# Chondrocyte DNA Double-Strand Breaks in the Pathogenesis of Osteoarthritis

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $338,800

## Abstract

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability in adults. While
aging is an important risk factor for the development of OA, the molecular mechanisms responsible for OA in the
context of aging remain unclear. Here, we propose to test the hypothesis that DNA DSBs in articular
chondrocytes promote cell cycle re-entry and induce both IKK/NF-B and IRF signaling downstream of STING
to mediate a pro-inflammatory secretory phenotype that leads to cartilage degeneration and inflammation in
surrounding joint tissues. We show that IKK/NF-B signaling increases with age in the articular chondrocytes
of wild type mice and that, by 24 months, these mice develop a knee joint phenotype exhibiting early hallmarks
of OA. We also show that sustained IKK activation in the chondrocytes of young mice greatly accelerates the
onset of this age-related OA phenotype likely through paracrine actions on surrounding cells via a
proinflammatory secretory program consisting of numerous cytokines, chemokines, growth factors, and MMPs
that can alter proliferation and viability of neighboring cells, remodel the cartilage ECM, and initiate an innate
immune response. DNA double-strand breaks (DSBs) are known to induce IKK/NF-B signaling and we provide
evidence here of DNA DSBs in aged murine articular chondrocytes. We also provide gene expression data
showing that IRF and Interferon signaling are among the most significantly affected pathways in aged articular
chondrocytes. DNA DSBs can induce both NF-B and IRF signaling through Stimulator of interferon genes, or
STING. Thus, we hypothesize that STING may be upstream of both NF-B and IRF to produce a proinflammatory
secretory phenotype in chondrocytes with DSBs. In the first Aim of this proposal, we will test the effects of
chondrocyte-specific DNA DSBs on chondrocyte function and OA development using AcanCreERT2/+; R26I-PpoI mice
where DSBs are produced specifically in chondrocytes upon administration of tamoxifen. We will determine how
chondrocytes respond to this genotoxic stress and also whether persistent DSBs are capable of promoting OA.
In the second Aim, we will test whether STING is specifically involved in the activation of IKK/NF-B and IRF
signaling following induction of DSBs and in the onset of age-related OA using in vitro cell culture methods as
well as an in vivo STING knockout model in combination with NF-B and IRF endogenous reporters. Results
from these studies will provide valuable insight to the effects of DNA DSBs on chondrocyte fate and also on the
identity of upstream activators of NF-B in aged chondrocytes, potentially leading to the identification of a novel
mechanism in which to inhibit IKK/NF-B signaling and inflammation in OA chondrocytes.

## Key facts

- **NIH application ID:** 9866064
- **Project number:** 1R01AR076623-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Jennifer Harrell Jonason
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,800
- **Award type:** 1
- **Project period:** 2020-05-07 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9866064

## Citation

> US National Institutes of Health, RePORTER application 9866064, Chondrocyte DNA Double-Strand Breaks in the Pathogenesis of Osteoarthritis (1R01AR076623-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9866064. Licensed CC0.

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