# Molecular and cellular mechanisms of heterotopic ossification

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $660,277

## Abstract

PROJECT SUMMARY/ABSTRACT
Heterotopic ossification (HO), the formation of ectopic endochondral bone in skeletal muscle and soft
tissues, is a significant cause of morbidity from joint immobility and pain. The precise mechanisms
responsible for HO are not known; however, its association with trauma, inflammation and
biomechanical stress suggests a process of disordered injury repair and homeostasis. We have
explored the underlying mechanisms of a monogenic cause of HO, fibrodysplasia ossificans
progressiva (FOP), caused by activating mutations of the bone morphogenetic protein (BMP) type I
receptor ALK2, whereas trauma-induced HO appears to be regulated by ALK2, ALK3 and potentially
ALK6. FOP and acquired forms of HO share a common mechanism of inappropriate BMP signaling,
but the manner by which BMP signals are interpreted to regulate ossification versus tissue
regeneration remain incompletely understood. Significant gaps exist in how combinatorial BMP/TGFb
signal transduction specifies diverse functions and cell fates in multipotent lineages. To address
these mechanistic gaps, an innovative chemical biology platform has been devised using human-
derived MSC that have been edited by CRISPR/Cas9 techniques, combined with a novel BMP/TGF-b
pharmacologic probe identified from an active NCATS-TRND collaboration. This platform will permit
the unequivocal mapping of individual ligand and receptor signaling, and the downstream impact on
MSC plasticity in a non-overexpressed human cell system. This assay provides a platform for a high
throughput screen to be performed with collaborators at NCATS-TRND to identify mechanistically
novel modulators of ALK2, ALK3 and ALK6. Finally, insights and candidate molecules identified from
these studies will be validated in a conditional knock-in mouse model of FOP, and in an authentic
mouse model of trauma- and inflammation-induced HO. These studies will provide critical tools and
insights into how the BMP signaling pathway contributes to pathologic tissue remodeling in
musculoskeletal and degenerative disease, as well as in a broader set of conditions in which HO is
associated with senescence, inflammation, and metabolic stress. New assay technologies, tool
compounds, and translatable insights will be produced as a result of this work that will be relevant to
many other disease-oriented fields of study.

## Key facts

- **NIH application ID:** 10005031
- **Project number:** 5R01AR057374-08
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** PAUL B YU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $660,277
- **Award type:** 5
- **Project period:** 2010-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005031

## Citation

> US National Institutes of Health, RePORTER application 10005031, Molecular and cellular mechanisms of heterotopic ossification (5R01AR057374-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10005031. Licensed CC0.

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