RGD Reference Report - Cia5d regulates a new fibroblast-like synoviocyte invasion-associated gene expression signature. - Rat Genome Database

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Cia5d regulates a new fibroblast-like synoviocyte invasion-associated gene expression signature.

Authors: Laragione, T  Brenner, M  Li, W  Gulko, PS 
Citation: Laragione T, etal., Arthritis Res Ther. 2008 Aug 15;10(4):R92.
RGD ID: 2300006
Pubmed: PMID:18706093   (View Abstract at PubMed)
PMCID: PMC2575606   (View Article at PubMed Central)
DOI: DOI:10.1186/ar2476   (Journal Full-text)

ABSTRACT: INTRODUCTION: The in vitro invasive properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) have been shown to correlate with disease severity and radiographic damage. We have recently determined that FLS obtained from pristane-induced arthritis (PIA)-susceptible DA rats are also highly invasive in the same in vitro assay through Matrigel. The transfer of alleles derived from the arthritis-resistant F344 strain at the arthritis severity locus Cia5d (RNO10), as in DA.F344(Cia5d) congenics, was enough to significantly and specifically reduce the invasive properties FLS. This genetically controlled difference in FLS invasion involves increased production of soluble membrane-type 1 matrix metalloproteinase (MT1-MMP) by DA, and is dependent on increased activation of matrix metalloproteinase-2 (MMP-2). In the present study we aimed at characterizing the pattern of gene expression that correlates with differences in invasion in order to identify pathways regulated by the Cia5d locus. METHODS: Synovial tissues were collected from DA and DA.F344(Cia5d) rats 21 days after the induction of PIA. Tissues were digested and FLS isolated. After a minimum of four passages FLS were plated on Matrigel-covered dishes at similar densities for 24h, followed by RNA extraction. Illumina RatRef-12 expression BeadChip arrays were used. Expression data were normalized, followed by t-test, logistic regression and cluster analysis. Real-time quantitative polymerase chain reaction (QPCR) was used for validation of the microarray data. RESULTS: 7,665 genes out of the 22,523 RefSeq gene probes present in the array were expressed by the FLS. The expression of 66 genes was significantly different between the DA and DA.F344(Cia5d) FLS (P<0.01). Nineteen of the 66 differentially expressed genes (28.7%) are genes involved in the regulation of cell cycle progression or cancer-associated phenotypes such as invasion and contact inhibition. These included Cxcl10, Vil2 and Nras, three genes up-regulated in DA and known to regulate MMP-2 expression and activation. Nine of the 66 genes (13.6%) are involved in the regulation of the estrogen receptor signaling or transcription. Five candidate genes located within the Cia5d interval were also differentially expressed. CONCLUSIONS: We have identified a novel FLS invasion-associated gene expression signature regulated by Cia5d. Many of the genes differentially expressed have been previously implicated in cancer cell phenotypes, including invasion, suggesting a parallel in the behavior of arthritis FLS and cancer cells, and raising novel pathways and genes for therapeutic intervention and prognostication.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Arthritis  ISONras (Rattus norvegicus)2300006; 2300006 RGD 
Experimental Arthritis  IEP 2300006 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Nras  (NRAS proto-oncogene, GTPase)

Genes (Mus musculus)
Nras  (neuroblastoma ras oncogene)

Genes (Homo sapiens)
NRAS  (NRAS proto-oncogene, GTPase)

Objects referenced in this article
Strain DA.F344-(D10Mit9-D10Rat24)/Nsi null Rattus norvegicus
QTL Pia26 Pristane induced arthritis QTL 26 Rattus norvegicus

Additional Information