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Flrt2 is involved in fine-tuning of osteoclast multinucleation

Osteoclasts are multinucleated giant cells derived from myeloid progenitors. Excessive bone resorption by osteoclasts can result in serious clinical outcomes for which better treatment options are needed. Here, we identified fibronectin leucine-rich transmembrane protein 2 (Flrt2), a ligand of the U...

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Autores principales: Shirakawa, Jumpei, Takegahara, Noriko, Kim, Hyunsoo, Lee, Seoung Hoon, Sato, Kohji, Yamagishi, Satoru, Choi, Yongwon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Society for Biochemistry and Molecular Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726208/
https://www.ncbi.nlm.nih.gov/pubmed/31383250
http://dx.doi.org/10.5483/BMBRep.2019.52.8.116
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author Shirakawa, Jumpei
Takegahara, Noriko
Kim, Hyunsoo
Lee, Seoung Hoon
Sato, Kohji
Yamagishi, Satoru
Choi, Yongwon
author_facet Shirakawa, Jumpei
Takegahara, Noriko
Kim, Hyunsoo
Lee, Seoung Hoon
Sato, Kohji
Yamagishi, Satoru
Choi, Yongwon
author_sort Shirakawa, Jumpei
collection PubMed
description Osteoclasts are multinucleated giant cells derived from myeloid progenitors. Excessive bone resorption by osteoclasts can result in serious clinical outcomes for which better treatment options are needed. Here, we identified fibronectin leucine-rich transmembrane protein 2 (Flrt2), a ligand of the Unc5 receptor family for neurons, as a novel target associated with the late/maturation stage of osteoclast differentiation. Flrt2 expression is induced by stimulation with receptor activator of nuclear factor-kB ligand (RANKL). Flrt2 deficiency in osteoclasts results in reduced hyper-multinucleation, which could be restored by RNAi-mediated knockdown of Unc5b. Treatment with Netrin1, another ligand of Unc5b which negatively controls osteoclast multinucleation through down regulation of RANKL-induced Rac1 activation, showed no inhibitory effects on Flrt2-deficient cells. In addition, RANKL-induced Rac1 activation was attenuated in Flrt2-deficient cells. Taken together, these results suggest that Flrt2 regulates osteoclast multinucleation by interfering with Netrin 1-Unc5b interaction and may be a suitable therapeutic target for diseases associated with bone remodeling.
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spelling pubmed-67262082019-09-09 Flrt2 is involved in fine-tuning of osteoclast multinucleation Shirakawa, Jumpei Takegahara, Noriko Kim, Hyunsoo Lee, Seoung Hoon Sato, Kohji Yamagishi, Satoru Choi, Yongwon BMB Rep Articles Osteoclasts are multinucleated giant cells derived from myeloid progenitors. Excessive bone resorption by osteoclasts can result in serious clinical outcomes for which better treatment options are needed. Here, we identified fibronectin leucine-rich transmembrane protein 2 (Flrt2), a ligand of the Unc5 receptor family for neurons, as a novel target associated with the late/maturation stage of osteoclast differentiation. Flrt2 expression is induced by stimulation with receptor activator of nuclear factor-kB ligand (RANKL). Flrt2 deficiency in osteoclasts results in reduced hyper-multinucleation, which could be restored by RNAi-mediated knockdown of Unc5b. Treatment with Netrin1, another ligand of Unc5b which negatively controls osteoclast multinucleation through down regulation of RANKL-induced Rac1 activation, showed no inhibitory effects on Flrt2-deficient cells. In addition, RANKL-induced Rac1 activation was attenuated in Flrt2-deficient cells. Taken together, these results suggest that Flrt2 regulates osteoclast multinucleation by interfering with Netrin 1-Unc5b interaction and may be a suitable therapeutic target for diseases associated with bone remodeling. Korean Society for Biochemistry and Molecular Biology 2019-08 2019-08-31 /pmc/articles/PMC6726208/ /pubmed/31383250 http://dx.doi.org/10.5483/BMBRep.2019.52.8.116 Text en Copyright © 2019 by the The Korean Society for Biochemistry and Molecular Biology This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Shirakawa, Jumpei
Takegahara, Noriko
Kim, Hyunsoo
Lee, Seoung Hoon
Sato, Kohji
Yamagishi, Satoru
Choi, Yongwon
Flrt2 is involved in fine-tuning of osteoclast multinucleation
title Flrt2 is involved in fine-tuning of osteoclast multinucleation
title_full Flrt2 is involved in fine-tuning of osteoclast multinucleation
title_fullStr Flrt2 is involved in fine-tuning of osteoclast multinucleation
title_full_unstemmed Flrt2 is involved in fine-tuning of osteoclast multinucleation
title_short Flrt2 is involved in fine-tuning of osteoclast multinucleation
title_sort flrt2 is involved in fine-tuning of osteoclast multinucleation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726208/
https://www.ncbi.nlm.nih.gov/pubmed/31383250
http://dx.doi.org/10.5483/BMBRep.2019.52.8.116
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