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A molecular basis for neurofibroma-associated skeletal manifestations in NF1
PURPOSE: Plexiform neurofibromas (NF) develop in children with Neurofibromatosis Type 1 (NF1) and can be associated with several skeletal co-morbidities. Preclinical mouse studies revealed Nf1 deficiency in osteoprogenitor cells disrupts, in a MEK-dependent manner, pyrophosphate (PPi) homeostasis an...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106869/ https://www.ncbi.nlm.nih.gov/pubmed/32601387 http://dx.doi.org/10.1038/s41436-020-0885-3 |
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author | Ma, Yun Gross, Andrea Dombi, Eva Pemov, Alex Choi, Kwangmin Chaney, Katherine Rhodes, Steven D. Angus, Steven P Sciaky, Noah Clapp, D Wade Ratner, Nancy Widemann, Brigitte C Rios, Jonathan J Elefteriou, Florent |
author_facet | Ma, Yun Gross, Andrea Dombi, Eva Pemov, Alex Choi, Kwangmin Chaney, Katherine Rhodes, Steven D. Angus, Steven P Sciaky, Noah Clapp, D Wade Ratner, Nancy Widemann, Brigitte C Rios, Jonathan J Elefteriou, Florent |
author_sort | Ma, Yun |
collection | PubMed |
description | PURPOSE: Plexiform neurofibromas (NF) develop in children with Neurofibromatosis Type 1 (NF1) and can be associated with several skeletal co-morbidities. Preclinical mouse studies revealed Nf1 deficiency in osteoprogenitor cells disrupts, in a MEK-dependent manner, pyrophosphate (PPi) homeostasis and skeletal mineralization. The etiology of NF-associated skeletal manifestations remains unknown. METHODS: We used mouse models of NF1 neurofibromas to assess bone mineralization of skeletal structures adjacent to tumors. Expression of genes involved in pyrophosphate homeostasis was assessed in mouse and human NF tumors and Schwann cell cultures. We used Dual-energy X-ray Absorptiometry (DXA) to assess tumor-associated changes in bone mineral density (BMD) in an individual with NF1 following treatment with the MEK inhibitor selumetinib. RESULTS: We detected increased non-mineralized bone surfaces adjacent to tumors in mouse models of NF1 neurofibromas. Expression of Enpp1, a PPi-generating ectophosphatase, and ANKH, a PPi transporter, was increased in mouse and human neurofibroma-derived tissues and Schwann cells, respectively. In one patient, tumor-associated reductions in BMD were partially rescued following therapy with selumetinib. CONCLUSION: Results indicate that NF-associated skeletal pathologies in NF1 are associated with dysregulated pyrophosphate homeostasis in adjacent NF tumors and suggest that treatment of NFs with MEK inhibitors may improve skeletal manifestations of the disease. |
format | Online Article Text |
id | pubmed-8106869 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-81068692021-05-09 A molecular basis for neurofibroma-associated skeletal manifestations in NF1 Ma, Yun Gross, Andrea Dombi, Eva Pemov, Alex Choi, Kwangmin Chaney, Katherine Rhodes, Steven D. Angus, Steven P Sciaky, Noah Clapp, D Wade Ratner, Nancy Widemann, Brigitte C Rios, Jonathan J Elefteriou, Florent Genet Med Article PURPOSE: Plexiform neurofibromas (NF) develop in children with Neurofibromatosis Type 1 (NF1) and can be associated with several skeletal co-morbidities. Preclinical mouse studies revealed Nf1 deficiency in osteoprogenitor cells disrupts, in a MEK-dependent manner, pyrophosphate (PPi) homeostasis and skeletal mineralization. The etiology of NF-associated skeletal manifestations remains unknown. METHODS: We used mouse models of NF1 neurofibromas to assess bone mineralization of skeletal structures adjacent to tumors. Expression of genes involved in pyrophosphate homeostasis was assessed in mouse and human NF tumors and Schwann cell cultures. We used Dual-energy X-ray Absorptiometry (DXA) to assess tumor-associated changes in bone mineral density (BMD) in an individual with NF1 following treatment with the MEK inhibitor selumetinib. RESULTS: We detected increased non-mineralized bone surfaces adjacent to tumors in mouse models of NF1 neurofibromas. Expression of Enpp1, a PPi-generating ectophosphatase, and ANKH, a PPi transporter, was increased in mouse and human neurofibroma-derived tissues and Schwann cells, respectively. In one patient, tumor-associated reductions in BMD were partially rescued following therapy with selumetinib. CONCLUSION: Results indicate that NF-associated skeletal pathologies in NF1 are associated with dysregulated pyrophosphate homeostasis in adjacent NF tumors and suggest that treatment of NFs with MEK inhibitors may improve skeletal manifestations of the disease. 2020-06-30 2020-11 /pmc/articles/PMC8106869/ /pubmed/32601387 http://dx.doi.org/10.1038/s41436-020-0885-3 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Ma, Yun Gross, Andrea Dombi, Eva Pemov, Alex Choi, Kwangmin Chaney, Katherine Rhodes, Steven D. Angus, Steven P Sciaky, Noah Clapp, D Wade Ratner, Nancy Widemann, Brigitte C Rios, Jonathan J Elefteriou, Florent A molecular basis for neurofibroma-associated skeletal manifestations in NF1 |
title | A molecular basis for neurofibroma-associated skeletal manifestations in NF1 |
title_full | A molecular basis for neurofibroma-associated skeletal manifestations in NF1 |
title_fullStr | A molecular basis for neurofibroma-associated skeletal manifestations in NF1 |
title_full_unstemmed | A molecular basis for neurofibroma-associated skeletal manifestations in NF1 |
title_short | A molecular basis for neurofibroma-associated skeletal manifestations in NF1 |
title_sort | molecular basis for neurofibroma-associated skeletal manifestations in nf1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106869/ https://www.ncbi.nlm.nih.gov/pubmed/32601387 http://dx.doi.org/10.1038/s41436-020-0885-3 |
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