Editors' ChoiceHETEROTOPIC OSSIFICATION

Problems with mast transit

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Science Translational Medicine  13 Sep 2017:
Vol. 9, Issue 407, eaao6125
DOI: 10.1126/scitranslmed.aao6125

Abstract

Mast cell inhibition prevents heterotopic ossification in a model of fibrodysplasia ossificans progressiva.

Whereas excessive people in mass transit causes inflamed tempers, excessive mast cell transit or mastocytosis, causes severe inflammation and even anaphylaxis. Mast cells are a type of white blood cells that play a key role in inflammatory responses by secreting inflammatory mediators, but their role in heterotopic ossification (HO), present in people living with fibrodysplasia ossificans progressiva (FOP), is less well defined. A recent study by Pignolo and colleagues characterizes the mastocytosis present in heterotopic ossification lesions.

Inflammation has been shown to play a central role in traumatic and genetic forms of heterotopic ossification. Several anti-inflammatory treatments have been effective in preventing HO in promising preclinical studies. Additionally, steroids have been a mainstay in attempts to combat new HO lesions or exacerbations in people living with FOP. Despite this known role of inflammatory cells, few studies exist characterizing the inflammatory cells involved and their functions at the HO site. The authors of this study used a ligand-independent FOP mouse model with hyperactivation of bone morphogenetic protein signaling in which adenovirus and cardiotoxin are injected to stimulate HO formation in the hind limb. Mast cell inhibitors/stabilizers, such as cromolyn, significantly diminished the number of mast cells and prevented HO formation in this model. Specifically, they demonstrated a decrease in total, resting, and degranulating mast cells with cromolyn treatment. Conversely, the use of aprepitant, a substance P/neurokinin1 receptor antagonist, did not decrease mast cell number or HO formation, which is surprising given previous studies implicating the role of sensory nerves and substance P.

This study importantly focuses on the role of nonresident inflammatory cells rather than local HO progenitor cells to better define the HO niche. The authors pretreat the animals, which makes the findings harder to translate to trauma patients; however, treatment could be used as a suppressive strategy for FOP. Based on these findings, researchers can now consider targeting mast cells with therapeutics, such as cromolyn, in attempts to quell the inflammatory niche necessary for HO and to improve the quality of life of those living with FOP. Future studies to identify the specific substance the mast cells secrete that exacerbates these HO lesions would be a significant step forward in our understanding of FOP.

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