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TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression

Osteoclasts are multinucleated giant cells responsible for bone resorption. Various mediators involved in osteoclast differentiation have been investigated as possible therapeutic targets for osteoporosis and rheumatoid arthritis (RA). Although transforming growth factor beta1 (TGFβ1) has been descr...

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Autores principales: Tokunaga, Tadahiro, Mokuda, Sho, Kohno, Hiroki, Yukawa, Kazutoshi, Kuranobu, Tatsuomi, Oi, Katsuhiro, Yoshida, Yusuke, Hirata, Shintaro, Sugiyama, Eiji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038124/
https://www.ncbi.nlm.nih.gov/pubmed/31991837
http://dx.doi.org/10.3390/ijms21030800
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author Tokunaga, Tadahiro
Mokuda, Sho
Kohno, Hiroki
Yukawa, Kazutoshi
Kuranobu, Tatsuomi
Oi, Katsuhiro
Yoshida, Yusuke
Hirata, Shintaro
Sugiyama, Eiji
author_facet Tokunaga, Tadahiro
Mokuda, Sho
Kohno, Hiroki
Yukawa, Kazutoshi
Kuranobu, Tatsuomi
Oi, Katsuhiro
Yoshida, Yusuke
Hirata, Shintaro
Sugiyama, Eiji
author_sort Tokunaga, Tadahiro
collection PubMed
description Osteoclasts are multinucleated giant cells responsible for bone resorption. Various mediators involved in osteoclast differentiation have been investigated as possible therapeutic targets for osteoporosis and rheumatoid arthritis (RA). Although transforming growth factor beta1 (TGFβ1) has been described as one such multifunctional cytokine essential for bone remodeling, its effect on osteoclastogenesis remains controversial. Therefore, we sought to examine the effect of TGFβ1 on osteoclast generation induced by receptor activator of nuclear factor (NF)-κB ligand (RANKL) in humans. Peripheral blood monocytes, isolated using magnetic bead sorting, were cultured with macrophage-colony stimulating factor (M-CSF) or RANKL with or without TGFβ1. Tartrate-resistant acid phosphatase (TRAP) staining, as well as bone resorption assays, revealed that TGFβ1 suppressed RANKL-mediated human osteoclast development. Real-time reverse transcription PCR and Western blotting revealed that TGFβ1 reduced the gene and protein expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), the master regulator of osteoclast differentiation, respectively. Luciferase assays indicated that TGFβ1 inhibited the NF-κB p65-stimulated promoter activity of NFATc1. Immunofluorescence analysis demonstrated that TGFβ1 abrogated RANKL-induced nuclear translocation of p65. Thus, TGFβ1 regulates human RANKL-induced osteoclastogenesis via downregulation of NFATc1 by blocking nuclear translocation of NF-κB, suggesting that TGFβ1 may be a potential therapeutic target for RA.
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spelling pubmed-70381242020-03-10 TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression Tokunaga, Tadahiro Mokuda, Sho Kohno, Hiroki Yukawa, Kazutoshi Kuranobu, Tatsuomi Oi, Katsuhiro Yoshida, Yusuke Hirata, Shintaro Sugiyama, Eiji Int J Mol Sci Article Osteoclasts are multinucleated giant cells responsible for bone resorption. Various mediators involved in osteoclast differentiation have been investigated as possible therapeutic targets for osteoporosis and rheumatoid arthritis (RA). Although transforming growth factor beta1 (TGFβ1) has been described as one such multifunctional cytokine essential for bone remodeling, its effect on osteoclastogenesis remains controversial. Therefore, we sought to examine the effect of TGFβ1 on osteoclast generation induced by receptor activator of nuclear factor (NF)-κB ligand (RANKL) in humans. Peripheral blood monocytes, isolated using magnetic bead sorting, were cultured with macrophage-colony stimulating factor (M-CSF) or RANKL with or without TGFβ1. Tartrate-resistant acid phosphatase (TRAP) staining, as well as bone resorption assays, revealed that TGFβ1 suppressed RANKL-mediated human osteoclast development. Real-time reverse transcription PCR and Western blotting revealed that TGFβ1 reduced the gene and protein expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), the master regulator of osteoclast differentiation, respectively. Luciferase assays indicated that TGFβ1 inhibited the NF-κB p65-stimulated promoter activity of NFATc1. Immunofluorescence analysis demonstrated that TGFβ1 abrogated RANKL-induced nuclear translocation of p65. Thus, TGFβ1 regulates human RANKL-induced osteoclastogenesis via downregulation of NFATc1 by blocking nuclear translocation of NF-κB, suggesting that TGFβ1 may be a potential therapeutic target for RA. MDPI 2020-01-25 /pmc/articles/PMC7038124/ /pubmed/31991837 http://dx.doi.org/10.3390/ijms21030800 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tokunaga, Tadahiro
Mokuda, Sho
Kohno, Hiroki
Yukawa, Kazutoshi
Kuranobu, Tatsuomi
Oi, Katsuhiro
Yoshida, Yusuke
Hirata, Shintaro
Sugiyama, Eiji
TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression
title TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression
title_full TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression
title_fullStr TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression
title_full_unstemmed TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression
title_short TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression
title_sort tgfβ1 regulates human rankl-induced osteoclastogenesis via suppression of nfatc1 expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038124/
https://www.ncbi.nlm.nih.gov/pubmed/31991837
http://dx.doi.org/10.3390/ijms21030800
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