# Mechanobiology of Progenitor Cells in Heterotopic Ossification

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $328,511

## Abstract

Abstract
Although rare genetic disorders directly impact relatively small segments of the population, they are caused by
mutations in genes with such critical importance that perturbed function is rarely tolerated, and therefore offer
unique insight into fundamental cellular mechanisms. One such disease, fibrodysplasia ossificans progressiva
(FOP), is caused by misregulated control of cell fate decisions that leads to congenital skeletal malformations
and disabling extra-skeletal (heterotopic) endochondral ossification (HO) that often forms in response to tissue
injury. Notably, this de novo bone formation is associated with an impaired muscle repair response. We
identified that all familial and sporadic cases with classic features of FOP carry the same heterozygous
mutation in ACVR1/ALK2 (R206H; c.617G>A), a cell surface receptor that mediates signal transduction of
bone morphogenetic proteins (BMPs). Our data showed that the ACVR1 R206H mutant receptors mildly
activate the BMP signaling pathway in the presence or absence of BMP ligands. This proposal seeks to
identify how the resulting gain of function in ACVR1/BMP signaling diverts the program of muscle repair from
one that normally culminates in restoration of muscle tissue to one in which muscle injury leads to
differentiation of endogenous mesenchymal progenitor cells (MSCs) to chondrocytes and osteoblasts and the
formation of heterotopic bone tissue. Previous studies confirmed cell autonomous effects of the mutation on
MSC differentiation, however, while the mutation enhances MSC chondro/osteogenesis, we have also
established that mutant cells do not spontaneously differentiate, but require additional signals. Since
commitment and differentiation of tissue-resident progenitor cells is regulated by signals from the tissue
microenvironment, and the tissue microenvironment is itself defined by matrix production by these
differentiating cells, this proposal focuses on how enhanced BMP pathway signaling in FOP changes cellular
interpretation and fabrication of the biomechanical environment during muscle repair. Based on our preliminary
data showing altered physical (mechanical) properties of mutant skeletal muscle tissue following injury, this
proposal will first investigate and identify the mechanisms (cellularity, matrix, and stiffness) through which
ACVR1 R206H mutant tissue alters the connective tissue microenvironment during the early response to
muscle injury (Aim 1). Next, we will examine the mechano-sensing signaling mechanisms through which
chondro/osseous mesenchymal (non-myogenic) progenitor cells (MSCs) differentially sense and interpret
signals from their microenvironment (Aim 2). Finally, we will determine the effects of the mutant tissue
microenvironment on endogenous myogenic muscle progenitor cells (MuSCs, Aim 3). Together, these data will
identify novel mechano-regulatory mechanisms controlling cell differentiation in heterotopic ossification and
muscle repair and as well as r...

## Key facts

- **NIH application ID:** 10169259
- **Project number:** 5R01AR071399-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Robert L Mauck
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $328,511
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169259

## Citation

> US National Institutes of Health, RePORTER application 10169259, Mechanobiology of Progenitor Cells in Heterotopic Ossification (5R01AR071399-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10169259. Licensed CC0.

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