# Talking Back: leveraging dysfunctional osteoclasts to identify novel pathways of osteoclast-osteoblast communication

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $232,456

## Abstract

PROJECT SUMMARY
Proper bone structure relies on a complex interplay of molecular signals between bone resorbing osteoclasts
(OCs) and bone forming osteoblasts (OBs). For skeletal integrity to be maintained, bone formation must match
resorption—that is OC must “talk back” to OB. This coupling requires recruitment of osteoprogenitors onto the
resorption surface. This process is perturbed in osteopetrosis (literally, “stone bone”), where bone formation
continues despite dysfunctional OC with very low levels of resorption. The signals coupling resorption to
formation are not fully understood, but appear to require OC.
We describe two new mouse models of dysregulated coupling. Mice with conditional deletion of Nfatc1, the key
driver of the OC transcriptional program, in mature OC (Ctks-Cre;Nfatc1fl/fl, henceforth Nfatc1DOC) have
accumulation of proliferating RUNX2+, alkaline phosphatase-expressing osteoblastic precursors in their marrow.
Mutant OC are both necessary and sufficient for this osteoblastic precursor expansion. We observe a similar
phenomenon in Slc4a2-/- mice, a model of bovine osteopetrosis. Our conceptual innovation is that dysregulated
coupling contributes to osteosclerosis in the settings of dysfunctional OC. This concept leads to our overarching
hypothesis that, despite disparate underlying genetic lesions, dysfunctional OC in Nfatc1DOC mice share a
common molecular derangement of the coupling process with mouse and zebrafish models of osteopetrosis. In
Aim 1, we propose transcriptomic analysis to identify differentially regulated OC-specific transcripts common to
these models as candidate mediators of OC:OB communication. In Aim 2, we test the specific hypothesis that
hematologic impairment in osteopetrosis is caused by OC-dependent obliteration of the marrow space by
osteoblastic precursors, using mouse models and human biopsy samples from individuals with osteopetrosis to
validate our hypothesis in vivo.
These studies leverage technical innovations including the isolation of pure populations of primary OC and
advanced molecular bone histology techniques to interrogate gene expression and are supported by an
outstanding team of collaborators with expertise in OC biology (Dr. Charles), zebrafish genetics and skeletal
development (Dr. Henke), molecular bone histology (Dr. Andersen), and bioinformatic expertise (Center for
Skeletal Research bone sequencing core run by Dr. Warman). This work will provide insight into normal OC:OB
coupling during bone remodeling, with the potential to identify new therapeutic targets for bone diseases where
coupling is either inappropriately low (osteoporosis) or inappropriately high (osteopetrosis).

## Key facts

- **NIH application ID:** 10218407
- **Project number:** 1R21AR077768-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Julia F Charles
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $232,456
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218407

## Citation

> US National Institutes of Health, RePORTER application 10218407, Talking Back: leveraging dysfunctional osteoclasts to identify novel pathways of osteoclast-osteoblast communication (1R21AR077768-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10218407. Licensed CC0.

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