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Characterization and Function of Tumor Necrosis Factor and Interleukin‐6–Induced Osteoclasts in Rheumatoid Arthritis
OBJECTIVE: We have previously reported that stimulation of mouse bone marrow–derived macrophages with tumor necrosis factor (TNF) and interleukin‐6 (IL‐6) induces differentiation of osteoclast‐like cells. We undertook this study to clarify the characterization and function of human TNF and IL‐6–indu...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361923/ https://www.ncbi.nlm.nih.gov/pubmed/33512089 http://dx.doi.org/10.1002/art.41666 |
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author | Yokota, Kazuhiro Sato, Kojiro Miyazaki, Takashi Aizaki, Yoshimi Tanaka, Shinya Sekikawa, Miyoko Kozu, Noritsune Kadono, Yuho Oda, Hiromi Mimura, Toshihide |
author_facet | Yokota, Kazuhiro Sato, Kojiro Miyazaki, Takashi Aizaki, Yoshimi Tanaka, Shinya Sekikawa, Miyoko Kozu, Noritsune Kadono, Yuho Oda, Hiromi Mimura, Toshihide |
author_sort | Yokota, Kazuhiro |
collection | PubMed |
description | OBJECTIVE: We have previously reported that stimulation of mouse bone marrow–derived macrophages with tumor necrosis factor (TNF) and interleukin‐6 (IL‐6) induces differentiation of osteoclast‐like cells. We undertook this study to clarify the characterization and function of human TNF and IL‐6–induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors. METHODS: Peripheral blood monocytes were cultured with a combination of TNF and IL‐6, TNF alone, IL‐6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL‐6–induced osteoclasts or RANKL‐induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole‐body bone mineral density (BMD) was examined. RESULTS: Peripheral blood monocytes stimulated with a TNF and IL‐6–induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL‐6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL‐6–induced osteoclast formation. Expression levels of IL1β, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL‐6–induced osteoclasts, but not in RANKL‐induced osteoclasts. The number of TNF and IL‐6–induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL‐induced osteoclast numbers negatively correlated with the whole‐body BMD of the same patients. CONCLUSION: Our results demonstrate that TNF and IL‐6–induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA. |
format | Online Article Text |
id | pubmed-8361923 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83619232021-08-17 Characterization and Function of Tumor Necrosis Factor and Interleukin‐6–Induced Osteoclasts in Rheumatoid Arthritis Yokota, Kazuhiro Sato, Kojiro Miyazaki, Takashi Aizaki, Yoshimi Tanaka, Shinya Sekikawa, Miyoko Kozu, Noritsune Kadono, Yuho Oda, Hiromi Mimura, Toshihide Arthritis Rheumatol Rheumatoid Arthritis OBJECTIVE: We have previously reported that stimulation of mouse bone marrow–derived macrophages with tumor necrosis factor (TNF) and interleukin‐6 (IL‐6) induces differentiation of osteoclast‐like cells. We undertook this study to clarify the characterization and function of human TNF and IL‐6–induced osteoclasts using peripheral blood collected from patients with rheumatoid arthritis (RA) and healthy donors. METHODS: Peripheral blood monocytes were cultured with a combination of TNF and IL‐6, TNF alone, IL‐6 alone, or with RANKL, and their bone resorption ability was evaluated. Expression levels of NFATc1, proinflammatory cytokines, and matrix metalloproteinase 3 were analyzed. The effects of NFAT inhibitor and JAK inhibitor were examined. Furthermore, the relationship between the number of TNF and IL‐6–induced osteoclasts or RANKL‐induced osteoclasts differentiated from peripheral blood mononuclear cells (PBMCs) in patients with RA and the modified total Sharp score (mTSS) or whole‐body bone mineral density (BMD) was examined. RESULTS: Peripheral blood monocytes stimulated with a TNF and IL‐6–induced osteoclasts were shown to demonstrate the ability to absorb bone matrix. Cell differentiation was not inhibited by the addition of osteoprotegerin. Stimulation with a combination of TNF and IL‐6 promoted NFATc1 expression, whereas the NFAT and JAK inhibitors prevented TNF and IL‐6–induced osteoclast formation. Expression levels of IL1β, TNF, IL12p40, and MMP3 were significantly increased in TNF and IL‐6–induced osteoclasts, but not in RANKL‐induced osteoclasts. The number of TNF and IL‐6–induced osteoclasts differentiated from PBMCs in patients with RA positively correlated with the mTSS, whereas RANKL‐induced osteoclast numbers negatively correlated with the whole‐body BMD of the same patients. CONCLUSION: Our results demonstrate that TNF and IL‐6–induced osteoclasts may contribute to the pathology of inflammatory arthritis associated with joint destruction, such as RA. John Wiley and Sons Inc. 2021-05-27 2021-07 /pmc/articles/PMC8361923/ /pubmed/33512089 http://dx.doi.org/10.1002/art.41666 Text en © 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Rheumatoid Arthritis Yokota, Kazuhiro Sato, Kojiro Miyazaki, Takashi Aizaki, Yoshimi Tanaka, Shinya Sekikawa, Miyoko Kozu, Noritsune Kadono, Yuho Oda, Hiromi Mimura, Toshihide Characterization and Function of Tumor Necrosis Factor and Interleukin‐6–Induced Osteoclasts in Rheumatoid Arthritis |
title | Characterization and Function of Tumor Necrosis Factor and Interleukin‐6–Induced Osteoclasts in Rheumatoid Arthritis |
title_full | Characterization and Function of Tumor Necrosis Factor and Interleukin‐6–Induced Osteoclasts in Rheumatoid Arthritis |
title_fullStr | Characterization and Function of Tumor Necrosis Factor and Interleukin‐6–Induced Osteoclasts in Rheumatoid Arthritis |
title_full_unstemmed | Characterization and Function of Tumor Necrosis Factor and Interleukin‐6–Induced Osteoclasts in Rheumatoid Arthritis |
title_short | Characterization and Function of Tumor Necrosis Factor and Interleukin‐6–Induced Osteoclasts in Rheumatoid Arthritis |
title_sort | characterization and function of tumor necrosis factor and interleukin‐6–induced osteoclasts in rheumatoid arthritis |
topic | Rheumatoid Arthritis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361923/ https://www.ncbi.nlm.nih.gov/pubmed/33512089 http://dx.doi.org/10.1002/art.41666 |
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