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Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology

Gaucher disease (GD) is caused by biallelic pathogenic variants in the acid β-glucosidase gene (GBA1), leading to a deficiency in the β-glucocerebrosidase (GCase) enzyme activity resulting in the intracellular accumulation of sphingolipids. Skeletal alterations are one of the most disabling features...

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Autores principales: Ormazabal, Maximiliano Emanuel, Pavan, Eleonora, Vaena, Emilio, Ferino, Dania, Biasizzo, Jessica, Mucci, Juan Marcos, Serra, Fabrizio, Cifù, Adriana, Scarpa, Maurizio, Rozenfeld, Paula Adriana, Dardis, Andrea Elena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10342917/
https://www.ncbi.nlm.nih.gov/pubmed/37446383
http://dx.doi.org/10.3390/ijms241311204
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author Ormazabal, Maximiliano Emanuel
Pavan, Eleonora
Vaena, Emilio
Ferino, Dania
Biasizzo, Jessica
Mucci, Juan Marcos
Serra, Fabrizio
Cifù, Adriana
Scarpa, Maurizio
Rozenfeld, Paula Adriana
Dardis, Andrea Elena
author_facet Ormazabal, Maximiliano Emanuel
Pavan, Eleonora
Vaena, Emilio
Ferino, Dania
Biasizzo, Jessica
Mucci, Juan Marcos
Serra, Fabrizio
Cifù, Adriana
Scarpa, Maurizio
Rozenfeld, Paula Adriana
Dardis, Andrea Elena
author_sort Ormazabal, Maximiliano Emanuel
collection PubMed
description Gaucher disease (GD) is caused by biallelic pathogenic variants in the acid β-glucosidase gene (GBA1), leading to a deficiency in the β-glucocerebrosidase (GCase) enzyme activity resulting in the intracellular accumulation of sphingolipids. Skeletal alterations are one of the most disabling features in GD patients. Although both defective bone formation and increased bone resorption due to osteoblast and osteoclast dysfunction contribute to GD bone pathology, the molecular bases are not fully understood, and bone disease is not completely resolved with currently available specific therapies. For this reason, using editing technology, our group has developed a reliable, isogenic, and easy-to-handle cellular model of GD monocytes (GBAKO-THP1) to facilitate GD pathophysiology studies and high-throughput drug screenings. In this work, we further characterized the model showing an increase in proinflammatory cytokines (Interleukin-1β and Tumor Necrosis Factor-α) release and activation of osteoclastogenesis. Furthermore, our data suggest that GD monocytes would display an increased osteoclastogenic potential, independent of their interaction with the GD microenvironment or other GD cells. Both proinflammatory cytokine production and osteoclastogenesis were restored at least, in part, by treating cells with the recombinant human GCase, a substrate synthase inhibitor, a pharmacological chaperone, and an anti-inflammatory compound. Besides confirming that this model would be suitable to perform high-throughput screening of therapeutic molecules that act via different mechanisms and on different phenotypic features, our data provided insights into the pathogenic cascade, leading to osteoclastogenesis exacerbation and its contribution to bone pathology in GD.
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spelling pubmed-103429172023-07-14 Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology Ormazabal, Maximiliano Emanuel Pavan, Eleonora Vaena, Emilio Ferino, Dania Biasizzo, Jessica Mucci, Juan Marcos Serra, Fabrizio Cifù, Adriana Scarpa, Maurizio Rozenfeld, Paula Adriana Dardis, Andrea Elena Int J Mol Sci Article Gaucher disease (GD) is caused by biallelic pathogenic variants in the acid β-glucosidase gene (GBA1), leading to a deficiency in the β-glucocerebrosidase (GCase) enzyme activity resulting in the intracellular accumulation of sphingolipids. Skeletal alterations are one of the most disabling features in GD patients. Although both defective bone formation and increased bone resorption due to osteoblast and osteoclast dysfunction contribute to GD bone pathology, the molecular bases are not fully understood, and bone disease is not completely resolved with currently available specific therapies. For this reason, using editing technology, our group has developed a reliable, isogenic, and easy-to-handle cellular model of GD monocytes (GBAKO-THP1) to facilitate GD pathophysiology studies and high-throughput drug screenings. In this work, we further characterized the model showing an increase in proinflammatory cytokines (Interleukin-1β and Tumor Necrosis Factor-α) release and activation of osteoclastogenesis. Furthermore, our data suggest that GD monocytes would display an increased osteoclastogenic potential, independent of their interaction with the GD microenvironment or other GD cells. Both proinflammatory cytokine production and osteoclastogenesis were restored at least, in part, by treating cells with the recombinant human GCase, a substrate synthase inhibitor, a pharmacological chaperone, and an anti-inflammatory compound. Besides confirming that this model would be suitable to perform high-throughput screening of therapeutic molecules that act via different mechanisms and on different phenotypic features, our data provided insights into the pathogenic cascade, leading to osteoclastogenesis exacerbation and its contribution to bone pathology in GD. MDPI 2023-07-07 /pmc/articles/PMC10342917/ /pubmed/37446383 http://dx.doi.org/10.3390/ijms241311204 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ormazabal, Maximiliano Emanuel
Pavan, Eleonora
Vaena, Emilio
Ferino, Dania
Biasizzo, Jessica
Mucci, Juan Marcos
Serra, Fabrizio
Cifù, Adriana
Scarpa, Maurizio
Rozenfeld, Paula Adriana
Dardis, Andrea Elena
Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology
title Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology
title_full Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology
title_fullStr Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology
title_full_unstemmed Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology
title_short Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology
title_sort exploring the pathophysiologic cascade leading to osteoclastogenic activation in gaucher disease monocytes generated via crispr/cas9 technology
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10342917/
https://www.ncbi.nlm.nih.gov/pubmed/37446383
http://dx.doi.org/10.3390/ijms241311204
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