# Intercellular Communication in Paget's Disease of Bone

> **NIH NIH R21** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2021 · $216,480

## Abstract

Project Summary
The interactions of osteoblasts (OB) and osteoclasts (OC) during bone remodeling are connected and highly
coordinated. Paget’s Disease of Bone (PDB) is a focal disease in which this coordinated activity has been
disrupted leading to exaggerated bone remodeling. As the second most common metabolic bone disease after
osteoporosis, it affects 1-3% of the U.S. population after age 50. PDB is a genetically heterogeneous disease,
however two strong associations have been linked to PDB: mutations in the Sequestosome 1 (SQSTM1) gene
have been found in familial and somatic PDB and studies have linked PDB with the presence of the measles
virus nucleocapsid protein (MVNP). Studies of the etiology of PDB has largely focused on osteoclast
dysregulation, however, when we examined the somatic form of the disease, our data suggest a self-amplifying
positive feedback loop signaling pathway between the pagetic OB and pagetic OC involving the chemokine
signaling molecules CCL5, CXCL6 and their respective receptors CCR5 and CXCR1 that we hypothesize is
responsible for the etiology of this disease. We found that these changes in chemokine signaling involved OBs
carrying a SQSTM1mut and OCs expressing MVNP. We also found that MVNP-expressing OCs strongly
upregulated a chemokine that attracts OB and pre-OC cells. Moreover, we found that not all the OB cells in the
PDB lesion carried the SQSTM1 mutation suggesting that PDB lesions are composed of a complex mosaic of
OB cell types, in which only a subset carry the SQSTM1 mutation validating the growth-by-recruitment
hypothesis. To test this, we propose three specific aims. Aim 1 will compare genomic expression of pagetic OC
from PDB with and without a SQSTM1 mutation and with and without MVNP expression. Aim 2 will test whether
MVNP-expressing pre-OC cells preferentially migrate in response to signals from SQSTM1mut-expressing OB.
Mixing experiments will use OB with or without a SQSTM1 mutation and pre-OC with or without MVNP
expression to examine chemokine signals directing migration and attraction. Aim 3 will test for a self-amplifying
positive feedback loop model involving MVNP-expressing OC cells amplifying the chemoattractant signals
initiated by SQSTM1mut-carrying OB. Together, this paradigm-shifting research will foster new understanding of
interactions between OB and OC during bone remodeling and disease and potentially open new approaches to
PDB treatment that target only the mutant OB and OC cells.

## Key facts

- **NIH application ID:** 10289153
- **Project number:** 1R21AR079681-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** MARC F HANSEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $216,480
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10289153

## Citation

> US National Institutes of Health, RePORTER application 10289153, Intercellular Communication in Paget's Disease of Bone (1R21AR079681-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10289153. Licensed CC0.

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