# Role of IL-17 receptor A in aging bone remodeling

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $428,901

## Abstract

Summary:
Inflammatory cytokines are potent stimulators of osteoclastic bone resorption. During aging, there are increased
levels of these inflammatory mediators that are widely associated with perturbed skeletal homeostasis, and more
recently fracture healing. During the past decade, the influence of inflammatory signals on bone health has been
the focus of many laboratories. One particular family of pro-inflammatory cytokines (IL-17 family) has been
increasingly shown to play key roles in controlling skeletal homeostasis. We came across the discovery that
serum levels of IL-17a in fractured old mice were dramatically increased compared to young controls. Conditional
deletion of the main receptor for IL-17a (IL-17ra) in osteoclasts resulted in decreased bone resorption and
increased bone mass in vivo. Based on additional preliminary findings, our postulated mechanism underlying IL-
17ra control of bone remodeling involves the newly discovered transcriptional repressor of osteoclastic bone
resorption, Runx1. Based on the above, we postulate that deletion of IL-17ra in OCLs will increase bone mass
during skeletal homeostasis and promote bone repair through stage specific inhibition of osteoclastic bone
resorption by Runx1 during fracture callus remodeling.
In Aim 1, we propose to examine the function of OCL-produced IL-17ra and mechanisms via which it modulates
bone remodeling during homeostasis in the aging skeleton. Specifically, we will determine if loss of IL-17ra in
OCLs will increase bone mass in aging mice (1A). We will then demonstrate that deletion of IL-17ra in OCLs
inhibits bone resorption through upregulation of Runx1 (1B). Finally, we will determine if deletion of IL-17ra in
OCLs is sufficient to halt ovariectomy-induced bone loss (1C). In the second Aim, we propose to evaluate
whether inhibition of IL-17ra or activation of Runx1 in OCLs can stage-dependently control bone healing in aging
mice by first evaluating the effects of IL-17ra abrogation on callus remodeling and bone repair in aging mice
(2A). We will then examine whether stage-dependent overexpression of Runx1 in OCLs is sufficient to accelerate
the healing of senile fractures (2B). Finally, we will devise a therapeutic strategy to accelerate fracture healing
in aging mice via delivery of a small molecule to temporally activate Runx1 during callus remodeling (2C).
The data obtained from the proposed experiments will reveal new anti-inflammatory downstream signaling
pathways that can serve as viable substitutes for the currently available anti-resorptive biologics.

## Key facts

- **NIH application ID:** 10719356
- **Project number:** 1R01AG083154-01
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Moulay Hicham DRISSI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $428,901
- **Award type:** 1
- **Project period:** 2023-08-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10719356

## Citation

> US National Institutes of Health, RePORTER application 10719356, Role of IL-17 receptor A in aging bone remodeling (1R01AG083154-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10719356. Licensed CC0.

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