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: Articulo
Lenguaje:Inglés
Publicado: 2023
Materias:
Biología
Gaucher disease
bone
monocytes
osteoclasts
inflammation
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/161002
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-161002
record_format dspace
spelling I19-R120-10915-1610022023-12-01T20:06:59Z http://sedici.unlp.edu.ar/handle/10915/161002 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 2023 2023-12-01T15:00:47Z en Biología Gaucher disease bone monocytes osteoclasts inflammation 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. Instituto de Estudios Inmunológicos y Fisiopatológicos Articulo Articulo http://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International (CC BY 4.0) application/pdf
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Biología
Gaucher disease
bone
monocytes
osteoclasts
inflammation
spellingShingle Biología
Gaucher disease
bone
monocytes
osteoclasts
inflammation
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
topic_facet Biología
Gaucher disease
bone
monocytes
osteoclasts
inflammation
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.
format Articulo
Articulo
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
title 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_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_sort exploring the pathophysiologic cascade leading to osteoclastogenic activation in gaucher disease monocytes generated via crispr/cas9 technology
publishDate 2023
url http://sedici.unlp.edu.ar/handle/10915/161002
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