Peripheral Blood Mononuclear Cell Immunophenotyping in Fibrodysplasia Ossificans Progressiva Patients: Evidence for Monocyte DNAM1 Up‐regulation

Zotto, Genny Del; Antonini, Francesca; Azzari, Irma; Ortolani, Claudio; Tripodi, Gino; Giacopelli, Francesca; Cappato, Serena; Moretta, Alessandro; Ravazzolo, Roberto; Bocciardi, Renata

doi:10.1002/cyto.b.21594

Cited by 13 publications

(13 citation statements)

References 45 publications

(58 reference statements)

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“…Another cohort of FOP patients using a different FACS gating strategy did not find significant differences by monocytes subtype fractionation. However, FOP monocytes expressed higher levels of DNAX accessory molecule 1 (DNAM1), a protein important for monocyte migration through the endothelial barrier, again suggesting a role of monocytes in the early phases of FOP flare-ups (104). Further investigation of this population of CD14 + CD16 + proinflammatory macrophages is warranted.…”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification

Barruet¹,

Morales²,

Cain³

et al. 2018

JCI Insight

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Statistics. All studies were performed with biological replicates as described in Supplemental Tables 1-11. The data were analyzed with GraphPad Prism v.7 software using 2-tailed Student's t test and 2-way ANOVA Sidak or Tukey's multiple comparison tests. The Sidak test was used when comparing means between WT and FOP, and the Tukey test was used when means of both WT and FOP were compared together with other groups. The software R was used for heatmaps and PCA. P < 0.05 were considered statistically significant. Study approvals. All of the human study and sample collection procedures were reviewed and approved by the UCSF Committee on Human Research. All subjects provided informed consent prior to their participation in the study.

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Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification

Barruet¹,

Morales²,

Cain³

et al. 2018

JCI Insight

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“…Increased expression of specific adhesion molecules and cytokine receptors in monocytes such as CXCR4/CD184 and HLA-DR, and in particular of DNAM1/CD226, was observed in patients’ cells compared to control cells. If confirmed in other studies this could extend the cohort of investigated patients, suggesting the existence of a slightly activated state of these cells and would provide indications for new therapeutic targets [ 77 ].…”

Section: Targeting the Immune Systemmentioning

confidence: 72%

“…Recently, a comprehensive immunophenotyping of peripheral blood mononuclear cells (PBMCs) from a set of FOP patients was carried out [ 77 ]. Increased expression of specific adhesion molecules and cytokine receptors in monocytes such as CXCR4/CD184 and HLA-DR, and in particular of DNAM1/CD226, was observed in patients’ cells compared to control cells.…”

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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“…As such, mutations in ACVR1 were identified in DNA sequencing in peripheral blood lymphoblastic lines from FOP donors [ 13 ]. Furthermore, peripheral blood monocytes have been used to profile immune cell populations in FOP [ 84 , 85 , 94 , 95 ]. Skin fibroblasts cultured from 3-mm-thick skin biopsies were reported to exhibit enhanced SMAD1/5 activation in the presence of serum and increased expression of osteogenic markers when cultured under osteogenic conditions [ 96 ].…”

Section: In Vitro Research Platforms Resembling Fopmentioning

confidence: 99%

Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva

et al. 2021

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Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I serine/threonine kinase receptor ALK2, termed activin receptor-like kinase (ALK)2. The mutant ALK2 displays neofunctional responses to activin, a closely related BMP cytokine that normally inhibits regular bone formation. Moreover, the mutant ALK2 becomes hypersensitive to BMPs. Both these activities contribute to enhanced ALK2 signalling and endochondral bone formation in connective tissue. Being a receptor with an extracellular ligand-binding domain and intrinsic intracellular kinase activity, the mutant ALK2 is a druggable target. Although there is no approved cure for FOP yet, a number of clinical trials have been recently initiated, aiming to identify a safe and effective treatment for FOP. Among other targeted approaches, several repurposed drugs have shown promising results. In this review, we describe the molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation. In addition, we recapitulate existing in vitro models to screen for novel compounds with a potential application in FOP. We summarize existing therapeutic alternatives and focus on repositioned drugs in FOP, at preclinical and clinical stages.

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Peripheral Blood Mononuclear Cell Immunophenotyping in Fibrodysplasia Ossificans Progressiva Patients: Evidence for Monocyte DNAM1 Up‐regulation

Cited by 13 publications

References 45 publications

NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification

NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification

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

Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva

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