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Elevation of Proinflammatory Cytokine HMGB1 in the Synovial Fluid of Patients With Legg‐Calvé‐Perthes Disease and Correlation With IL‐6

Legg‐Calvé‐Perthes disease (LCPD) is a childhood ischemic osteonecrosis (ON) of the femoral head associated with the elevation of proinflammatory cytokine interleukin‐6 (IL‐6) in the synovial fluid. Currently, there is no effective medical therapy for patients with LCPD. In animal models of ischemic...

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Autores principales: Kamiya, Nobuhiro, Kim, Harry KW
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872337/
https://www.ncbi.nlm.nih.gov/pubmed/33615102
http://dx.doi.org/10.1002/jbm4.10429
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author Kamiya, Nobuhiro
Kim, Harry KW
author_facet Kamiya, Nobuhiro
Kim, Harry KW
author_sort Kamiya, Nobuhiro
collection PubMed
description Legg‐Calvé‐Perthes disease (LCPD) is a childhood ischemic osteonecrosis (ON) of the femoral head associated with the elevation of proinflammatory cytokine interleukin‐6 (IL‐6) in the synovial fluid. Currently, there is no effective medical therapy for patients with LCPD. In animal models of ischemic ON, articular chondrocytes produce IL‐6 in response to ischemic ON induction and IL‐6 receptor blockade improves bone healing. High‐mobility group box 1 (HMGB1) is a damage‐associated molecular pattern released from dying cells. In addition, extracellular HMGB1 protein is a well‐known proinflammatory cytokine elevated in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. The purpose of this study was to investigate IL‐6–related proinflammatory cytokines, including HMGB1, in the synovial fluid of patients with LCPD. Our working hypothesis was that HMGB1, produced by articular chondrocytes following ischemic ON, plays an important role in IL‐6 upregulation. Here, HMGB1 protein levels were significantly higher in the synovial fluid of patients with LCPD by threefold compared with controls (p < 0.05), and were highly correlated with IL‐6 levels (Pearson correlation coefficient 0.94, p < 0.001, R (2) = 0.87). In the mouse model of ischemic ON, both HMGB1 gene expression and protein levels were elevated in the articular cartilage. In vitro studies revealed a significant elevation of HMGB1 and IL‐6 proteins in the supernatants of human chondrocytes exposed to hypoxic and oxidative stresses. Overexpressed HMGB1 protein in the supernatants of chondrocytes synergistically increased IL‐6 protein. Silencing HMGB1 RNA in human chondrocytes significantly repressed inteleukin‐1β (IL‐1β) gene expression, but not IL‐6. Further, both IL‐1β and tumor necrosis factor‐α (TNF‐α) protein levels in the synovial fluid of patients with LCPD were significantly correlated with IL‐6 protein levels. Taken together, these results suggest that proinflammatory cytokines, HMGB1, tumor necrosis factor‐α (TNF‐α), and IL‐1β, are significantly involved with IL‐6 in the pathogenesis of LCPD. This study is clinically relevant because the availability of multiple therapeutic targets may improve the development of therapeutic strategy for LCPD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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spelling pubmed-78723372021-02-19 Elevation of Proinflammatory Cytokine HMGB1 in the Synovial Fluid of Patients With Legg‐Calvé‐Perthes Disease and Correlation With IL‐6 Kamiya, Nobuhiro Kim, Harry KW JBMR Plus Original Articles Legg‐Calvé‐Perthes disease (LCPD) is a childhood ischemic osteonecrosis (ON) of the femoral head associated with the elevation of proinflammatory cytokine interleukin‐6 (IL‐6) in the synovial fluid. Currently, there is no effective medical therapy for patients with LCPD. In animal models of ischemic ON, articular chondrocytes produce IL‐6 in response to ischemic ON induction and IL‐6 receptor blockade improves bone healing. High‐mobility group box 1 (HMGB1) is a damage‐associated molecular pattern released from dying cells. In addition, extracellular HMGB1 protein is a well‐known proinflammatory cytokine elevated in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. The purpose of this study was to investigate IL‐6–related proinflammatory cytokines, including HMGB1, in the synovial fluid of patients with LCPD. Our working hypothesis was that HMGB1, produced by articular chondrocytes following ischemic ON, plays an important role in IL‐6 upregulation. Here, HMGB1 protein levels were significantly higher in the synovial fluid of patients with LCPD by threefold compared with controls (p < 0.05), and were highly correlated with IL‐6 levels (Pearson correlation coefficient 0.94, p < 0.001, R (2) = 0.87). In the mouse model of ischemic ON, both HMGB1 gene expression and protein levels were elevated in the articular cartilage. In vitro studies revealed a significant elevation of HMGB1 and IL‐6 proteins in the supernatants of human chondrocytes exposed to hypoxic and oxidative stresses. Overexpressed HMGB1 protein in the supernatants of chondrocytes synergistically increased IL‐6 protein. Silencing HMGB1 RNA in human chondrocytes significantly repressed inteleukin‐1β (IL‐1β) gene expression, but not IL‐6. Further, both IL‐1β and tumor necrosis factor‐α (TNF‐α) protein levels in the synovial fluid of patients with LCPD were significantly correlated with IL‐6 protein levels. Taken together, these results suggest that proinflammatory cytokines, HMGB1, tumor necrosis factor‐α (TNF‐α), and IL‐1β, are significantly involved with IL‐6 in the pathogenesis of LCPD. This study is clinically relevant because the availability of multiple therapeutic targets may improve the development of therapeutic strategy for LCPD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. John Wiley & Sons, Inc. 2020-12-03 /pmc/articles/PMC7872337/ /pubmed/33615102 http://dx.doi.org/10.1002/jbm4.10429 Text en © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Kamiya, Nobuhiro
Kim, Harry KW
Elevation of Proinflammatory Cytokine HMGB1 in the Synovial Fluid of Patients With Legg‐Calvé‐Perthes Disease and Correlation With IL‐6
title Elevation of Proinflammatory Cytokine HMGB1 in the Synovial Fluid of Patients With Legg‐Calvé‐Perthes Disease and Correlation With IL‐6
title_full Elevation of Proinflammatory Cytokine HMGB1 in the Synovial Fluid of Patients With Legg‐Calvé‐Perthes Disease and Correlation With IL‐6
title_fullStr Elevation of Proinflammatory Cytokine HMGB1 in the Synovial Fluid of Patients With Legg‐Calvé‐Perthes Disease and Correlation With IL‐6
title_full_unstemmed Elevation of Proinflammatory Cytokine HMGB1 in the Synovial Fluid of Patients With Legg‐Calvé‐Perthes Disease and Correlation With IL‐6
title_short Elevation of Proinflammatory Cytokine HMGB1 in the Synovial Fluid of Patients With Legg‐Calvé‐Perthes Disease and Correlation With IL‐6
title_sort elevation of proinflammatory cytokine hmgb1 in the synovial fluid of patients with legg‐calvé‐perthes disease and correlation with il‐6
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872337/
https://www.ncbi.nlm.nih.gov/pubmed/33615102
http://dx.doi.org/10.1002/jbm4.10429
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