# Fate and Regulation of Fracture-induced Prx1 Cells

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2021 · $333,017

## Abstract

PROJECT SUMMARY
Fracture healing is a well-orchestrated regenerative process that remains largely unknown. Revealing the cellular
and molecular mechanisms governing fracture repair will help identify novel therapeutic targets to treat patients
that suffer of non-unions, a clinically relevant problem that affects annually 600,000 people in the United States.
Bone autografts, the gold-standard treatment for non-unions, have multiple drawbacks: they are invasive, costly,
risky, and sometime ineffective. Therefore, there is an urgent and unmet need for alternative and novel therapies
to treat non-unions. The ultimate goal of this proposal is to gain new knowledge on pivotal mechanisms driving
fracture repair and to devise them to promote healing. The highly regenerative ability of bones after fracture
implies the existence of adult progenitors that contribute to the reparative process. However, the nature and the
expression pattern of these progenitors is still elusive. We have discovered a discrete population of perivascular
cells expressing Prx1 (Prx1+) that reside in recognized regenerative niches. By investigating functionality, we
have found that facture elicits Prx1expression and Prx1+ expressing cells that contribute to the fracture repair
process, but cells lose Prx1 expression with differentiation. We have also found that during fracture repair, Prx1+
cells co-express BMP2 and CXCL12. On the way to further explore this crosstalk, we discovered that the
impaired fracture healing found in mice lacking a full complement of BMP2 in Prx1 osteochondroprogenitors,
was characterized by an abnormally persistent increase of Prx1 and the cytokine CXCL12. These abnormalities
were corrected by AMD3100, a CXCL12 receptor antagonist that restored healing. Lastly, by using in vivo and
in vitro approaches, we have indicated that BMP2 through CXCL12 signaling regulates Prx1 expression. Current
knowledge and these exciting novel observations set the scientific premise to the central hypothesis of
this proposal, namely that Prx1 expressing cells are a crossroad in fracture repair and their commitment
to regeneration and their Prx1 expression pattern is regulated by a well-timed interplay between BMP2
and CXCL12. Two specific aims are proposed to test this novel hypothesis. Aim 1 is designed to determine the
requirement of Prx1 and Prx1 expressing cells and their fate and nature during fracture repair. Aim 2 is designed
to determine the mechanisms by which the expression of Prx1 and the fate of Prx1+ cells is regulated by the
interplay between BMP2 and CXCL12 during fracture repair. A comprehensive approach will be applied to
accomplish the proposed aims, by combining generation of ad hoc genetically engineered mice; cell-tracing;
educated use of animal models; pharmacological and cell transplant studies; and in vitro studies. A team of
expert research investigators has been assembled to ensure successful achievement of the project. It is
expected that the novel...

## Key facts

- **NIH application ID:** 10179322
- **Project number:** 5R01AR074049-04
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Anna Spagnoli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $333,017
- **Award type:** 5
- **Project period:** 2020-03-25 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179322

## Citation

> US National Institutes of Health, RePORTER application 10179322, Fate and Regulation of Fracture-induced Prx1 Cells (5R01AR074049-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10179322. Licensed CC0.

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