Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
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
_version_ 1783689848360534016
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
work_keys_str_mv AT mayun amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT grossandrea amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT dombieva amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT pemovalex amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT choikwangmin amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT chaneykatherine amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT rhodesstevend amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT angusstevenp amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT sciakynoah amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT clappdwade amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT ratnernancy amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT widemannbrigittec amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT riosjonathanj amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT elefteriouflorent amolecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT mayun molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT grossandrea molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT dombieva molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT pemovalex molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT choikwangmin molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT chaneykatherine molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT rhodesstevend molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT angusstevenp molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT sciakynoah molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT clappdwade molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT ratnernancy molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT widemannbrigittec molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT riosjonathanj molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1
AT elefteriouflorent molecularbasisforneurofibromaassociatedskeletalmanifestationsinnf1