# Joint-location specific pathogenic pathways in rheumatoid arthritis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $344,124

## Abstract

ABSTRACT
Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target
pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of
rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and
transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS,
but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we discovered
differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as
IL-6 signaling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee
and hip FLS using RNA-seq. This proposal is designed to dissect joint-specific epigenetic and functional
aspects of RA. To accomplish this, we will 1) develop a high resolution map of joint-specific and disease-
specific DNA methylation patterns in RA including pathway analysis that integrates genomics and
transcriptomics data; 2) determine the functional consequences of differential epigenetic marks by evaluating
joint-specific FLS transcriptome patterns and cytokine responses; and 3) determine the mechanisms that
define joint specific epigenetic marks, with a focus on the role of transcription factor motifs. These joint-specific
epigenetic and functional signatures suggest that RA disease mechanisms might vary from joint to joint and
potentially explain some of the diversity of drug responses in RA patients.

## Key facts

- **NIH application ID:** 10159865
- **Project number:** 5R01AR071321-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** GARY S FIRESTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $344,124
- **Award type:** 5
- **Project period:** 2018-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159865

## Citation

> US National Institutes of Health, RePORTER application 10159865, Joint-location specific pathogenic pathways in rheumatoid arthritis (5R01AR071321-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10159865. Licensed CC0.

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