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Review
. 2024 Mar 16;14(3):357.
doi: 10.3390/biom14030357.

Immunologic Aspects in Fibrodysplasia Ossificans Progressiva

Anastasia Diolintzi  1 , Mst Shaela Pervin  1 , Edward C Hsiao  1
Affiliations
Review

Immunologic Aspects in Fibrodysplasia Ossificans Progressiva

Anastasia Diolintzi et al. Biomolecules. .

Abstract

Background: Inflammation is a major driver of heterotopic ossification (HO), a condition of abnormal bone growth in a site that is not normally mineralized.

Purpose of review: This review will examine recent findings on the roles of inflammation and the immune system in fibrodysplasia ossificans progressiva (FOP). FOP is a genetic condition of aggressive and progressive HO formation. We also examine how inflammation may be a valuable target for the treatment of HO. Rationale/Recent findings: Multiple lines of evidence indicate a key role for the immune system in driving FOP pathogenesis. Critical cell types include macrophages, mast cells, and adaptive immune cells, working through hypoxia signaling pathways, stem cell differentiation signaling pathways, vascular regulatory pathways, and inflammatory cytokines. In addition, recent clinical reports suggest a potential role for immune modulators in the management of FOP.

Future perspectives: The central role of inflammatory mediators in HO suggests that the immune system may be a common target for blocking HO in both FOP and non-genetic forms of HO. Future research focusing on the identification of novel inflammatory targets will help support the testing of potential therapies for FOP and other related conditions.

Keywords: cytokines; fibrodysplasia ossificans progressiva (FOP); heterotopic ossification; immune activation; inflammation; macrophages.

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Conflict of interest statement

ECH serves in a volunteer capacity on the Medical Registry Advisory Board of the International Fibrodysplasia Ossificans Progressiva Association, the International Clinical Council on FOP, and on the Fibrous Dysplasia Foundation Medical Advisory Board. ECH receives clinical trial research support from Ipsen Pharmaceuticals Inc. to support clinical trials in FOP, and from Ascendis Bio for a clinical trial in hypoparathyroidism. These pose no conflicts of interest.

Figures

Figure 1
Figure 1
Potential inflammatory contributors to the pathogenesis of FOP. The ACVR1R206H genetic variant causes osteoprogenitors, such as fibroadipocyte progenitor cells (FAPs) to have an increased ability to enter the osteogenic pathway, possibly due to cell fate instability [49] and the abnormal mechanosensation [50] seen in other cell types. The ACVR1R206H variant also causes innate immune cells to be in a “primed” inflammatory state [20], where a subsequent trigger results in immune hyperactivation. Macrophages appear to be a potential source of activin A [51], which then leads to neo-ligand activation of ACVR1R206H [52], with subsequent tissue inflammation, fibrosis, and endochondral ossification leading to the formation of heterotopic ossification. Figure created with Biorender.
Figure 2
Figure 2
Potential therapies and investigational compounds for FOP and their relation to inflammation. Multiple therapies are being used or developed to treat FOP. These include investigational agents (green), and current medications used for standard of care. Palovarotene is approved by the US Food and Drug Administration and by Health Canada. Therapies that directly target the ACVR1 receptor or signaling pathway will also likely mitigate the inflammatory response induced by the FOP mutation. The long-term goal is to eventually develop strategies by which to reverse or allow for surgical resection of HO in patients with FOP.
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