# Studies of Osteoclast Lineage in Health and Diseases

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2022 · $428,406

## Abstract

Although, we know much about the molecular signals that regulate OC function, we know relatively little about
the lineage and mechanisms that OC use to develop from progenitors. The goal of this application is to better
define OC progenitor (OCP) maturation and trafficking and the mechanisms regulating this process in health
and disease so that we can identify potential drug targets to develop superior therapies for bone diseases. The
central hypotheses are: 1) During homeostasis marrow-resident cells are the principal OCP source,
while during inflammation or fracture repair, circulating cells become a significant source of OCP.
2) The mechanisms regulating OCP migration, engraftment and maturation to OC in bone differ
between healthy and disease states. To test these hypotheses, we propose the following aims:
1. Define the role that CX3CR1+ OCP have in OC development during homeostasis and identify
mechanisms regulating their homing, engraftment and maturation to OC:
1A) Perform time course studies in CX3CR1-CreERT2-Ai14 mice at various ages to examine labeled OC
formation kinetics. We will also monitor the kinetics of labeled OCP in the bone marrow, blood and spleen.
1B) The chemokine receptor CX3CR1 is expressed on OCP and has previously been implicated to influence
OCP homing, engraftment and maturation. We will determine its role in OCP lineage development and
trafficking in vivo under homeostatic conditions (when marrow-derived cells predominate as the OCP source)
using CX3CR1-CreERT2-Ai14 mice to generate Cx3cr1 gene deletions.
2. Examine OCP homing from the circulation during bone inflammation and fracture repair.
These studies will examine two disease models in which we previously demonstrated that circulating OCP are
recruited to engraft in bone: TNFa-induced bone inflammation and a repairing fracture.
2A) Study a TNFa-induced inflammatory bone model (a WT parabiont has TNFα injected over its calvaria; the
other parabiont is a CX3CR1-EGFP; TRAP-tdTomato mouse) and determine the rate that circulating labeled
cells home to the inflammatory site, form OC and disappear.
2B) Study a parabiosis fracture model (a WT parabiont receives a femur fracture; the other parabiont is a
CX3CR1-EGFP; TRAP-tdTomato mouse) and determine the rate that circulating labeled cells home to the
repairing callus, form OC and disappear.
2C) Determine the phenotype and kinetics of circulating OCP that home, mature and engraft in bone with
TNFa-induced inflammation or fracture repair by injecting selected populations of OCP from CX3CR1-EGFP;
TRAP-tdTomato mice and monitoring the rates that labeled OC appear and disappear in bone.
2D) Determine the effect that deletion of Cx3cr1 has on the ability of circulating OCP to home, engraft and
mature in bone with TNFa-induced inflammation or a fracture repair using parabiosis and adoptive transfer.

## Key facts

- **NIH application ID:** 10436833
- **Project number:** 5R01AR077534-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Joseph A Lorenzo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $428,406
- **Award type:** 5
- **Project period:** 2021-06-23 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436833

## Citation

> US National Institutes of Health, RePORTER application 10436833, Studies of Osteoclast Lineage in Health and Diseases (5R01AR077534-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436833. Licensed CC0.

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