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Potential protein targets of the peptidylarginine deiminase 2 and peptidylarginine deiminase 4 enzymes in rheumatoid synovial tissue and its possible meaning.

ABSTRACT: OBJECTIVE:The molecular mechanism of citrullination involves the calcium-dependent peptidylarginine deiminase (PAD) family of enzymes. These enzymes induce a stereochemical modification of normal proteins and transform them into autoantigens, which in rheumatoid arthritis trigger a complex cascade of joint inflammatory events followed by chronic synovitis, pannus formation, and finally, cartilage destruction. By hypothesizing that PAD2 and PAD4 enzymes produce autoantigens, we investigated five possible synovial protein targets of PAD enzymes. MATERIAL AND METHODS:We measured PAD2, PAD4, and citrullinated proteins in 10 rheumatoid and 10 osteoarthritis synovial biopsies and then assessed the post-translational modifications of fibrinogen, cytokeratin, tubulin, IgG, and vimentin proteins using a double-fluorescence assay with specific antibodies and an affinity-purified anti-citrullinated peptide (CCP) antibody. The degree of co-localization was analyzed, and statistical significance was determined by ANOVA, Fisher's exact test, and regression analysis. RESULTS:The principal results of this study demonstrated that citrullinated proteins, such as fibrinogen, IgG, and other probed proteins, were targets of PAD2 and PAD4 activity in rheumatoid synovial biopsies, whereas osteoarthritis biopsies were negative for this enzyme (p<0.0001). An analysis of citrullination sites using the UniProtKB/Swiss-Prot data bank predicts that the secondary structure of the analyzed proteins displays most of the sites for citrullination; a discussion regarding its possible meaning in terms of pathogenesis is made. CONCLUSION:Our results support the conclusion that the synovial citrullination of proteins is PAD2 and PAD4 dependent. Furthermore, there is a collection of candidate proteins that can be citrullinated.

SUBMITTER: Badillo-Soto MA

PROVIDER: S-EPMC5042229 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Potential protein targets of the peptidylarginine deiminase 2 and peptidylarginine deiminase 4 enzymes in rheumatoid synovial tissue and its possible meaning.

Badillo-Soto Martha Adriana MA Rodríguez-Rodríguez Mayra M Pérez-Pérez María Elena ME Daza-Benitez Leonel L Bollain-Y-Goytia Juan José JJ Carrillo-Jiménez Miguel Angel MA Avalos-Díaz Esperanza E Herrera-Esparza Rafael R

European journal of rheumatology 20160201 2

<h4>Objective</h4>The molecular mechanism of citrullination involves the calcium-dependent peptidylarginine deiminase (PAD) family of enzymes. These enzymes induce a stereochemical modification of normal proteins and transform them into autoantigens, which in rheumatoid arthritis trigger a complex cascade of joint inflammatory events followed by chronic synovitis, pannus formation, and finally, cartilage destruction. By hypothesizing that PAD2 and PAD4 enzymes produce autoantigens, we investigat ...[more]

PMID: 27708970

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Project description:ObjectiveTo determine if the baseline presence of autoantibodies to peptidylarginine deiminase 4 (PAD4) predicts therapeutic response to biologic and conventional disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) in whom methotrexate (MTX) monotherapy was unsuccessful.MethodsBaseline serum from 282 RA patients in whom MTX monotherapy was unsuccessful was screened for the presence of anti-PAD4 antibodies by immunoprecipitation. Clinical response to either triple DMARD (MTX, sulfasalazine, and hydroxychloroquine) or MTX/etanercept combination therapy was determined at 24 and 48 weeks post-treatment initiation. Disease activity was measured using the Disease Activity Score 28-joint assessment (DAS28), and erosive disease was quantified using the Sharp/van der Heijde scoring method. Generalized estimating equations (GEEs) were used to model the clinical responses to treatment in patients with and those without baseline anti-PAD4 antibodies.ResultsAnti-PAD4 antibody positivity was associated with male sex, a history of never smoking, and anti-citrullinated protein antibodies. At baseline, patients with anti-PAD4 antibodies had longer disease duration and significantly more radiographic joint damage than anti-PAD4-negative patients, but did not differ in disease activity according to the DAS28. In unadjusted analyses and multivariable GEE models, patients with anti-PAD4 antibodies exhibited greater improvements in DAS28 (adjusted P = 0.02 and P = 0.008, respectively) and less radiographic progression (adjusted P = 0.01 and P = 0.002, respectively) compared to anti-PAD antibody-negative patients, independent of treatment received.ConclusionAlthough anti-PAD4 antibodies were associated with worse baseline radiographic joint damage, suggesting a history of active or undiagnosed disease, treatment escalation therapy was more effective in reducing disease activity and slowing the progression of joint damage in this patient subset.

Dataset Information

Potential protein targets of the peptidylarginine deiminase 2 and peptidylarginine deiminase 4 enzymes in rheumatoid synovial tissue and its possible meaning.

Publications

Potential protein targets of the peptidylarginine deiminase 2 and peptidylarginine deiminase 4 enzymes in rheumatoid synovial tissue and its possible meaning.

Similar Datasets

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