Session Type: Poster Session (Sunday)
Session Time: 9:00AM-11:00AM
Background/Purpose: We have previously identified new key regulators of Rheumatoid arthritis (RA) synovial pathology using a systems biology approach that combined RA gene expression datasets, epigenomics data, genetics and rodent studies. The RA fibroblast-like synoviocytes (RA-FLS) have a central role in RA pathogenesis and joint damage, and their in vitro invasive properties correlate with in vivo joint damage. In the present study were examine the effect of different key regulators identified in the systems biology study in phenotypes relevant to disease and joint damage.
Methods: RA-FLS cell lines (n=4-6 cell lines per gene) were treated with siRNA smartpool targeting the top key network and subnetwork regulators, and compared with control siRNA. RA-FLS were then examined in different in vitro phenotypes that strongly correlate with joint damage in RA and rodent models of RA. These phenotypes included FLS invasiveness, FLS proliferation, cell adhesion, the wound healing model, and IL-1b-induced expression and production of IL-1b, IL-6, TNFa and MMPs (MMP1, 2, 3 and 14).
Results: Knock down of LOXL2 and NUSAP with siRNA significantly decreased FLS invasiveness by 30% (p=0.03) and 60% (p=0.002), respectively, compared with siRNA control. RA-FLS mobility in the wound healing assay was inhibited by knock down of AKT3, BACH1 and DLX4 (p=0.008). Knock down of TRIM22, an interferon-induced protein involved in innate immunity, decreased the IL-1b-induced release of IL-6 (p=0.03). RA-FLS proliferation and adhesion were not affected by any of the siRNA tested.
Conclusion: This study validated new key regulators identified in our systems biology discovery approach generating potential new understanding of events regulating FLS behavior in RA and potential new targets for the development of new treatments aimed at reducing joint damage.
To cite this abstract in AMA style:Laragione T, Harris C, Wang W, Zhu J, Gulko P. Validation of New Genes Identified in a Molecular Bayesian Network of Rheumatoid Arthritis Synovitis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/validation-of-new-genes-identified-in-a-molecular-bayesian-network-of-rheumatoid-arthritis-synovitis/. Accessed May 18, 2022.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/validation-of-new-genes-identified-in-a-molecular-bayesian-network-of-rheumatoid-arthritis-synovitis/