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Mechanical Stress Activates Smad Pathway through PKCδ to Enhance Interleukin-11 Gene Transcription in Osteoblasts
BACKGROUND: Mechanical stress rapidly induces ΔFosB expression in osteoblasts, which binds to interleukin (IL)-11 gene promoter to enhance IL-11 expression, and IL-11 enhances osteoblast differentiation. Because bone morphogenetic proteins (BMPs) also stimulate IL-11 expression in osteoblasts, there...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947522/ https://www.ncbi.nlm.nih.gov/pubmed/20927330 http://dx.doi.org/10.1371/journal.pone.0013090 |
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author | Kido, Shinsuke Kuriwaka-Kido, Rika Umino-Miyatani, Yuka Endo, Itsuro Inoue, Daisuke Taniguchi, Hisaaki Inoue, Yasumichi Imamura, Takeshi Matsumoto, Toshio |
author_facet | Kido, Shinsuke Kuriwaka-Kido, Rika Umino-Miyatani, Yuka Endo, Itsuro Inoue, Daisuke Taniguchi, Hisaaki Inoue, Yasumichi Imamura, Takeshi Matsumoto, Toshio |
author_sort | Kido, Shinsuke |
collection | PubMed |
description | BACKGROUND: Mechanical stress rapidly induces ΔFosB expression in osteoblasts, which binds to interleukin (IL)-11 gene promoter to enhance IL-11 expression, and IL-11 enhances osteoblast differentiation. Because bone morphogenetic proteins (BMPs) also stimulate IL-11 expression in osteoblasts, there is a possibility that BMP-Smad signaling is involved in the enhancement of osteoblast differentiation by mechanical stress. The present study was undertaken to clarify whether mechanical stress affects BMP-Smad signaling, and if so, to elucidate the role of Smad signaling in mechanical stress-induced enhancement of IL-11 gene transcription. METHODOLOGY/PRINCIPAL FINDINGS: Mechanical loading by fluid shear stress (FSS) induced phosphorylation of BMP-specific receptor-regulated Smads (BR-Smads), Smad1/5, in murine primary osteoblasts (mPOBs). FSS rapidly phosphorylated Y311 of protein kinase C (PKC)δ, and phosphorylated PKCδ interacted with BR-Smads to phosphorylate BR-Smads. Transfection of PKCδ siRNA or Y311F mutant PKCδ abrogated BR-Smads phosphorylation and suppressed IL-11 gene transcription enhanced by FSS. Activated BR-Smads bound to the Smad-binding element (SBE) of IL-11 gene promoter and formed complex with ΔFosB/JunD heterodimer via binding to the C-terminal region of JunD. Site-directed mutagenesis in the SBE and the AP-1 site revealed that both SBE and AP-1 sites were required for full activation of IL-11 gene promoter by FSS. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that PKCδ-BR-Smads pathway plays an important role in the intracellular signaling in response to mechanical stress, and that a cross-talk between PKCδ-BR-Smads and ΔFosB/JunD pathways synergistically stimulates IL-11 gene transcription in response to mechanical stress. |
format | Text |
id | pubmed-2947522 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29475222010-10-06 Mechanical Stress Activates Smad Pathway through PKCδ to Enhance Interleukin-11 Gene Transcription in Osteoblasts Kido, Shinsuke Kuriwaka-Kido, Rika Umino-Miyatani, Yuka Endo, Itsuro Inoue, Daisuke Taniguchi, Hisaaki Inoue, Yasumichi Imamura, Takeshi Matsumoto, Toshio PLoS One Research Article BACKGROUND: Mechanical stress rapidly induces ΔFosB expression in osteoblasts, which binds to interleukin (IL)-11 gene promoter to enhance IL-11 expression, and IL-11 enhances osteoblast differentiation. Because bone morphogenetic proteins (BMPs) also stimulate IL-11 expression in osteoblasts, there is a possibility that BMP-Smad signaling is involved in the enhancement of osteoblast differentiation by mechanical stress. The present study was undertaken to clarify whether mechanical stress affects BMP-Smad signaling, and if so, to elucidate the role of Smad signaling in mechanical stress-induced enhancement of IL-11 gene transcription. METHODOLOGY/PRINCIPAL FINDINGS: Mechanical loading by fluid shear stress (FSS) induced phosphorylation of BMP-specific receptor-regulated Smads (BR-Smads), Smad1/5, in murine primary osteoblasts (mPOBs). FSS rapidly phosphorylated Y311 of protein kinase C (PKC)δ, and phosphorylated PKCδ interacted with BR-Smads to phosphorylate BR-Smads. Transfection of PKCδ siRNA or Y311F mutant PKCδ abrogated BR-Smads phosphorylation and suppressed IL-11 gene transcription enhanced by FSS. Activated BR-Smads bound to the Smad-binding element (SBE) of IL-11 gene promoter and formed complex with ΔFosB/JunD heterodimer via binding to the C-terminal region of JunD. Site-directed mutagenesis in the SBE and the AP-1 site revealed that both SBE and AP-1 sites were required for full activation of IL-11 gene promoter by FSS. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that PKCδ-BR-Smads pathway plays an important role in the intracellular signaling in response to mechanical stress, and that a cross-talk between PKCδ-BR-Smads and ΔFosB/JunD pathways synergistically stimulates IL-11 gene transcription in response to mechanical stress. Public Library of Science 2010-09-29 /pmc/articles/PMC2947522/ /pubmed/20927330 http://dx.doi.org/10.1371/journal.pone.0013090 Text en Kido 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 Kido, Shinsuke Kuriwaka-Kido, Rika Umino-Miyatani, Yuka Endo, Itsuro Inoue, Daisuke Taniguchi, Hisaaki Inoue, Yasumichi Imamura, Takeshi Matsumoto, Toshio Mechanical Stress Activates Smad Pathway through PKCδ to Enhance Interleukin-11 Gene Transcription in Osteoblasts |
title | Mechanical Stress Activates Smad Pathway through PKCδ to Enhance Interleukin-11 Gene Transcription in Osteoblasts |
title_full | Mechanical Stress Activates Smad Pathway through PKCδ to Enhance Interleukin-11 Gene Transcription in Osteoblasts |
title_fullStr | Mechanical Stress Activates Smad Pathway through PKCδ to Enhance Interleukin-11 Gene Transcription in Osteoblasts |
title_full_unstemmed | Mechanical Stress Activates Smad Pathway through PKCδ to Enhance Interleukin-11 Gene Transcription in Osteoblasts |
title_short | Mechanical Stress Activates Smad Pathway through PKCδ to Enhance Interleukin-11 Gene Transcription in Osteoblasts |
title_sort | mechanical stress activates smad pathway through pkcδ to enhance interleukin-11 gene transcription in osteoblasts |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947522/ https://www.ncbi.nlm.nih.gov/pubmed/20927330 http://dx.doi.org/10.1371/journal.pone.0013090 |
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