# Non-hormonal function of locally delivered PTH for rescue of impaired fracture healing

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $468,247

## Abstract

This A1 translational therapeutic research proposal seeks to enhance fracture repair with a locally delivered
parathyroid hormone (hPTH1-34) as a fracture repair enhancing factor in the setting of impaired fracture
healing as seen in diabetic patients, chronic smokers, and elderly people with the goal of avoiding fracture-
associated complications.
Existing literature (Clinical Premise) and our preliminary Data (Scientific Premise) suggest that osteochondral
fracture-activated stem cells (FASCs) are low in number or functionally less robust in elderly patients, T2DM
patients, and chronic smokers than in young healthy subjects.
Although hormones classically act on target cells at the remote sites through secondary messengers or
directly, PTH is a paradoxical hormone. From an endocrine perspective, PTH is well known to have bone
catabolic or anabolic functions depending on high vs. low doses or continuous vs. intermittent systemic
administration. Despite presumed beneficial effects of systemic intermittent PTH treatments on fracture
healing, effects of locally delivered PTH on fracture healing are not well known. It is scientifically logical and
clinically pragmatic to deliver PTH locally at the fracture site if PTH receptors are expressed by the FASCs.
The goal of this research program is to establish a new pragmatic and cost-effective way of enhancing
impaired fracture healing with a locally delivered PTH1-34 that directly boost FASCs with PTH-receptors at the
fracture site during the early critical phase of FASC proliferation and differentiation.
Our preliminary data showed identification of FASCs with PTH receptors; optimization of localized PTH release
kinetics and optimal dose justification in vivo and in vitro; decreased number or function of FASCs and
therapeutic rescue of impaired fracture healing by locally delivered PTH1-34 in elderly, T2DM, or chronic
cigarette-smoking mice; and secondary anabolic BMP2/4 production by locally delivered PTH in vivo.
We posit a central hypothesis that locally delivered PTH results in superior fracture healing by increasing the
population of and enhancing differentiation of Fracture Activated Stem Cells (FASCs) in aged, Type 2 diabetic,
or chronic smoker subject. In order to maximize clinical impact, we will test whether hPTH1-34 enhances
proliferation and early osteo-/chondral/angiogenic-differentiation of FASCs in elderly subjects (Aim 1), in 3
different clinically relevant T2DM mouse models, and chronic cigarette smoking mice (Aim 3).
Our dose-escalated experiments and analysis will be blinded in order to simulate rigorous clinical trials.
Translational innovation and impact lie in establishment of a simple, pragmatic, and cost-effective therapeutic
platform to use locally delivered PTH as a fracture-healing enhancer in impaired fracture healing in aged,
T2DM, and chronic cigarette smoking subjects, which are 3 most commonly seen types of impaired fracture
healing in clinical orthopaedic surgery.

## Key facts

- **NIH application ID:** 10092111
- **Project number:** 5R01AR073607-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Francis Young-In Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $468,247
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092111

## Citation

> US National Institutes of Health, RePORTER application 10092111, Non-hormonal function of locally delivered PTH for rescue of impaired fracture healing (5R01AR073607-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10092111. Licensed CC0.

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