# Spatial and Temporal Role of the Runx3 Transcription Factor in Secondary Fracture Healing

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Clinical Dilemma: The frequency of impaired fracture healing is increased with aging as well as in the
presence of other patient-related factors such as smoking, osteoporosis, and diabetes. Treatment of fractures
in this setting continues to pose a significant economic burden on the US healthcare system due to increases
in time lost from work as well as increases in the expenses associated with fracture-associated complications.
While various bone anabolic drugs are successful in increasing homeostatic bone mass in osteoporotic
patients and decreasing fracture incidence, they have not demonstrated significant success in enhancing
fracture repair. Therefore, identifying novel molecular targets to accelerate secondary fracture healing in this
very common setting remains of paramount importance.
Relevance to the VA: According to the Office of VA Inspector General report in 2010, osteoporotic patients
who suffered a single fracture present a higher incidence of subsequent fractures (20-fold increase) than
unaffected populations. Impaired or delayed bony union following fracture of long bones prevents or delays a
significant percentage of VA patients from resuming their daily activities and returning to work. Ineffective
treatment of these fractures maximizes the economic burden on the VA healthcare system. Identifying novel
molecular targets to enhance secondary bone repair remains of paramount importance. The objective of this
translational research application is to enhance secondary fracture healing by targeting novel regulatory
pathways that enhance periosteal cell-induced osteogenesis and angiogenesis during fracture callus formation.
Scientific premise: We provide compelling preliminary evidence of the following:
1. Runx3 is expressed in chondrocytes, osteoblasts and osteocytes of C57BL6j murine long bones.
2. Runx3 expression levels are increased in soft cartilaginous calluses and subsequently decreased in bony
 calluses of murine femoral fractures.
3. Conditional deletion of Runx3 in periosteal cells (cKO) resulted in enhanced secondary bone healing as
 evidenced by histological, histomorphometric, and molecular analyses.
4. The cellular mechanisms underlying these positive effects on secondary bone healing implicate increased
 osteogenesis as well as angiogenesis of fractured periosteal cells from Runx3 cKO compared to control
mice.
5. Use of multiphoton microscopy demonstrate the feasibility of tracking Prx1+ skeletal progenitor cells during
 bone repair and longitudinally monitor the bone healing process for lineage tracing experiments.
Here we hypothesize that Runx3 is a molecular switch that controls the transition from cartilaginous to
bony callus, and its deletion in the chondrogenic cell lineage will accelerate secondary fracture
healing.
To verify this hypothesis, we propose to first establish the effects of stage-specific repression of Runx3 on
secondary fracture healing (Aim 1). We will then determine the mechanisms via which Runx3...

## Key facts

- **NIH application ID:** 10105189
- **Project number:** 5I01BX004708-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Moulay Hicham DRISSI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105189

## Citation

> US National Institutes of Health, RePORTER application 10105189, Spatial and Temporal Role of the Runx3 Transcription Factor in Secondary Fracture Healing (5I01BX004708-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10105189. Licensed CC0.

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