Phosphoproteomic profiling of early rheumatoid arthritis synovium reveals active signalling pathways and differentiates inflammatory pathotypes.
Journal
Arthritis research & therapy
ISSN: 1478-6362
Titre abrégé: Arthritis Res Ther
Pays: England
ID NLM: 101154438
Informations de publication
Date de publication:
12 Jun 2024
12 Jun 2024
Historique:
received:
10
01
2024
accepted:
06
06
2024
medline:
13
6
2024
pubmed:
13
6
2024
entrez:
12
6
2024
Statut:
epublish
Résumé
Kinases are intracellular signalling mediators and key to sustaining the inflammatory process in rheumatoid arthritis (RA). Oral inhibitors of Janus Kinase family (JAKs) are widely used in RA, while inhibitors of other kinase families e.g. phosphoinositide 3-kinase (PI3K) are under development. Most current biomarker platforms quantify mRNA/protein levels, but give no direct information on whether proteins are active/inactive. Phosphoproteome analysis has the potential to measure specific enzyme activation status at tissue level. We validated the feasibility of phosphoproteome and total proteome analysis on 8 pre-treatment synovial biopsies from treatment-naive RA patients using label-free mass spectrometry, to identify active cell signalling pathways in synovial tissue which might explain failure to respond to RA therapeutics. Differential expression analysis and functional enrichment revealed clear separation of phosphoproteome and proteome profiles between lymphoid and myeloid RA pathotypes. Abundance of specific phosphosites was associated with the degree of inflammatory state. The lymphoid pathotype was enriched with lymphoproliferative signalling phosphosites, including Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted novel kinases not previously linked to RA, such as Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotype. Several phosphosites correlated with clinical features, such as Disease-Activity-Score (DAS)-28, suggesting that phosphosite analysis has potential for identifying novel biomarkers at tissue-level of disease severity and prognosis. Specific phosphoproteome/proteome signatures delineate RA pathotypes and may have clinical utility for stratifying patients for personalised medicine in RA.
Sections du résumé
BACKGROUND
BACKGROUND
Kinases are intracellular signalling mediators and key to sustaining the inflammatory process in rheumatoid arthritis (RA). Oral inhibitors of Janus Kinase family (JAKs) are widely used in RA, while inhibitors of other kinase families e.g. phosphoinositide 3-kinase (PI3K) are under development. Most current biomarker platforms quantify mRNA/protein levels, but give no direct information on whether proteins are active/inactive. Phosphoproteome analysis has the potential to measure specific enzyme activation status at tissue level.
METHODS
METHODS
We validated the feasibility of phosphoproteome and total proteome analysis on 8 pre-treatment synovial biopsies from treatment-naive RA patients using label-free mass spectrometry, to identify active cell signalling pathways in synovial tissue which might explain failure to respond to RA therapeutics.
RESULTS
RESULTS
Differential expression analysis and functional enrichment revealed clear separation of phosphoproteome and proteome profiles between lymphoid and myeloid RA pathotypes. Abundance of specific phosphosites was associated with the degree of inflammatory state. The lymphoid pathotype was enriched with lymphoproliferative signalling phosphosites, including Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted novel kinases not previously linked to RA, such as Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotype. Several phosphosites correlated with clinical features, such as Disease-Activity-Score (DAS)-28, suggesting that phosphosite analysis has potential for identifying novel biomarkers at tissue-level of disease severity and prognosis.
CONCLUSIONS
CONCLUSIONS
Specific phosphoproteome/proteome signatures delineate RA pathotypes and may have clinical utility for stratifying patients for personalised medicine in RA.
Identifiants
pubmed: 38867295
doi: 10.1186/s13075-024-03351-4
pii: 10.1186/s13075-024-03351-4
doi:
Substances chimiques
Phosphoproteins
0
Proteome
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
120Subventions
Organisme : Barts and The London School of Medicine and Dentistry
ID : 523/819
Organisme : Barts and The London School of Medicine and Dentistry
ID : 523/819
Organisme : Barts and The London School of Medicine and Dentistry
ID : 523/819
Organisme : Barts and The London School of Medicine and Dentistry
ID : 523/819
Organisme : Barts and The London School of Medicine and Dentistry
ID : 523/819
Organisme : Barts and The London School of Medicine and Dentistry
ID : 523/819
Organisme : Barts and The London School of Medicine and Dentistry
ID : 523/819
Organisme : Barts and The London School of Medicine and Dentistry
ID : 523/819
Organisme : Medical Research Council
ID : G0800648, MR/K015346/1 and MR/V012509/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800648, MR/K015346/1 and MR/V012509/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800648, MR/K015346/1 and MR/V012509/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800648, MR/K015346/1 and MR/V012509/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800648, MR/K015346/1 and MR/V012509/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800648, MR/K015346/1 and MR/V012509/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800648, MR/K015346/1 and MR/V012509/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0800648, MR/K015346/1 and MR/V012509/1
Pays : United Kingdom
Organisme : National Institute for Health and Care Research
ID : 131575 and 203330
Organisme : National Institute for Health and Care Research
ID : 131575 and 203330
Organisme : National Institute for Health and Care Research
ID : 131575 and 203330
Organisme : National Institute for Health and Care Research
ID : 131575 and 203330
Organisme : National Institute for Health and Care Research
ID : 131575 and 203330
Organisme : National Institute for Health and Care Research
ID : 131575 and 203330
Organisme : National Institute for Health and Care Research
ID : 131575 and 203330
Organisme : National Institute for Health and Care Research
ID : 131575 and 203330
Organisme : Arthritis Research UK
ID : 20022 and 20670
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : 20022 and 20670
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : 20022 and 20670
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : 20022 and 20670
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : 20022 and 20670
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : 20022 and 20670
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : 20022 and 20670
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : 20022 and 20670
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C15966/A24375 and C16420/A18066
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C15966/A24375 and C16420/A18066
Pays : United Kingdom
Informations de copyright
© 2024. The Author(s).
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