ArticleArthritis & rheumatology (Hoboken, N.J.)2026
Tissue Damage in Rheumatoid Arthritis Is Genetically Linked to Low Peptidylglycine Alpha-Amidating Monooxygenase Activity in Synovial Fibroblasts.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- From Genome-Wide Association Study Signal to Mechanism in Rheumatoid Arthritis: Lessons From a Single Risk Locus.Arthritis & rheumatology (Hoboken, N.J.) · 2026Article
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Authors and funding
13 authors.
Funding
Abstract
objectiveBoth susceptibility to, and severity of, rheumatoid arthritis (RA) is associated with the rs26232 C allele. Our primary aim was to identify the biologic mechanism underlying this association.
methodsExpression of surrounding genes was compared among rs26232 genotypes. Publicly available databases were used to correlate expression with RA inflammation and single-cell synovial distribution. Inhibition of gene expression and activity was achieved using small interfering RNA and a pharmacology agent and effects on RA synovial fibroblasts (RASFs) characteristics in vitro were assayed. The amidated secretome of synovial fibroblasts were characterized by mass spectrometry and enzyme-linked immunosorbent assay. Effects of amidated peptides on macrophage polarity were determined using an RASF-macrophage coculture module.
resultsrs26232 C is associated with low expression of peptidylglycine alpha-amidating monooxygenase (PAM) in multiple tissues including RASFs. Synovial PAM is highly expressed in RASFs but not immune cells, and levels are inversely correlated with synovial and systemic levels of inflammation. Inhibition of PAM in RASFs increased tissue-damaging activities such as invasiveness in vitro. The most abundant amidated peptides secreted by RASFs were adrenomedullin (ADM) and pro-ADM N-terminal peptide (PAMP). Incubation of RASFs with either peptide inhibited interleukin-6 (IL-6) and IL-8, increased transforming growth factor β production, and reduced invasiveness in vitro. Inhibition of amidation in an RASF-macrophage coculture model skewed the macrophages to proinflammatory MerTK
conclusionGenetically determined low PAM reduces the anti-inflammatory and tissue-damaging activities of ADM and PAMP mediated by macrophages and RASFs, explaining the association of rs26232 C with RA severity.
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