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 language | English (US) |
|---|---|
| Pages (from-to) | 2316-2322 |
| Number of pages | 7 |
| Journal | Journal of Immunology |
| Volume | 199 |
| Issue number | 7 |
| DOIs | |
| State | Published - Oct 1 2017 |
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ASJC Scopus subject areas
- Immunology
Cite this
Regulation of the cell cycle and inflammatory arthritis by the transcription cofactor LBH gene. / Matsuda, Shinji; Hammaker, Deepa; Topolewski, Katharyn; Briegel, Karoline; Boyle, David L.; Dowdy, Steven; Wang, Wei; Firestein, Gary S.
In: Journal of Immunology, Vol. 199, No. 7, 01.10.2017, p. 2316-2322.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regulation of the cell cycle and inflammatory arthritis by the transcription cofactor LBH gene
AU - Matsuda, Shinji
AU - Hammaker, Deepa
AU - Topolewski, Katharyn
AU - Briegel, Karoline
AU - Boyle, David L.
AU - Dowdy, Steven
AU - Wang, Wei
AU - Firestein, Gary S.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85029684678&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029684678&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1700719
DO - 10.4049/jimmunol.1700719
M3 - Article
C2 - 28807995
AN - SCOPUS:85029684678
VL - 199
SP - 2316
EP - 2322
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 7
ER -