# The role of efferocytic macrophages in bone formation

> **NIH NIH R56** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $445,583

## Abstract

ABSTRACT
Skeletal disorders such as osteoporosis and fractures are extremely widespread and result in debilitation, high
morbidity, and compromise in quality of life. Remodeling of the skeleton is a continuous process dependent on
osteoblasts to form new mineralized matrix. Mesenchymal stem and progenitor cells (MSPC) and osteoblasts
lining the endosteal surface undergo cell death by apoptosis, yet the consequences of osteoblast-lineage
apoptotic bodies in the bone microenvironment are unknown. The endosteum abuts bone marrow, which is rich
in cells of the myeloid lineage including osteal macrophages that play essential roles in bone development,
tissue homeostasis, and wound healing and repair. A vital function of macrophages is their specialized
phagocytosis of apoptotic cells (termed efferocytosis). In response to efferocytosis macrophages activate a
transcriptional profile, which results in the production of specific cytokines/growth factors unique to the
efferocytosed cell type. Macrophages adapt to environmental changes in correlation with specialized
alterations in their transcriptional profile. The project hypothesis is that bone marrow macrophage efferocytosis
of apoptotic osteoblast-lineage cells induces an inflammation-resolving response including the attraction of
MSPCs to the endosteal surface and new bone formation. Three specific aims will dissect these mechanisms
using novel animal models. Aim one will identify the role of bone marrow macrophages in recruiting MSPCs to
the bone-forming surface. The second aim will elucidate the osteoblastic differentiation stage dependence for
macrophage driven efferocytosis and bone formation using a novel apoptosis induction mouse model that will
target osteoblast cell death in progenitors, differentiated osteoblasts, and mature osteoblast/osteocytes. The
third aim will determine the impact of facilitating macrophage efferocytosis and resolution of inflammation on
bone formation using a specialized pro-resolving mediator lipoxinA4 (LXA4). The impact of LXA4 in the
clearance of apoptotic osteoblast-lineage cells and its ability to modulate inflammation and recruit MSPCs
during osseous healing will be determined. Detailed analyses of bone marrow macrophage function as well as
skeletal phenotyping will provide deeper mechanistic insights as well as translational potential. New cellular
and molecular information will be garnered from this project as well as strategic discernment of bone
remodeling and regeneration to inform therapeutic approaches for metabolic bone disease and local osseous
wound healing.

## Key facts

- **NIH application ID:** 10479430
- **Project number:** 1R56AR077539-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Laurie K. McCauley
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $445,583
- **Award type:** 1
- **Project period:** 2021-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10479430

## Citation

> US National Institutes of Health, RePORTER application 10479430, The role of efferocytic macrophages in bone formation (1R56AR077539-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10479430. Licensed CC0.

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