# Function of Fibro-Adipogenic Progenitors in Heterotopic Ossification of Skeletal Muscle

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2021 · $334,965

## Abstract

Project Summary
 Heterotopic ossification (HO), the formation of bone in skeletal muscle and associated soft tissues, can
result from traumatic injury or disease. The most extreme form of HO is manifested in the rare, autosomal-
dominant genetic disorder, Fibrodysplasia ossificans progressiva (FOP), in which HO continues progressively
throughout life, resulting in devastating effects on health and life expectancy. We developed a new genetic model
of FOP based on conditional expression of the disease-causing BMP receptor, Acvr1(R206H). Using this model,
we identified fibro-adipogenic progenitors (FAPs), a multipotent mesenchymal progenitor in muscle tissue, as
the disease-causing cell population. Notably, we have shown that intramuscular injection of BMP2 into wild type
mice also leads to FAP-derived HO, suggesting mechanistic similarities of HO pathogenesis in FOP patients and
the general population. Studies of HO have focused almost entirely on mechanisms of bone growth, yet severe
muscle loss can be a significant contributing factor to patient morbidity. The overarching objectives of this
research are to 1) understand how FAP programming becomes subverted for pathological bone formation; 2)
understand how regeneration is inhibited in skeletal muscle susceptible to HO; 3) determine whether HO of
skeletal muscle is entirely dependent on FAPs. By targeting Acvr1R206H expression to FAPs using PdgrfαCreER
and Tie2-Cre drivers, Aim 1 will quantify regeneration impairment, and will determine whether muscle stem cell
(satellite cell; SC) dysfunction is responsible for regeneration deficits. These studies will quantify SC proliferation
and apoptosis after muscle injury and will define the SC mRNA transcriptome. Aim 1 will also determine whether
Acvr1(R206H) expression in FAPs disrupts FAP-SC interactions. Aim 2 will use RNA-Seq to define the FAP
transcriptome at early, critical, times after injury to identify gene targets of Acvr1(R206H) signaling. Gro-Seq
(Genome-wide Run-On) analyses will quantify changes in active gene transcription, will identify candidate genes
regulated by promoter-proximal polymerase pausing, and will identify potential enhancer targets of
Acvr1(R206H) signaling. Lineage tracing will determine whether the abnormal muscle environment differentially
affects the fate of normal and mutant FAPs. In Aim 3, DTA ablation approaches will determine whether FAPs
are the sole source of osteogenic cells in muscle, information that is essential for evaluating the possible efficacy
of cell-specific therapies. Activin inhibition has recently emerged as a powerful potential therapy for FOP. Aim 4
will use lineage tracing to address how Activin blockade affects proliferation, survival and developmental capacity
of FAPs and SCs. RNA-Seq will define the extent to which Activin inhibition “normalizes” FAP and SC
transcriptomes. The proposed research will contribute significantly to an understanding of the cells and cellular
interactions responsible f...

## Key facts

- **NIH application ID:** 10218059
- **Project number:** 5R01AR072052-05
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** DAVID J GOLDHAMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $334,965
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218059

## Citation

> US National Institutes of Health, RePORTER application 10218059, Function of Fibro-Adipogenic Progenitors in Heterotopic Ossification of Skeletal Muscle (5R01AR072052-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10218059. Licensed CC0.

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