Regulation of the cell cycle and inflammatory arthritis by the transcription cofactor LBH gene

Shinji Matsuda, Deepa Hammaker, Katharyn Topolewski, Karoline Briegel, David L. Boyle, Steven Dowdy, Wei Wang, Gary S. Firestein

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development (LBH) gene as a key dysregulated gene in RA and other autoimmune diseases. Although some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined. Our cell cycle analysis studies show that LBH deficiency in FLS leads to Sphase arrest and failure to progress through the cell cycle. LBH-deficient FLS had increased DNA damage and reduced expression of the catalytic subunit of DNA polymerase a. Decreased DNA polymerase a was followed by checkpoint arrest due to phosphorylation of checkpoint kinase 1. Because DNA fragments can increase arthritis severity in preclinical models, we then explored the effect of LBH deficiency in the K/BxN serum transfer model. Lbh knockout exacerbated disease severity, which is associated with elevated levels of IL-1β and checkpoint kinase 1 phosphorylation. These studies indicate that LBH deficiency induces S-phase arrest that, in turn, exacerbates inflammation. Because LBH gene variants are associated with type I diabetes mellitus, systemic lupus erythematosus, RA, and celiac disease, these results suggest a general mechanism that could contribute to immune-mediated diseases.

Original languageEnglish (US)
Pages (from-to)2316-2322
Number of pages7
JournalJournal of Immunology
Volume199
Issue number7
DOIs
StatePublished - Oct 1 2017

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ASJC Scopus subject areas

  • Immunology

Cite this

Matsuda, S., Hammaker, D., Topolewski, K., Briegel, K., Boyle, D. L., Dowdy, S., Wang, W., & Firestein, G. S. (2017). Regulation of the cell cycle and inflammatory arthritis by the transcription cofactor LBH gene. Journal of Immunology, 199(7), 2316-2322. https://doi.org/10.4049/jimmunol.1700719