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 TNF? 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.

Public Health Relevance

Fibrodysplasia ossificans progressiva is a rare disease characterized by heterotopic ossification of skeletal muscles that leads to immobilization. This project aims to understand Activin A- and TNF?-mediated interactions between macrophages and chondrocyte progenitors in the skeletal muscle during the early stage of HO.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR073874-02
Application #
9782698
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Chen, Faye H
Project Start
2018-09-10
Project End
2023-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232