# Epigenetic Regulation of Bone Regeneration in Inflammatory Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $532,763

## Abstract

ABSTRACT
 Inflamed bone fracture poses a significant clinical problem. In the United States, approximately 1.6 million
bone fractures encounter prolonged healing or non-union each year, among which, the major population bearing
with these clinical complications are patients with inflammatory conditions, e.g, elder patients, smoking, diabetic
or rheumatoid arthritis (RA) patients. In these patients, the fracture risk is increased due to the poor bone quality,
highlighting the potential deleterious role of chronic systemic inflammation in fracture repair.
 The overarching hypothesis of this proposal is that under inflammatory conditions, NF-κB, the principal
mediator of inflammation, induces Rbpjκ expression through downregulating Dnmt3b and its DNA methylation
activity. We further hypothesize that Dnmt3b GOF or Rbpjκ inhibition restores MPC differentiation and
chondrocyte maturation that are reduced by inflammation during fracture repair. This hypothesis is supported by
our preliminary data wherein we show that Dnmt3b is highly expressed in fracture callus during fracture repair
and Dnmt3b is the major DNA methyltransferase (Dnmt) responsive to cytokine in MPCs and chondrocytes.
Relevant to our proposal, we provide evidence that inflammatory signals inhibit Dnmt3b in MPCs and
chondrocytes in an NF-κB-dependent manner. Consistently, mice with Dnmt3b loss-of-function (LOF) in MPCs
and chondrocytes display delayed fracture repair; and Dnmt3b gain-of-function (GOF) in MPCs or chondrocytes
shows protective effect from inflammation in vitro and accelerates fracture repair in mice. Mechanistically, MPC
differentiation defect mediated by inflammation and Dnmt3b LOF coincide with upregulation of Rbpjκ in MPCs
and Rbpjκ inhibition can restore differentiation capacity in vitro.
 In vitro mechanistic studies and in vivo LOF and GOF approaches will be used to modulate IKK2, Dnmt3b
and Rbpjκ expression in MPCs and chondrocytes to dissect its effects during fracture repair process. Three main
Specific Aims are proposed. Specific Aim 1 will delineate the effect of constitutively active NF-κB signaling
(IKK2ca), as the principal molecular driver of inflammation, on Dnmt3b expression and fracture repair. Specific
Aim 2 will establish the effect of Dnmt3b GOF in MPCs and chondrocytes on accelerating fracture repair.
Specific Aim 3 will delineate the mechanism by which Dnmt3b regulates downstream target, Rbpjκ, during
fracture repair. This work will enhance our understanding of mechanisms by which systemic inflammation (via
the NF-κB pathway) affects the fracture healing process through Dnmt3b and identify downstream targets of
Dnmt3b (such as Rbpjκ) as novel candidates for therapeutic intervention.

## Key facts

- **NIH application ID:** 9974476
- **Project number:** 5R01AR075860-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Jie Shen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $532,763
- **Award type:** 5
- **Project period:** 2019-07-08 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974476

## Citation

> US National Institutes of Health, RePORTER application 9974476, Epigenetic Regulation of Bone Regeneration in Inflammatory Disease (5R01AR075860-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974476. Licensed CC0.

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