Electronic ISSN: 1471-2474
DOI: https://doi.org/10.1186/s12891-022-05846-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A_2A adenosine receptor agonist reduced MMP8 expression in healthy M2-like macrophages but not in macrophages from ankylosing spondylitis patients

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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