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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8707819 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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