# Resolving the mechanism of osteoclast multinucleation and signaling in bone remodeling

> **NIH NIH R00** · UNIVERSITY OF VIRGINIA · 2024 · $249,000

## Abstract

PROJECT SUMMARY:
Essential, life-long bone remodeling is coordinated by osteoclasts (OCs) that resorb old bone and osteoblasts
that deposit new bone. Elevated OC formation/function erodes excess bone, weakens the skeleton, and
underpins bone disease in >200 million individuals world-wide. Mononucleated preOCs fuse and form
multinucleated OCs through a formative process – multinucleation. OC multinucleation regulates how much
bone OCs resorb and is often elevated in OC-based bone disease. Despite its role in skeletal health and
disease, how OC multinucleation is regulated remains poorly understood. We discovered that lupus la protein’s
(La) expression, cleavage, and trafficking to the plasma membrane (PM) regulate OC fusion, multinucleation,
and bone resorption. Moreover, our preliminary findings demonstrate that inhibiting PM La during OC
multinucleation suppresses the progression of OC-based bone disease. Resolving the mechanism of OC
multinucleation will fill fundamental gaps in our understanding of skeletal health, identify pathways perturbed in
disease, and establish novel therapeutic targets for preventing bone loss.
In this study, we will resolve the mechanism by which La regulates OC multinucleation (Aims 1 & 3) and employ
a novel, ex vivo model to characterize the contribution of perturbed OC-to-osteoblast signaling in the progression
of OC-based bone disease. First, we will use a semi-automated peptide screening assay to identify the La
domain that facilitates its regulatory function in OC multinucleation (Aim 1). Second, we will resolve how La
traffics to the OC PM to promote multinucleation, is removed and degraded to stop multinucleation, and how
perturbed La membrane trafficking contributes to the uncontrolled multinucleation observed in SNX10-linked
infantile osteopetrosis (Aim 3). Finally, we find that ectopic OC multinucleation in fibrous dysplasia, an OC-based
bone disease, leads to excessive OC signaling and disease related changes in preosteoblasts. In Aim 2, we will
characterize perturbed OC signaling in a novel ex vivo model of fibrous dysplasia, assess its impact on
preosteoblast function, and test whether perturbed OC-to-osteoblast signaling contributes to disease
progression in vivo. This research firmly aligns with NICHD’s mission to resolve fundamental gaps in our
understanding of life-long human development and will identify novel targets and test treatment strategies for
addressing the childhood bone diseases fibrous dysplasia and infantile osteopetrosis. In addition to completing
the proposed aims, I will gain critical experience in the implementation of in vivo models to study the development
of bone diseases, machine learning approaches for studying osteoclast multinucleation, and effective mentorship
and management strategies for leading my independent laboratory. My proposed aims will generate new
research directions, and my career development, networking, and training goals will prepare me to become a
leading ind...

## Key facts

- **NIH application ID:** 11138921
- **Project number:** 4R00HD110609-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Jarred Marcus Whitlock
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11138921

## Citation

> US National Institutes of Health, RePORTER application 11138921, Resolving the mechanism of osteoclast multinucleation and signaling in bone remodeling (4R00HD110609-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11138921. Licensed CC0.

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