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Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects

Shwachman–Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, caused by loss-of-function mutations in the SBDS gene, a factor involved in ribosome biogenesis. By analyzing osteoblasts from...

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Autores principales: Frattini, Annalisa, Bolamperti, Simona, Valli, Roberto, Cipolli, Marco, Pinto, Rita Maria, Bergami, Elena, Frau, Maria Rita, Cesaro, Simone, Signo, Michela, Bezzerri, Valentino, Porta, Giovanni, Khan, Abdul Waheed, Rubinacci, Alessandro, Villa, Isabella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707819/
https://www.ncbi.nlm.nih.gov/pubmed/34948128
http://dx.doi.org/10.3390/ijms222413331
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author Frattini, Annalisa
Bolamperti, Simona
Valli, Roberto
Cipolli, Marco
Pinto, Rita Maria
Bergami, Elena
Frau, Maria Rita
Cesaro, Simone
Signo, Michela
Bezzerri, Valentino
Porta, Giovanni
Khan, Abdul Waheed
Rubinacci, Alessandro
Villa, Isabella
author_facet Frattini, Annalisa
Bolamperti, Simona
Valli, Roberto
Cipolli, Marco
Pinto, Rita Maria
Bergami, Elena
Frau, Maria Rita
Cesaro, Simone
Signo, Michela
Bezzerri, Valentino
Porta, Giovanni
Khan, Abdul Waheed
Rubinacci, Alessandro
Villa, Isabella
author_sort Frattini, Annalisa
collection PubMed
description Shwachman–Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, caused by loss-of-function mutations in the SBDS gene, a factor involved in ribosome biogenesis. By analyzing osteoblasts from SDS patients (SDS-OBs), we show that SDS-OBs displayed reduced SBDS gene expression and reduced/undetectable SBDS protein compared to osteoblasts from healthy subjects (H-OBs). SDS-OBs cultured in an osteogenic medium displayed a lower mineralization capacity compared to H-OBs. Whole transcriptome analysis showed significant differences in the gene expression of SDS-OBs vs. H-OBs, particularly in the ossification pathway. SDS-OBs expressed lower levels of the main genes responsible for osteoblastogenesis. Of all downregulated genes, Western blot analyses confirmed lower levels of alkaline phosphatase and collagen type I in SDS-OBs than in H-OBs. Interestingly, SDS-OBs showed higher protein levels of p53, an inhibitor of osteogenesis, compared to H-OBs. Silencing of Tp53 was associated with higher collagen type I and alkaline phosphatase protein levels and an increase in SDS-OB mineralization capacity. In conclusion, our results show that the reduced capacity of SDS-OBs to mineralize is mediated, at least in part, by the high levels of p53 and highlight an important role of SBDS in osteoblast functions.
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spelling pubmed-87078192021-12-25 Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects Frattini, Annalisa Bolamperti, Simona Valli, Roberto Cipolli, Marco Pinto, Rita Maria Bergami, Elena Frau, Maria Rita Cesaro, Simone Signo, Michela Bezzerri, Valentino Porta, Giovanni Khan, Abdul Waheed Rubinacci, Alessandro Villa, Isabella Int J Mol Sci Article Shwachman–Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, caused by loss-of-function mutations in the SBDS gene, a factor involved in ribosome biogenesis. By analyzing osteoblasts from SDS patients (SDS-OBs), we show that SDS-OBs displayed reduced SBDS gene expression and reduced/undetectable SBDS protein compared to osteoblasts from healthy subjects (H-OBs). SDS-OBs cultured in an osteogenic medium displayed a lower mineralization capacity compared to H-OBs. Whole transcriptome analysis showed significant differences in the gene expression of SDS-OBs vs. H-OBs, particularly in the ossification pathway. SDS-OBs expressed lower levels of the main genes responsible for osteoblastogenesis. Of all downregulated genes, Western blot analyses confirmed lower levels of alkaline phosphatase and collagen type I in SDS-OBs than in H-OBs. Interestingly, SDS-OBs showed higher protein levels of p53, an inhibitor of osteogenesis, compared to H-OBs. Silencing of Tp53 was associated with higher collagen type I and alkaline phosphatase protein levels and an increase in SDS-OB mineralization capacity. In conclusion, our results show that the reduced capacity of SDS-OBs to mineralize is mediated, at least in part, by the high levels of p53 and highlight an important role of SBDS in osteoblast functions. MDPI 2021-12-11 /pmc/articles/PMC8707819/ /pubmed/34948128 http://dx.doi.org/10.3390/ijms222413331 Text en © 2021 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
Frattini, Annalisa
Bolamperti, Simona
Valli, Roberto
Cipolli, Marco
Pinto, Rita Maria
Bergami, Elena
Frau, Maria Rita
Cesaro, Simone
Signo, Michela
Bezzerri, Valentino
Porta, Giovanni
Khan, Abdul Waheed
Rubinacci, Alessandro
Villa, Isabella
Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects
title Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects
title_full Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects
title_fullStr Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects
title_full_unstemmed Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects
title_short Enhanced p53 Levels Are Involved in the Reduced Mineralization Capacity of Osteoblasts Derived from Shwachman–Diamond Syndrome Subjects
title_sort enhanced p53 levels are involved in the reduced mineralization capacity of osteoblasts derived from shwachman–diamond syndrome subjects
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707819/
https://www.ncbi.nlm.nih.gov/pubmed/34948128
http://dx.doi.org/10.3390/ijms222413331
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