Cellular and Molecular Mechanisms of Heterotopic Ossification in Fibrodysplasia Ossificans Progressiva

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a debilitating genetic disorder characterized by recurrent episodes of heterotopic ossification (HO) formation in muscles, tendons, and ligaments. FOP is caused by a missense mutation in the ACVR1 gene (activin A receptor type I), an important signaling receptor involved in endochondral ossification. The ACVR1^R206H mutation induces increased downstream canonical SMAD-signaling and drives tissue-resident progenitor cells with osteogenic potential to participate in endochondral HO formation. In this article, we review aberrant ACVR1^R206H signaling and the cells that give rise to HO in FOP. FOP mouse models and lineage tracing analyses have been used to provide strong evidence for tissue-resident mesenchymal cells as cellular contributors to HO. We assess how the underlying mutation in FOP disrupts muscle-specific dynamics during homeostasis and repair, with a focus on muscle-resident mesenchymal cells known as fibro-adipogenic progenitors (FAPs). Accumulating research points to FAPs as a prominent HO progenitor population, with ACVR1^R206H FAPs not only aberrantly differentiating into chondro-osteogenic lineages but creating a permissive environment for bone formation at the expense of muscle regeneration. We will further discuss the emerging role of ACVR1^R206H FAPs in muscle regeneration and therapeutic targeting of these cells to reduce HO formation in FOP.

Keywords: ACVR1 mutation; FOP; HO progenitor cells; fibro-adipogenic progenitors; heterotopic ossification; muscle regeneration; musculoskeletal disease.

Figure 1

ACVR1 mutations and dysregulated downstream signaling in FOP. (A) Heterotetrameric receptor complex of BMP type II receptors (pink) and BMP type I receptors, ACVR1 (purple). ACVR1 has 4 domains, an extracellular (EC) binding domain, where ligands can bind and induce or inhibit downstream signaling, and a transmembrane (TM) domain. Known FOP causative mutations occur in the glycine–serine (GS) rich activation domain and the protein kinase (PK) domain. Both the GS and PK domains are important for downstream signaling activation. The most recurrent mutation found in FOP patients is R206H (red), located in the GS domain. (B) ACVR1^R206H-mediated signaling in FOP. Signaling can be ligand-dependent (BMPs/Activin A) as depicted here or ligand-independent (not shown). Canonically, ACVR1^R206H hyperactivity induces increased SMAD1/5/8 phosphorylation and SMAD complex localization into the nucleus, ultimately increasing the expression of target osteogenic genes. Non-canonically, ACVR1^R206H induces PI3K-AKT-mTOR signaling; increases p38 phosphorylation and activity, later activating downstream transcription factor targets (i.e., RUNX2); and increases RhoA activation and mediated downstream effectors to increase YAP/TAZ nuclear localization to induce HO formation. Negative regulation by FKBP12 is affected and reduced in ACVR1^R206H by changes in binding affinity. Abbreviations: phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), runt-related transcription factor 2 (RUNX2), Ras homolog gene family member A (RhoA), yes-associated protein (YAP), tafazzin (TAZ), and 12-kDa FK506-binding protein (FKBP12). Created with BioRender.com.

Figure 2

Model for FOP muscle regeneration. After muscle injury, quiescent ACVR1^R206H FAPs become activated and proliferate. However, abnormal FAP-derived soluble secretions decrease ACVR1^R206H MuSC myogenic commitment and ability to fuse to pre-existing myofibers. At the same time, there is increased immune cell infiltration, while FAPs resist macrophage-derived TNFa-mediated apoptosis and continue to accumulate within the FOP tissue, giving rise to aberrant osteochondrogenesis. This leads to reduced muscle regeneration and increased heterotopic ossification in FOP tissue. Created with BioRender.com.