# RA synovial fibroblast exosomes(RA-EXo) mediated bone erosion via AhR/TRAF2pathway

> **NIH VA I01** · LOUISVILLE VA MEDICAL MEDICAL CENTER · 2024 · —

## Abstract

Rheumatoid Arthritis (RA) is more prevalent among veterans than nonveterans. Women comprise an
increasing proportion of military personnel and have a higher prevalence of arthritis than men. Thus, RA is a highly
relevant problem for the Veterans Administration (VA). In RA synovium, rheumatoid arthritis synovial fibroblasts
(RASFs) are hyper proliferated, the leading cell type in the terminal layer of the hyperplastic synovial tissue that
invades and degrades adjacent cartilage and bone. TRAF2 mediated activation of NF-B and JNK leads to
hyperproliferation of RASFs, chronic inflammation and the erosive arthritis which is the hallmark of RA. How NF-
B and JNK is activated in rheumatoid synovial fibroblast remains elusive, though studies have demonstrated that
the blockade of TNF mediated activation of NF-B and JNK attenuates the RA progression. However, a large
population of RA patients are non-response to anti-TNF therapy. Research from our group and others has shown
that exosomes released from rheumatoid synovial fibroblasts (RA-Exo) contribute to RA pathogenicity and
inflammation in several different animal models of joint disease, including RA. Exosomes are small cell derived
vesicles that are 30-100 nm in size and of endocytic origin. Exosomes released by exocytosis into the extracellular
space, where they are considered important drivers of intercellular communication. Exosomes in synovial fluid of
RA patients can lead to inflammation, degeneration of cartilage, and destruction of joints. However, exosomes in
synovial fluid could be released by different types of cells including RASFs in the synovium. Which cell types
release exosomes that contribute to joint inflammation and degeneration of cartilage is not well studied.
Of particular relevance to this proposal, we have demonstrated that RASF exosomes (RA-Exo) activate the TNF-
receptor-associated factor 2 (TRAF2) mediated activation of the NF-B and JNK pathways is promoted by
stabilization of TRAF2. More importantly, our preliminary data clearly demonstrate that aryl hydrocarbon receptor
(AhR) expression is significantly elevated in synovium from patients with RA. Expression positively correlates with
bone erosion and is localized with TRAF2, strongly supporting the relevance of this pathway in the pathogenesis
of RA in humans. Mechanistically, AhR is enriched in the RA-Exo and RA-Exo AhR is required for stabilizing
TRAF2. Our OVERALL HYPOTHESIS is that targeting AhR centered networks in RA-Exo leads to TRAF2
degradation, and the prevention of TRAF2 mediated activation of the NF-B and JNK pathways in RASFs.
Therefore, disruption of the AhR network in RA exosomes will eliminate/attenuate bone erosion and inflammation
by affecting RA-Exo mediated pathways contributing to the development of bone erosion in synovium of RA
patients.
Our plan to accomplish this objective are outlined in these three specific aims:
 1. Identify the RA-Exo AhR network that results in the development of arthri...

## Key facts

- **NIH application ID:** 10873002
- **Project number:** 5I01BX005254-03
- **Recipient organization:** LOUISVILLE VA MEDICAL MEDICAL CENTER
- **Principal Investigator:** HUANG-GE ZHANG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873002

## Citation

> US National Institutes of Health, RePORTER application 10873002, RA synovial fibroblast exosomes(RA-EXo) mediated bone erosion via AhR/TRAF2pathway (5I01BX005254-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10873002. Licensed CC0.

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