Increased synovial expression of nuclear receptors correlates with protection in pristane-induced arthritis: A possible novel genetically regulated homeostatic mechanism
Max Brenner
Feinstein Institute for Medical Research and Elmezzi Graduate School of Molecular Medicine, Manhasset, New York
Drs. Brenner and Linge contributed equally to this work.
Search for more papers by this authorCarl P. Linge
Feinstein Institute for Medical Research and Elmezzi Graduate School of Molecular Medicine, Manhasset, New York
Drs. Brenner and Linge contributed equally to this work.
Search for more papers by this authorWentian Li
Feinstein Institute for Medical Research and Elmezzi Graduate School of Molecular Medicine, Manhasset, New York
Search for more papers by this authorCorresponding Author
Pércio S. Gulko
Feinstein Institute for Medical Research and Elmezzi Graduate School of Molecular Medicine, Manhasset, New York
Laboratory of Experimental Rheumatology, Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, 350 Community Drive, Room 139, Manhasset, NY 11030Search for more papers by this authorMax Brenner
Feinstein Institute for Medical Research and Elmezzi Graduate School of Molecular Medicine, Manhasset, New York
Drs. Brenner and Linge contributed equally to this work.
Search for more papers by this authorCarl P. Linge
Feinstein Institute for Medical Research and Elmezzi Graduate School of Molecular Medicine, Manhasset, New York
Drs. Brenner and Linge contributed equally to this work.
Search for more papers by this authorWentian Li
Feinstein Institute for Medical Research and Elmezzi Graduate School of Molecular Medicine, Manhasset, New York
Search for more papers by this authorCorresponding Author
Pércio S. Gulko
Feinstein Institute for Medical Research and Elmezzi Graduate School of Molecular Medicine, Manhasset, New York
Laboratory of Experimental Rheumatology, Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, 350 Community Drive, Room 139, Manhasset, NY 11030Search for more papers by this authorAbstract
Objective
To use microarray analyses of gene expression to characterize the synovial molecular pathways regulated by the arthritis regulatory locus Cia25 and to determine how it operates to control disease severity and joint damage.
Methods
Synovial tissues from DA rats and DA.ACI(Cia25) rats obtained 21 days after induction of pristane-induced arthritis were used for RNA extraction and hybridization to Illumina RatRef-12 Expression BeadChips (22,228 genes). Genes with a P value ≤0.01 and a fold difference in expression ≥1.5 between DA rats and DA.ACI(Cia25) rats were considered significant.
Results
Interleukin-1β (IL-1β) (7.4-fold), IL-6 (67-fold), Ccl2, Cxcl10, Mmp3, Mmp14, and innate immunity genes were expressed at increased levels in DA rats and at significantly lower levels in DA.ACI(Cia25) congenic rats. DA.ACI(Cia25) rats had increased expression of 10 nuclear receptor (NR) genes, including those known to interfere with NF-κB activity and cytokine expression, such as Lxra, Pparg, and Rxrg. DA.ACI(Cia25) rats also had increased expression of NR targets, suggesting increased NR activity. While Vdr was not differentially expressed, a Vdr expression signature was detected in congenic rats, along with up-regulation of mediators of vitamin D synthesis.
Conclusion
This is the first description of the association between increased synovial levels of NRs and arthritis protection. The expression of NRs was inversely correlated with the expression of key mediators of arthritis, suggesting reciprocally opposing effects either via NF-κB or at the genomic level in the synovial tissue. We consider that the NR signature may have an important role in maintaining synovial homeostasis and an inflammation-free tissue. These processes are regulated by the Cia25 gene and suggest a new function for this gene.
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