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Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis
BACKGROUND: Elevated levels of periostin (Postn) in the cartilage and bone are associated with osteoarthritis (OA). However, it remains unknown whether Postn loss-of-function can delay or prevent the development of OA. In this study, we sought to better understand the role of Postn in OA development...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028178/ https://www.ncbi.nlm.nih.gov/pubmed/33832532 http://dx.doi.org/10.1186/s13075-021-02477-z |
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author | Attur, Mukundan Duan, Xin Cai, Lei Han, Tianzhen Zhang, Weili Tycksen, Eric D. Samuels, Jonathan Brophy, Robert H. Abramson, Steven B. Rai, Muhammad Farooq |
author_facet | Attur, Mukundan Duan, Xin Cai, Lei Han, Tianzhen Zhang, Weili Tycksen, Eric D. Samuels, Jonathan Brophy, Robert H. Abramson, Steven B. Rai, Muhammad Farooq |
author_sort | Attur, Mukundan |
collection | PubMed |
description | BACKGROUND: Elevated levels of periostin (Postn) in the cartilage and bone are associated with osteoarthritis (OA). However, it remains unknown whether Postn loss-of-function can delay or prevent the development of OA. In this study, we sought to better understand the role of Postn in OA development and assessed the functional impact of Postn deficiency on post-traumatic and age-related OA in mice. METHODS: The effects of Postn deficiency were studied in two murine experimental OA models using Postn(−/−) (n = 32) and littermate wild-type (wt) mice (n = 36). Post-traumatic OA was induced by destabilization of the medial meniscus (DMM) in 10-week-old mice (n = 20); age-related OA was analyzed in 24-month-old mice (n = 13). Cartilage degeneration was assessed histologically using the OARSI scoring system, and synovitis was evaluated by measuring the synovial lining cell layer and the cells density in the synovial stroma. Bone changes were measured by μCT analysis. Serum levels of Postn were determined by ELISA. Expression of Postn and collagenase-3 (MMP-13) was measured by immunostaining. RNA-seq was performed on chondrocytes isolated from 21-day old Postn(−/−) (n = 3) and wt mice (n = 3) to discover genes and pathways altered by Postn knockout. RESULTS: Postn(−/−) mice exhibited significantly reduced cartilage degeneration and OARSI score relative to wt mice in post-traumatic OA after 8 weeks (maximum: 2.37 ± 0.74 vs. 4.00 ± 1.20, P = 0.011; summed: 9.31 ± 2.52 vs. 21.44 ± 6.01, P = 0.0002) and spontaneous OA (maximum: 1.93 ± 0.45 vs. 3.58 ± 1.16, P = 0.014; summed: 6.14 ± 1.57 vs. 11.50 ± 3.02, P = 0.003). Synovitis was significantly lower in Postn(−/−) mice than wt only in the DMM model (1.88 ± 1.01 vs. 3.17 ± 0.63; P = 0.039). Postn(−/−) mice also showed lower trabecular bone parameters such as BV/TV, vBMD, Tb.Th, and Tb.N and high Tb. Sp in both models. Postn(−/−) mice had negligible levels of serum Postn compared with wt. Immunofluorescent studies of cartilage indicated that Postn(−/−) mice expressed lower MMP-13 levels than wt mice. RNA-seq revealed that cell-cell-adhesion and cell-differentiation processes were enriched in Postn(−/−) mice, while those related to cell-cycle and DNA-repair were enriched in wt mice. CONCLUSIONS: Postn deficiency protects against DMM-induced post-traumatic and age-related spontaneous OA. RNA-seq findings warrant further investigations to better understand the mechanistic role of Postn and its potential as a therapeutic target in OA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-021-02477-z. |
format | Online Article Text |
id | pubmed-8028178 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-80281782021-04-08 Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis Attur, Mukundan Duan, Xin Cai, Lei Han, Tianzhen Zhang, Weili Tycksen, Eric D. Samuels, Jonathan Brophy, Robert H. Abramson, Steven B. Rai, Muhammad Farooq Arthritis Res Ther Research Article BACKGROUND: Elevated levels of periostin (Postn) in the cartilage and bone are associated with osteoarthritis (OA). However, it remains unknown whether Postn loss-of-function can delay or prevent the development of OA. In this study, we sought to better understand the role of Postn in OA development and assessed the functional impact of Postn deficiency on post-traumatic and age-related OA in mice. METHODS: The effects of Postn deficiency were studied in two murine experimental OA models using Postn(−/−) (n = 32) and littermate wild-type (wt) mice (n = 36). Post-traumatic OA was induced by destabilization of the medial meniscus (DMM) in 10-week-old mice (n = 20); age-related OA was analyzed in 24-month-old mice (n = 13). Cartilage degeneration was assessed histologically using the OARSI scoring system, and synovitis was evaluated by measuring the synovial lining cell layer and the cells density in the synovial stroma. Bone changes were measured by μCT analysis. Serum levels of Postn were determined by ELISA. Expression of Postn and collagenase-3 (MMP-13) was measured by immunostaining. RNA-seq was performed on chondrocytes isolated from 21-day old Postn(−/−) (n = 3) and wt mice (n = 3) to discover genes and pathways altered by Postn knockout. RESULTS: Postn(−/−) mice exhibited significantly reduced cartilage degeneration and OARSI score relative to wt mice in post-traumatic OA after 8 weeks (maximum: 2.37 ± 0.74 vs. 4.00 ± 1.20, P = 0.011; summed: 9.31 ± 2.52 vs. 21.44 ± 6.01, P = 0.0002) and spontaneous OA (maximum: 1.93 ± 0.45 vs. 3.58 ± 1.16, P = 0.014; summed: 6.14 ± 1.57 vs. 11.50 ± 3.02, P = 0.003). Synovitis was significantly lower in Postn(−/−) mice than wt only in the DMM model (1.88 ± 1.01 vs. 3.17 ± 0.63; P = 0.039). Postn(−/−) mice also showed lower trabecular bone parameters such as BV/TV, vBMD, Tb.Th, and Tb.N and high Tb. Sp in both models. Postn(−/−) mice had negligible levels of serum Postn compared with wt. Immunofluorescent studies of cartilage indicated that Postn(−/−) mice expressed lower MMP-13 levels than wt mice. RNA-seq revealed that cell-cell-adhesion and cell-differentiation processes were enriched in Postn(−/−) mice, while those related to cell-cycle and DNA-repair were enriched in wt mice. CONCLUSIONS: Postn deficiency protects against DMM-induced post-traumatic and age-related spontaneous OA. RNA-seq findings warrant further investigations to better understand the mechanistic role of Postn and its potential as a therapeutic target in OA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-021-02477-z. BioMed Central 2021-04-08 2021 /pmc/articles/PMC8028178/ /pubmed/33832532 http://dx.doi.org/10.1186/s13075-021-02477-z Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Attur, Mukundan Duan, Xin Cai, Lei Han, Tianzhen Zhang, Weili Tycksen, Eric D. Samuels, Jonathan Brophy, Robert H. Abramson, Steven B. Rai, Muhammad Farooq Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis |
title | Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis |
title_full | Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis |
title_fullStr | Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis |
title_full_unstemmed | Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis |
title_short | Periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis |
title_sort | periostin loss-of-function protects mice from post-traumatic and age-related osteoarthritis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028178/ https://www.ncbi.nlm.nih.gov/pubmed/33832532 http://dx.doi.org/10.1186/s13075-021-02477-z |
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