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Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγ(null) mice

Many human viruses, including Epstein-Barr virus (EBV), do not infect mice, which is challenging for biomedical research. We have previously reported that EBV infection induces erosive arthritis, which histologically resembles rheumatoid arthritis, in humanized NOD/Shi-scid/IL-2Rγ(null) (hu-NOG) mic...

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Autores principales: Nagasawa, Yosuke, Takei, Masami, Iwata, Mitsuhiro, Nagatsuka, Yasuko, Tsuzuki, Hiroshi, Imai, Kenichi, Imadome, Ken-Ichi, Fujiwara, Shigeyoshi, Kitamura, Noboru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029598/
https://www.ncbi.nlm.nih.gov/pubmed/33793647
http://dx.doi.org/10.1371/journal.pone.0249340
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author Nagasawa, Yosuke
Takei, Masami
Iwata, Mitsuhiro
Nagatsuka, Yasuko
Tsuzuki, Hiroshi
Imai, Kenichi
Imadome, Ken-Ichi
Fujiwara, Shigeyoshi
Kitamura, Noboru
author_facet Nagasawa, Yosuke
Takei, Masami
Iwata, Mitsuhiro
Nagatsuka, Yasuko
Tsuzuki, Hiroshi
Imai, Kenichi
Imadome, Ken-Ichi
Fujiwara, Shigeyoshi
Kitamura, Noboru
author_sort Nagasawa, Yosuke
collection PubMed
description Many human viruses, including Epstein-Barr virus (EBV), do not infect mice, which is challenging for biomedical research. We have previously reported that EBV infection induces erosive arthritis, which histologically resembles rheumatoid arthritis, in humanized NOD/Shi-scid/IL-2Rγ(null) (hu-NOG) mice; however, the underlying mechanisms are not known. Osteoclast-like multinucleated cells were observed during bone erosion in this mouse model, and therefore, we aimed to determine whether the human or mouse immune system activated bone erosion and analyzed the characteristics and origin of the multinucleated cells in hu-NOG mice. Sections of the mice knee joint tissues were immunostained with anti-human antibodies against certain osteoclast markers, including cathepsin K and matrix metalloproteinase-9 (MMP-9). Multinucleated cells observed during bone erosion stained positively for human cathepsin K and MMP-9. These results indicate that human osteoclasts primarily induce erosive arthritis during EBV infections. Human osteoclast development from hematopoietic stem cells transplanted in hu-NOG mice remains unclear. To confirm their differentiation potential into human osteoclasts, we cultured bone marrow cells of EBV-infected hu-NOG mice and analyzed their characteristics. Multinucleated cells cultured from the bone marrow cells stained positive for human cathepsin K and human MMP-9, indicating that bone marrow cells of hu-NOG mice could differentiate from human osteoclast progenitor cells into human osteoclasts. These results indicate that the human immune response to EBV infection may induce human osteoclast activation and cause erosive arthritis in this mouse model. Moreover, this study is the first, to our knowledge, to demonstrate human osteoclastogenesis in humanized mice. We consider that this model is useful for studying associations of EBV infections with rheumatoid arthritis and human bone metabolism.
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spelling pubmed-80295982021-04-14 Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγ(null) mice Nagasawa, Yosuke Takei, Masami Iwata, Mitsuhiro Nagatsuka, Yasuko Tsuzuki, Hiroshi Imai, Kenichi Imadome, Ken-Ichi Fujiwara, Shigeyoshi Kitamura, Noboru PLoS One Research Article Many human viruses, including Epstein-Barr virus (EBV), do not infect mice, which is challenging for biomedical research. We have previously reported that EBV infection induces erosive arthritis, which histologically resembles rheumatoid arthritis, in humanized NOD/Shi-scid/IL-2Rγ(null) (hu-NOG) mice; however, the underlying mechanisms are not known. Osteoclast-like multinucleated cells were observed during bone erosion in this mouse model, and therefore, we aimed to determine whether the human or mouse immune system activated bone erosion and analyzed the characteristics and origin of the multinucleated cells in hu-NOG mice. Sections of the mice knee joint tissues were immunostained with anti-human antibodies against certain osteoclast markers, including cathepsin K and matrix metalloproteinase-9 (MMP-9). Multinucleated cells observed during bone erosion stained positively for human cathepsin K and MMP-9. These results indicate that human osteoclasts primarily induce erosive arthritis during EBV infections. Human osteoclast development from hematopoietic stem cells transplanted in hu-NOG mice remains unclear. To confirm their differentiation potential into human osteoclasts, we cultured bone marrow cells of EBV-infected hu-NOG mice and analyzed their characteristics. Multinucleated cells cultured from the bone marrow cells stained positive for human cathepsin K and human MMP-9, indicating that bone marrow cells of hu-NOG mice could differentiate from human osteoclast progenitor cells into human osteoclasts. These results indicate that the human immune response to EBV infection may induce human osteoclast activation and cause erosive arthritis in this mouse model. Moreover, this study is the first, to our knowledge, to demonstrate human osteoclastogenesis in humanized mice. We consider that this model is useful for studying associations of EBV infections with rheumatoid arthritis and human bone metabolism. Public Library of Science 2021-04-01 /pmc/articles/PMC8029598/ /pubmed/33793647 http://dx.doi.org/10.1371/journal.pone.0249340 Text en © 2021 Nagasawa et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Nagasawa, Yosuke
Takei, Masami
Iwata, Mitsuhiro
Nagatsuka, Yasuko
Tsuzuki, Hiroshi
Imai, Kenichi
Imadome, Ken-Ichi
Fujiwara, Shigeyoshi
Kitamura, Noboru
Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγ(null) mice
title Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγ(null) mice
title_full Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγ(null) mice
title_fullStr Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγ(null) mice
title_full_unstemmed Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγ(null) mice
title_short Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγ(null) mice
title_sort human osteoclastogenesis in epstein-barr virus-induced erosive arthritis in humanized nod/shi-scid/il-2rγ(null) mice
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029598/
https://www.ncbi.nlm.nih.gov/pubmed/33793647
http://dx.doi.org/10.1371/journal.pone.0249340
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