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FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling

Most cartilaginous tumors are formed during skeletal development in locations adjacent to growth plates, suggesting that they arise from disordered endochondral bone growth. Fibroblast growth factor receptor (FGFR)3 signaling plays essential roles in this process; however, the role of FGFR3 in carti...

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Autores principales: Zhou, Siru, Xie, Yangli, Tang, Junzhou, Huang, Junlan, Huang, Qizhao, Xu, Wei, Wang, Zuqiang, Luo, Fengtao, Wang, Quan, Chen, Hangang, Du, Xiaolan, Shen, Yue, Chen, Di, Chen, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4474636/
https://www.ncbi.nlm.nih.gov/pubmed/26091072
http://dx.doi.org/10.1371/journal.pgen.1005214
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author Zhou, Siru
Xie, Yangli
Tang, Junzhou
Huang, Junlan
Huang, Qizhao
Xu, Wei
Wang, Zuqiang
Luo, Fengtao
Wang, Quan
Chen, Hangang
Du, Xiaolan
Shen, Yue
Chen, Di
Chen, Lin
author_facet Zhou, Siru
Xie, Yangli
Tang, Junzhou
Huang, Junlan
Huang, Qizhao
Xu, Wei
Wang, Zuqiang
Luo, Fengtao
Wang, Quan
Chen, Hangang
Du, Xiaolan
Shen, Yue
Chen, Di
Chen, Lin
author_sort Zhou, Siru
collection PubMed
description Most cartilaginous tumors are formed during skeletal development in locations adjacent to growth plates, suggesting that they arise from disordered endochondral bone growth. Fibroblast growth factor receptor (FGFR)3 signaling plays essential roles in this process; however, the role of FGFR3 in cartilaginous tumorigenesis is not known. In this study, we found that postnatal chondrocyte-specific Fgfr3 deletion induced multiple chondroma-like lesions, including enchondromas and osteochondromas, adjacent to disordered growth plates. The lesions showed decreased extracellular signal-regulated kinase (ERK) activity and increased Indian hedgehog (IHH) expression. The same was observed in Fgfr3-deficient primary chondrocytes, in which treatment with a mitogen-activated protein kinase (MEK) inhibitor increased Ihh expression. Importantly, treatment with an inhibitor of IHH signaling reduced the occurrence of chondroma-like lesions in Fgfr3-deficient mice. This is the first study reporting that the loss of Fgfr3 function leads to the formation of chondroma-like lesions via downregulation of MEK/ERK signaling and upregulation of IHH, suggesting that FGFR3 has a tumor suppressor-like function in chondrogenesis.
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spelling pubmed-44746362015-06-30 FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling Zhou, Siru Xie, Yangli Tang, Junzhou Huang, Junlan Huang, Qizhao Xu, Wei Wang, Zuqiang Luo, Fengtao Wang, Quan Chen, Hangang Du, Xiaolan Shen, Yue Chen, Di Chen, Lin PLoS Genet Research Article Most cartilaginous tumors are formed during skeletal development in locations adjacent to growth plates, suggesting that they arise from disordered endochondral bone growth. Fibroblast growth factor receptor (FGFR)3 signaling plays essential roles in this process; however, the role of FGFR3 in cartilaginous tumorigenesis is not known. In this study, we found that postnatal chondrocyte-specific Fgfr3 deletion induced multiple chondroma-like lesions, including enchondromas and osteochondromas, adjacent to disordered growth plates. The lesions showed decreased extracellular signal-regulated kinase (ERK) activity and increased Indian hedgehog (IHH) expression. The same was observed in Fgfr3-deficient primary chondrocytes, in which treatment with a mitogen-activated protein kinase (MEK) inhibitor increased Ihh expression. Importantly, treatment with an inhibitor of IHH signaling reduced the occurrence of chondroma-like lesions in Fgfr3-deficient mice. This is the first study reporting that the loss of Fgfr3 function leads to the formation of chondroma-like lesions via downregulation of MEK/ERK signaling and upregulation of IHH, suggesting that FGFR3 has a tumor suppressor-like function in chondrogenesis. Public Library of Science 2015-06-19 /pmc/articles/PMC4474636/ /pubmed/26091072 http://dx.doi.org/10.1371/journal.pgen.1005214 Text en © 2015 Zhou et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zhou, Siru
Xie, Yangli
Tang, Junzhou
Huang, Junlan
Huang, Qizhao
Xu, Wei
Wang, Zuqiang
Luo, Fengtao
Wang, Quan
Chen, Hangang
Du, Xiaolan
Shen, Yue
Chen, Di
Chen, Lin
FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling
title FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling
title_full FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling
title_fullStr FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling
title_full_unstemmed FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling
title_short FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling
title_sort fgfr3 deficiency causes multiple chondroma-like lesions by upregulating hedgehog signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4474636/
https://www.ncbi.nlm.nih.gov/pubmed/26091072
http://dx.doi.org/10.1371/journal.pgen.1005214
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