# The contribution of innate immunity to heterotopic ossification in fibrodysplasia ossificans progressiva

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $443,285

## Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare, currently untreatable, congenital disease in which
skeletal muscle repair is redirected to endochondral bone formation (heterotopic ossification, HO) causing
pain, muscle destruction, and joint fusion, leading to progressive immobilization and eventually premature
death. FOP is caused by a mutation in Alk2 (most commonly R206H) that renders the receptor sensitive to
aberrant activation by Activin A (ActA). However, the “flares” that lead to HO appear to be initiated by
inflammatory insults, and HO can be reduced in FOP mice by depletion of inflammatory innate immune cells
including macrophages. Fibroadipoprogenitors (FAPs), residing in the muscle interstitium appear to be the
critical precursors of chondrocytes in FOP. However, in healthy muscle repair, macrophages secrete TNFα at
a critical time to trigger apoptosis of FAPs. The fact that FAPs survive and differentiate into chondrocytes
suggests their interaction with macrophages is disrupted in FOP. Therefore, this proposal will explore the
hypothesis that pro-inflammatory M1-like and anti-inflammatory M2-like macrophages are critical sources of
cytokines that enable survival and expansion of the chondrogenic fibroadipoprogenitors in FOP. Specifically,
it seeks to determine whether macrophages are a critical source of ActA and what signals pathways in FAPS
are disrupted to block their normal apoptotic fate. These studies will be the first to explore the mechanisms by
which macrophages interact with chondrogenic FAPs to support chondrogenesis and HO, and they will provide
critical insights to the early stages of FOP flares.

## Key facts

- **NIH application ID:** 9971465
- **Project number:** 5R01AR073874-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Daniel S Perrien
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $443,285
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971465

## Citation

> US National Institutes of Health, RePORTER application 9971465, The contribution of innate immunity to heterotopic ossification in fibrodysplasia ossificans progressiva (5R01AR073874-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971465. Licensed CC0.

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