# Diversity Supplement:  Talking Back:  Leveraging dysfunctional osteoclasts to identify novel pathways of osteoclast-osteoblast communication

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $31,120

## Abstract

Project Summary
Proper bone structure relies on a complex interplay of molecular signals between bone resorbing osteoclasts
(OCs) and bone forming osteoblasts (OBs). The integral role of OB lineage cells in OC formation, through
production of receptor activator of NF-kB ligand (RANKL) and osteoprotegrin, is well described. However, for
skeletal integrity to be maintained, bone formation must be matched to resorption - that is, OC must “talk back”
to OB. While the mechanism of osteoclast:osteoblast coupling is poorly understood, it is clear that dysregulation
of this interaction results in bone disease. At one end of the spectrum, resorption exceeds formation resulting in
the common and costly osteoporosis and fractures. At the other end of the spectrum, bone formation continues
despite dysfunctional OC with very low levels of resorption, resulting in OC-rich osteopetrosis (literally, “stone
bone”). This rare family of diseases is characterized by abnormally dense, osteosclerotic bone. In its autosomal
recessive form, osteopetrosis is potentially fatal due to stromal cell infiltration of the bone marrow and marrow
failure. The parent R21 proposal seeks to obtain critical experimental support for the hypothesis that studying
dysfunctional OC:OB coupling in osteopetrosis will reveal novel molecular mechanisms driving excess bone
formation and replacement of the marrow niche with OC-misdirected OB. The proposed supplement project
extends the analysis of osteopetrosis models to incorporate a mouse model of the very recently identified
osteopetrosis due to mutations in SLC4A2.

## Key facts

- **NIH application ID:** 10518427
- **Project number:** 3R21AR077768-02S1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Julia F Charles
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $31,120
- **Award type:** 3
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518427

## Citation

> US National Institutes of Health, RePORTER application 10518427, Diversity Supplement:  Talking Back:  Leveraging dysfunctional osteoclasts to identify novel pathways of osteoclast-osteoblast communication (3R21AR077768-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10518427. Licensed CC0.

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