Cargando…

Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway

Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, we reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical “dripping candle wax” melorheostosis. We now report somatic SMAD3 mutations in bone lesions of four...

Descripción completa

Detalles Bibliográficos
Autores principales: Kang, Heeseog, Jha, Smita, Ivovic, Aleksandra, Fratzl-Zelman, Nadja, Deng, Zuoming, Mitra, Apratim, Cabral, Wayne A., Hanson, Eric P., Lange, Eileen, Cowen, Edward W., Katz, James, Roschger, Paul, Klaushofer, Klaus, Dale, Ryan K., Siegel, Richard M., Bhattacharyya, Timothy, Marini, Joan C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201932/
https://www.ncbi.nlm.nih.gov/pubmed/32232430
http://dx.doi.org/10.1084/jem.20191499
_version_ 1783529636399939584
author Kang, Heeseog
Jha, Smita
Ivovic, Aleksandra
Fratzl-Zelman, Nadja
Deng, Zuoming
Mitra, Apratim
Cabral, Wayne A.
Hanson, Eric P.
Lange, Eileen
Cowen, Edward W.
Katz, James
Roschger, Paul
Klaushofer, Klaus
Dale, Ryan K.
Siegel, Richard M.
Bhattacharyya, Timothy
Marini, Joan C.
author_facet Kang, Heeseog
Jha, Smita
Ivovic, Aleksandra
Fratzl-Zelman, Nadja
Deng, Zuoming
Mitra, Apratim
Cabral, Wayne A.
Hanson, Eric P.
Lange, Eileen
Cowen, Edward W.
Katz, James
Roschger, Paul
Klaushofer, Klaus
Dale, Ryan K.
Siegel, Richard M.
Bhattacharyya, Timothy
Marini, Joan C.
author_sort Kang, Heeseog
collection PubMed
description Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, we reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical “dripping candle wax” melorheostosis. We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis. In vitro, the SMAD3 mutations stimulated the TGF-β pathway in osteoblasts, enhanced nuclear translocation and target gene expression, and inhibited proliferation. Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation–positive melorheostosis. Conversely, osteoblast differentiation and mineralization were inhibited when osteogenesis of affected osteoblasts was driven in the presence of BMP2. Transcriptome profiling displayed that TGF-β pathway activation and ossification-related processes were significantly influenced by the SMAD3 mutation. Co-expression clustering illuminated melorheostosis pathophysiology, including alterations in ECM organization, cell growth, and interferon signaling. These data reveal antagonism of TGF-β/SMAD3 activation by BMP signaling in SMAD3 mutation–positive endosteal melorheostosis, which may guide future therapies.
format Online
Article
Text
id pubmed-7201932
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-72019322020-11-04 Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway Kang, Heeseog Jha, Smita Ivovic, Aleksandra Fratzl-Zelman, Nadja Deng, Zuoming Mitra, Apratim Cabral, Wayne A. Hanson, Eric P. Lange, Eileen Cowen, Edward W. Katz, James Roschger, Paul Klaushofer, Klaus Dale, Ryan K. Siegel, Richard M. Bhattacharyya, Timothy Marini, Joan C. J Exp Med Article Melorheostosis is a rare sclerosing dysostosis characterized by asymmetric exuberant bone formation. Recently, we reported that somatic mosaicism for MAP2K1-activating mutations causes radiographical “dripping candle wax” melorheostosis. We now report somatic SMAD3 mutations in bone lesions of four unrelated patients with endosteal pattern melorheostosis. In vitro, the SMAD3 mutations stimulated the TGF-β pathway in osteoblasts, enhanced nuclear translocation and target gene expression, and inhibited proliferation. Osteoblast differentiation and mineralization were stimulated by the SMAD3 mutation, consistent with higher mineralization in affected than in unaffected bone, but differing from MAP2K1 mutation–positive melorheostosis. Conversely, osteoblast differentiation and mineralization were inhibited when osteogenesis of affected osteoblasts was driven in the presence of BMP2. Transcriptome profiling displayed that TGF-β pathway activation and ossification-related processes were significantly influenced by the SMAD3 mutation. Co-expression clustering illuminated melorheostosis pathophysiology, including alterations in ECM organization, cell growth, and interferon signaling. These data reveal antagonism of TGF-β/SMAD3 activation by BMP signaling in SMAD3 mutation–positive endosteal melorheostosis, which may guide future therapies. Rockefeller University Press 2020-03-31 /pmc/articles/PMC7201932/ /pubmed/32232430 http://dx.doi.org/10.1084/jem.20191499 Text en © 2020 Kang et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Kang, Heeseog
Jha, Smita
Ivovic, Aleksandra
Fratzl-Zelman, Nadja
Deng, Zuoming
Mitra, Apratim
Cabral, Wayne A.
Hanson, Eric P.
Lange, Eileen
Cowen, Edward W.
Katz, James
Roschger, Paul
Klaushofer, Klaus
Dale, Ryan K.
Siegel, Richard M.
Bhattacharyya, Timothy
Marini, Joan C.
Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway
title Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway
title_full Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway
title_fullStr Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway
title_full_unstemmed Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway
title_short Somatic SMAD3-activating mutations cause melorheostosis by up-regulating the TGF-β/SMAD pathway
title_sort somatic smad3-activating mutations cause melorheostosis by up-regulating the tgf-β/smad pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201932/
https://www.ncbi.nlm.nih.gov/pubmed/32232430
http://dx.doi.org/10.1084/jem.20191499
work_keys_str_mv AT kangheeseog somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT jhasmita somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT ivovicaleksandra somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT fratzlzelmannadja somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT dengzuoming somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT mitraapratim somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT cabralwaynea somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT hansonericp somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT langeeileen somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT cowenedwardw somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT katzjames somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT roschgerpaul somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT klaushoferklaus somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT daleryank somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT siegelrichardm somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT bhattacharyyatimothy somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway
AT marinijoanc somaticsmad3activatingmutationscausemelorheostosisbyupregulatingthetgfbsmadpathway