Local Administration of Glucocorticoids Decreases Synovial Citrullination in Rheumatoid Arthritis

Overview

Journal Arthritis Res Ther

Publisher Biomed Central

Specialty Rheumatology

Date 2012 Jan 31

PMID 22284820

Citations 23

Authors

Dimitrios Makrygiannakis

Shankar Revu

Marianne Engstrom

Erik af Klint

Anthony P Nicholas

Ger Jm Pruijn

Anca I Catrina

Affiliations

Soon will be listed here.

Abstract

Introduction: Protein citrullination is present in the rheumatoid synovium, presumably contributing to the perpetuation of chronic inflammation, in the presence of specific autoimmunity. As a result, the present study examined the possibility that effective antirheumatic treatment will decrease the level of synovial citrullination.

Methods: Synovial biopsies were obtained from 11 rheumatoid arthritis (RA) patients before and after 8 weeks of treatment with 20 mg methotrexate weekly, 15 RA patients before and 2 weeks after an intraarticular glucocorticoid injection, and eight healthy volunteers. Synovial inflammation was assessed with double-blind semiquantitative analysis of lining thickness, cell infiltration, and vascularity by using a 4-point scale. Expression of citrullinated proteins (CPs) with the monoclonal antibody F95 and peptidylarginine deiminase (PAD) 2 and 4 was assessed immunohistochemically with double-blind semiquantitative analysis. In vitro synovial fluid (SF), peripheral blood (PB), mononuclear cells (MCs), and synovial explants obtained from RA patients were incubated with dexamethasone and analyzed with immunohistochemistry for expression of CP as well as PAD2 and PAD4 enzymes.

Results: The presence of synovial CP was almost exclusive in RA compared with healthy synovium and correlated with the degree of local inflammation. Treatment with glucocorticoids but not methotrexate alters expression of synovial CP and PAD enzymes, in parallel with a decrease of synovial inflammation. Ex vivo and in vitro studies suggest also a direct effect of glucocorticoids on citrullination, as demonstrated by the decrease in the level of citrullination and PAD expression after incubation of SFMC and synovial explants with dexamethasone.

Conclusion: Synovial citrullination and PAD expression are dependent on local inflammation and targeted by glucocorticoids.

Citing Articles

Inhibition of ASIC1a reduces ferroptosis in rheumatoid arthritis articular chondrocytes via the p53/NRF2/SLC7A11 pathway.

Tang J, Liu W, Li Z, Shen C, Zhang L, Wang C FASEB J. 2025; 39(1):e70298.

PMID: 39760183 PMC: 11712546. DOI: 10.1096/fj.202402134RR.

New Posttranslational Modification Lactylation Brings New Inspiration for the Treatment of Rheumatoid Arthritis.

Yang Y, Shi J, Yu J, Zhao X, Zhu K, Wang S J Inflamm Res. 2025; 17:11845-11860.

PMID: 39758940 PMC: 11697653. DOI: 10.2147/JIR.S497240.

The Role of Citrullination Modification in CD4 T Cells in the Pathogenesis of Immune-Related Diseases.

Chen Y, Teng Y, Xu P, Wang S Biomolecules. 2024; 14(4).

PMID: 38672418 PMC: 11047979. DOI: 10.3390/biom14040400.

Dexamethasone, but Not Vitamin D or A, Dampens the Inflammatory Neutrophil Response to Protect At-risk COVID-19 Patients.

Hafkamp F, Mol S, Waque I, de Jong E Immune Netw. 2022; 22(4):e36.

PMID: 36081524 PMC: 9433192. DOI: 10.4110/in.2022.22.e36.

Impact of Posttranslational Modification in Pathogenesis of Rheumatoid Arthritis: Focusing on Citrullination, Carbamylation, and Acetylation.

Kwon E, Ju J Int J Mol Sci. 2021; 22(19).

PMID: 34638916 PMC: 8508717. DOI: 10.3390/ijms221910576.

References

Senshu T, Akiyama K, Nomura K . Identification of citrulline residues in the V subdomains of keratin K1 derived from the cornified layer of newborn mouse epidermis. Exp Dermatol. 1999; 8(5):392-401. DOI: 10.1111/j.1600-0625.1999.tb00388.x. View

Makrygiannakis D, Hermansson M, Ulfgren A, Nicholas A, Zendman A, Eklund A . Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis. 2008; 67(10):1488-92. DOI: 10.1136/ard.2007.075192. View

Vossenaar E, Smeets T, Kraan M, Raats J, van Venrooij W, Tak P . The presence of citrullinated proteins is not specific for rheumatoid synovial tissue. Arthritis Rheum. 2004; 50(11):3485-94. DOI: 10.1002/art.20584. View

Varani K, Massara A, Vincenzi F, Tosi A, Padovan M, Trotta F . Normalization of A2A and A3 adenosine receptor up-regulation in rheumatoid arthritis patients by treatment with anti-tumor necrosis factor alpha but not methotrexate. Arthritis Rheum. 2009; 60(10):2880-91. DOI: 10.1002/art.24794. View

Vossenaar E, Radstake T, van der Heijden A, van Mansum M, Dieteren C, de Rooij D . Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann Rheum Dis. 2004; 63(4):373-81. PMC: 1754951. DOI: 10.1136/ard.2003.012211. View

Catrina A, Trollmo C, af Klint E, Engstrom M, Lampa J, Hermansson Y . Evidence that anti-tumor necrosis factor therapy with both etanercept and infliximab induces apoptosis in macrophages, but not lymphocytes, in rheumatoid arthritis joints: extended report. Arthritis Rheum. 2005; 52(1):61-72. DOI: 10.1002/art.20764. View

Raijmakers R, Vogelzangs J, Croxford J, Wesseling P, van Venrooij W, Pruijn G . Citrullination of central nervous system proteins during the development of experimental autoimmune encephalomyelitis. J Comp Neurol. 2005; 486(3):243-53. DOI: 10.1002/cne.20529. View

Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J . A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2005; 54(1):38-46. DOI: 10.1002/art.21575. View

Hermansson M, Artemenko K, Ossipova E, Eriksson H, Lengqvist J, Makrygiannakis D . MS analysis of rheumatoid arthritic synovial tissue identifies specific citrullination sites on fibrinogen. Proteomics Clin Appl. 2010; 4(5):511-8. DOI: 10.1002/prca.200900088. View

10.

Nicholas A, Whitaker J . Preparation of a monoclonal antibody to citrullinated epitopes: its characterization and some applications to immunohistochemistry in human brain. Glia. 2002; 37(4):328-36. View

11.

Schellekens G, Visser H, de Jong B, van den Hoogen F, Hazes J, Breedveld F . The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 2000; 43(1):155-63. DOI: 10.1002/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2-3. View

12.

Chapuy-Regaud S, Sebbag M, Baeten D, Clavel C, Foulquier C, De Keyser F . Fibrin deimination in synovial tissue is not specific for rheumatoid arthritis but commonly occurs during synovitides. J Immunol. 2005; 174(8):5057-64. DOI: 10.4049/jimmunol.174.8.5057. View

13.

Neeli I, Khan S, Radic M . Histone deimination as a response to inflammatory stimuli in neutrophils. J Immunol. 2008; 180(3):1895-902. DOI: 10.4049/jimmunol.180.3.1895. View

14.

Klareskog L, Ronnelid J, Lundberg K, Padyukov L, Alfredsson L . Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol. 2008; 26:651-75. DOI: 10.1146/annurev.immunol.26.021607.090244. View

15.

Lu M, Lai N, Yu H, Huang H, Hsieh S, Yu C . Anti-citrullinated protein antibodies bind surface-expressed citrullinated Grp78 on monocyte/macrophages and stimulate tumor necrosis factor alpha production. Arthritis Rheum. 2010; 62(5):1213-23. DOI: 10.1002/art.27386. View

16.

De Rycke L, Nicholas A, Cantaert T, Kruithof E, Echols J, Vandekerckhove B . Synovial intracellular citrullinated proteins colocalizing with peptidyl arginine deiminase as pathophysiologically relevant antigenic determinants of rheumatoid arthritis-specific humoral autoimmunity. Arthritis Rheum. 2005; 52(8):2323-30. DOI: 10.1002/art.21220. View

17.

Cronstein B, Montesinos M, Weissmann G . Sites of action for future therapy: an adenosine-dependent mechanism by which aspirin retains its antiinflammatory activity in cyclooxygenase-2 and NFkappaB knockout mice. Osteoarthritis Cartilage. 1999; 7(4):361-3. DOI: 10.1053/joca.1998.0236. View

18.

Chang X, Yamada R, Suzuki A, Kochi Y, Sawada T, Yamamoto K . Citrullination of fibronectin in rheumatoid arthritis synovial tissue. Rheumatology (Oxford). 2005; 44(11):1374-82. DOI: 10.1093/rheumatology/kei023. View

19.

Ishigami A, Ohsawa T, Asaga H, Akiyama K, Kuramoto M, Maruyama N . Human peptidylarginine deiminase type II: molecular cloning, gene organization, and expression in human skin. Arch Biochem Biophys. 2002; 407(1):25-31. DOI: 10.1016/s0003-9861(02)00516-7. View

20.

Arnett F, Edworthy S, Bloch D, McShane D, Fries J, Cooper N . The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31(3):315-24. DOI: 10.1002/art.1780310302. View