Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP)

Brennan, Tracy A.; Lindborg, Carter M.; Bergbauer, Christian R.; Wang, Haitao; Kaplan, Frederick S.; Pignolo, Robert J.

doi:10.1016/j.bone.2017.08.023

Cited by 30 publications

(24 citation statements)

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“…(4) Our group further reported that inhibition of mast cell degranulation by cromolyn reduced HO formation. (11) These data support that mast cells are additionally integral to the development of HO.The overlapping inflammatory features among genetic and nongenetic HO disorders has increasingly been confirmed over recent years, and future studies will further clarify commonalities, such as the role of additional cytokines, macrophage polarization, and other immune cell contributions to HO formation. Although it is important to note the unique aspects of FOP pathology, including accelerated cartilage and bone cell differentiation caused by the R206H mutation, (12,13) we fully agree with Levesque and colleagues that the overlapping…”

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confidence: 53%

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Reply to: Macrophages Driving Heterotopic Ossification: Convergence of Genetically-Driven and Trauma-Driven Mechanisms

Convente¹,

Chakkalakal²,

Yang

et al. 2017

Journal of Bone and Mineral Research

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We appreciate the comments by Levesque and colleagues and that they have brought attention to the consistencies between our data using the genetic Acvr1 R206H/+ mouse model of heterotopic ossification (HO) and their model of HO formation in wild-type mice with spinal cord injury (SCI)-induced neurogenic heterotopic ossification (Genet and colleagues (1) and Torossian and colleagues (2) ). We agree that together these studies provide strong support for cytokine production by macrophages as a common inducer of HO.We previously have discussed common immunological contributions among multiple HO disorders, (3) and the investigations of neurogenic heterotopic ossification (NHO) (1,2) importantly emphasize the role of macrophages and identify the cytokine Oncostatin M in a SCI and injury model that faithfully replicates symptoms of NHO. Our study investigating the role of inflammation in the initiation and development of HO in the rare genetic disorder fibrodysplasia ossifications progressiva (FOP) (4) further emphasizes the integral role of inflammation and immune cells in HO pathology.In both our FOP Acvr1 R206H/+ model and the NHO/SCI model, cardiotoxin injury to skeletal muscle was used to induce HO. We identified a robust cellular and molecular inflammatory response to injury in our Acvr1 R206H model of HO (4) with increased presence of innate immune cells, including macrophages and mast cells, as well as increased expression of proinflammatory cytokines, in mutant mice compared to controls. Upon depleting macrophages using clodronate-liposomes-also the same approach used by Genet and colleagues (1) -we likewise observed a significant decrease in HO formation. (4) The relevancy of macrophages and cytokines in the development of HO across multiple disorders is becoming increasingly apparent. In addition to our study and the aforementioned NHO studies, macrophages have been implicated in the development of cardiac HO (5) and in a BMP4 overexpression HO model that showed robustly reduced HO formation in response to clodronate-liposome-mediated depletion of macrophages. (6) Furthermore, IL-6, a cytokine that we determined to be highly upregulated in Acvr1 R206H/+ mutant tissue postinjury and in mast cells, (4) has been previously reported as a predictive biomarker for HO development in blast injury patients, (7,8) as noted in our Discussion. (4) We also want to highlight the contribution of mast cells to HO development in both FOP and nongenetic HO disorders. Genet and colleagues (1) identified Substance P as a secreted factor that was significantly upregulated in human NHO patients, and treatment of their NHO/SCI model with an antagonist of Nk1r (the obligate Substance P receptor) significantly reduced HO volume. Notably, high levels of Substance P have been observed in early lesion biopsies from FOP patients, (9) and inhibition of the Substance P neuroinflammatory pathway impaired HO in BMP4 overexpression and BMP2 implant models. (9,10) Our in vivo results showed that genetic ablation of mast cells in Acvr1 R206H/+...

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confidence: 61%

Reply to: Macrophages Driving Heterotopic Ossification: Convergence of Genetically-Driven and Trauma-Driven Mechanisms

Convente¹,

Chakkalakal²,

Yang

et al. 2017

Journal of Bone and Mineral Research

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“…Also mast cells are massively present in early lesions from FOP patients and in those observed in an injury-mediated mouse model [ 67 , 73 ]. These tissues expressed increased levels of Substance P, a known potent neuro-inflammatory factor, as a consequence of the dysregulated BMP pathway.…”

Section: Targeting the Immune Systemmentioning

confidence: 99%

The Horizon of a Therapy for Rare Genetic Diseases: A “Druggable” Future for Fibrodysplasia Ossificans Progressiva

Cappato

Giacopelli

Ravazzolo

et al. 2018

IJMS

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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition characterized by progressive extra-skeletal ossification leading to cumulative and severe disability. FOP has an extremely variable and episodic course and can be induced by trauma, infections, iatrogenic harms, immunization or can occur in an unpredictable way, without any recognizable trigger. The causative gene is ACVR1, encoding the Alk-2 type I receptor for bone morphogenetic proteins (BMPs). The signaling is initiated by BMP binding to a receptor complex consisting of type I and II molecules and can proceed into the cell through two main pathways, a canonical, SMAD-dependent signaling and a p38-mediated cascade. Most FOP patients carry the recurrent R206H substitution in the receptor Glycine-Serine rich (GS) domain, whereas a few other mutations are responsible for a limited number of cases. Mutations cause a dysregulation of the downstream BMP-dependent pathway and make mutated ACVR1 responsive to a non-canonical ligand, Activin A. There is no etiologic treatment for FOP. However, many efforts are currently ongoing to find specific therapies targeting the receptor activity and the downstream aberrant pathway at different levels or targeting cellular components and/or processes that are important in modifying the local environment leading to bone neo-formation.

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“…Récemment, des travaux ont démontré que l'inhibition des mastocytes pouvait diminuer fortement les formations osseuses hétérotopiques dans un modèle murin de fibrodysplasie ossifiante progressive (FOP, ou maladie de l'homme de pierre), une maladie congénitale rare caractérisée par la transformation des tissus mous (tendons, muscles, ligaments) en os. Aucun traitement n'existe aujourd'hui contre la FOP et la considérer comme une mastocytose localisée pourrait offrir des possibilités thérapeutiques aux patients dans le futur [17]. Les mastocytes font également partie des nombreux types cellulaires qui sont présents au sein, ou à proximité, des tumeurs, dont ils pourraient favoriser la croissance par leurs propriétés pro-angiogéniques et pro-lymphangiogéniques [18].…”

Section: Histamineunclassified

Les mastocytes, stakhanovistes de l’immunité

Milliat

François

2018

Med Sci (Paris)

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Mast cells are immune cells that mature within the host tissue. The acquired phenotype is dictated by the tissue microenvironment, giving rise to diverse tissue-dependent phenotypes and functions. The lack of cellular models reflecting phenotypes found in vivo and important differences between human and rodent mast cells are obstacles to the understanding of their exact role in several pathophysiological processes. Studies published over the past few years showed that mast cells' role lies far beyond their involvement in allergy and anaphylaxis. Studies demonstrating their participation in innate immune responses as well as tissue scaring and vascular pathologies allowed the understanding of their role in several diseases, but also gave contradictory results, especially concerning tissue response to ionizing radiations. Nevertheless, therapeutic tools exist to target mast cells, such as degranulation inhibitors, antihistamine, protease inhibitors or tyrosine kinase receptors antagonists, and may offer some interesting new therapeutic perspectives to manage acute and chronic after-effects of radiation therapy.

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Mast cell inhibition as a therapeutic approach in fibrodysplasia ossificans progressiva (FOP)

Abstract: This work demonstrates that consideration of FOP as a type of localized mastocytosis may offer new therapeutic interventions for treatment of this devastating condition.

Cited by 30 publications

References 33 publications

Reply to: Macrophages Driving Heterotopic Ossification: Convergence of Genetically-Driven and Trauma-Driven Mechanisms

Reply to: Macrophages Driving Heterotopic Ossification: Convergence of Genetically-Driven and Trauma-Driven Mechanisms

The Horizon of a Therapy for Rare Genetic Diseases: A “Druggable” Future for Fibrodysplasia Ossificans Progressiva

Les mastocytes, stakhanovistes de l’immunité

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