Rheumatoid arthritis (RA)-associated cytokine networks, cellular receptors, and signal transduction pathways have been fairly well characterized. However, gene regulatory networks that may drive and amplify inflammatory processes in RA have not been explored. Using mice with cartilage proteoglycan (PG)-induced arthritis (an autoimmune animal model of RA), we detected arthritis-specific epigenetic changes in B lymphocytes, which caused markedly upregulated expression of the gene encoding the "zinc finger and BTB domain containing 38" (ZBTB38) transcription factor. The ZBTB38 gene was similarly upregulated in lymphocytes of the majority of tested RA patients as compared to healthy individuals. We also found that ZBTB38 could facilitate its own transcription, and stimulate the expression of a number of other genes including those coding for transcription factors, pro-inflammatory cytokines, as well as chemokine and Toll-like receptors. Intriguingly, many of the gene products affected by ZBTB38's transcription factor activity have been implicated in RA pathogenesis. Our preliminary data argue for the involvement of ZBTB38 in an intricate gene regulatory network that controls inflammatory/autoimmune processes in RA. We will identify the members of this network and delineate their interactions in lymphocytes from arthritic mice and from patients with RA. In addition, we will further investigate arthritis-relate epigenetic events in selected RA patients. The proposed project should help in exploring genetic/epigenetic mechanisms involved in the regulation of a major RA- associated inflammatory pathway, and may also identify genes as novel biomarkers and drug targets for RA.

Public Health Relevance

Over 1% of the human population suffers from rheumatoid arthritis (RA), a destructive inflammatory disease affecting the peripheral joints. Although significant progress has been made in the clinical management of RA in recent years, not all patients respond to currently available therapies. Better understanding of the molecular basis of the disease could provide new treatment options. Genetic and environmental components clearly contribute to RA, but the nature of these risk factors is largely unknown. Environmental insults (such as smoking or pollution) can alter gene function without changing the DNA sequence, and epigenetics is a new area of research that deals with such alterations. Our epigenetic investigations have revealed an arthritis- specific alteration in a gene, which appears to be in the center of a gene regulatory network that controls the inflammatory process involving the joints. In this study we will explore the epigenetic factors and genes participating in this regulatory network. The results should provide new insights into disease mechanisms and also help identify genes that can serve as targets for the development of new RA therapeutics.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR064948-02
Application #
8692542
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Glant, Tibor T; Mikecz, Katalin; Rauch, Tibor A (2014) Epigenetics in the pathogenesis of rheumatoid arthritis. BMC Med 12:35
Kurkó, Júlia; Vida, András; Ocskó, Tímea et al. (2014) Suppression of proteoglycan-induced autoimmune arthritis by myeloid-derived suppressor cells generated in vitro from murine bone marrow. PLoS One 9:e111815