# Osteogenic and angiogenic tissue regeneration to accelerate secondary bone healing during aging

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $262,810

## Abstract

Clinical premise: Aging is associated with increased frequency of fragility fractures, which often result in
significant economic and emotional burden. Ineffective treatment of these fractures leads to lost productivity and
often increased expenses of fracture-associated complications, including increased mortality. Moreover, the risk
of impaired or delayed bony union is further enhanced by patient co-morbidities and metabolic diseases such as
diabetes or osteoporosis. The vast majority of these fractures target the vertebrae, proximal femur, distal femur,
proximal humerus and distal radius. Whether they are treated operatively (i.e. nailing a femur fracture or plating
a distal radius fracture) or non-operatively (i.e. cast or sling), these fractures heal via endochondral ossification
in a process called secondary fracture healing. Various bone anabolic drugs, which were initially designed to
treat osteoporotic patients, have been tested to enhance fracture repair. However, despite their established
efficacy in increasing homeostatic bone mass, limited success was achieved in their clinical use to accelerate
fracture repair. Therefore, identifying novel molecular targets to enhance secondary bone repair remains of
paramount importance. The objective of this translational research application is to accelerate secondary bone
repair in vivo by targeting novel regulatory pathways in aging mice 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
mesenchymal cells of both human and murine fractures. 2. Runx3 expression in the callus decreases as the
fracture heals. 3. Conditional deletion of Runx3 in periosteal cells (cKO) results in enhanced secondary bone
healing through increased osteogenesis and angiogenesis. 4. Runx3 deletion in the periosteum resulted in
increased expression of IL-17a receptor (IL-17ra) in fractured femurs of cKO mice compared to controls animals.
5. Runx3 directly binds to the proximal promoter of IL-17ra. Finally, 6. Runx3 protein levels remain elevated in
mesenchymal cells in fracture calluses of aged compared to juvenile mice.
Our central hypothesis is that repression of Runx3 in periosteal cells will accelerate secondary fracture healing
in aging mice through activation of IL-17 signaling in mesenchymal cell populations.
Specific objectives: We will establish that Runx3 deletion in periosteal cells accelerates bone regeneration and
secondary bone healing in aging mice through enhanced bone formation and angiogenesis at the fracture site.
(Aim 1). We will then demonstrate that Runx3 delays callus bone formation and vascular invasion by age-
dependently inhibiting IL-17ra signaling in mesenchymal cells. (Aim 2A). Finally, we will use hydrogels to locally
deliver Runx3 siRNA-complexed nanoparticles and examine the efficacy and safety of this therapeutic approach
in accelerati...

## Key facts

- **NIH application ID:** 9980268
- **Project number:** 5R01AG064464-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Moulay Hicham DRISSI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $262,810
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980268

## Citation

> US National Institutes of Health, RePORTER application 9980268, Osteogenic and angiogenic tissue regeneration to accelerate secondary bone healing during aging (5R01AG064464-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9980268. Licensed CC0.

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