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Unbiased gene expression analysis of the delayed fracture healing observed in Zucker diabetic fatty rats
AIMS: Impaired fracture repair in patients with type 2 diabetes mellitus (T2DM) is not fully understood. In this study, we aimed to characterize the local changes in gene expression (GE) associated with diabetic fracture. We used an unbiased approach to compare GE in the fracture callus of Zucker di...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The British Editorial Society of Bone & Joint Surgery
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578971/ https://www.ncbi.nlm.nih.gov/pubmed/37844909 http://dx.doi.org/10.1302/2046-3758.1210.BJR-2023-0062.R1 |
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author | Sung, Jonghoo Barratt, Kate R. Pederson, Stephen M. Chenu, Chantal Reichert, Ines Atkins, Gerald J. Anderson, Paul H. Smitham, Peter J. |
author_facet | Sung, Jonghoo Barratt, Kate R. Pederson, Stephen M. Chenu, Chantal Reichert, Ines Atkins, Gerald J. Anderson, Paul H. Smitham, Peter J. |
author_sort | Sung, Jonghoo |
collection | PubMed |
description | AIMS: Impaired fracture repair in patients with type 2 diabetes mellitus (T2DM) is not fully understood. In this study, we aimed to characterize the local changes in gene expression (GE) associated with diabetic fracture. We used an unbiased approach to compare GE in the fracture callus of Zucker diabetic fatty (ZDF) rats relative to wild-type (WT) littermates at three weeks following femoral osteotomy. METHODS: Zucker rats, WT and homozygous for leptin receptor mutation (ZDF), were fed a moderately high-fat diet to induce T2DM only in the ZDF animals. At ten weeks of age, open femoral fractures were simulated using a unilateral osteotomy stabilized with an external fixator. At three weeks post-surgery, the fractured femur from each animal was retrieved for analysis. Callus formation and the extent of healing were assessed by radiograph and histology. Bone tissue was processed for total RNA extraction and messenger RNA (mRNA) sequencing (mRNA-Seq). RESULTS: Radiographs and histology demonstrated impaired fracture healing in ZDF rats with incomplete bony bridge formation and an influx of intramedullary inflammatory tissue. In comparison, near-complete bridging between cortices was observed in Sham WT animals. Of 13,160 genes, mRNA-Seq analysis identified 13 that were differentially expressed in ZDF rat callus, using a false discovery rate (FDR) threshold of 10%. Seven genes were upregulated with high confidence (FDR = 0.05) in ZDF fracture callus, most with known roles in inflammation. CONCLUSION: These findings suggest that elevated or prolonged inflammation contributes to delayed fracture healing in T2DM. The identified genes may be used as biomarkers to monitor and treat delayed fracture healing in diabetic patients. Cite this article: Bone Joint Res 2023;12(10):657–666. |
format | Online Article Text |
id | pubmed-10578971 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The British Editorial Society of Bone & Joint Surgery |
record_format | MEDLINE/PubMed |
spelling | pubmed-105789712023-10-17 Unbiased gene expression analysis of the delayed fracture healing observed in Zucker diabetic fatty rats Sung, Jonghoo Barratt, Kate R. Pederson, Stephen M. Chenu, Chantal Reichert, Ines Atkins, Gerald J. Anderson, Paul H. Smitham, Peter J. Bone Joint Res Bone Fracture AIMS: Impaired fracture repair in patients with type 2 diabetes mellitus (T2DM) is not fully understood. In this study, we aimed to characterize the local changes in gene expression (GE) associated with diabetic fracture. We used an unbiased approach to compare GE in the fracture callus of Zucker diabetic fatty (ZDF) rats relative to wild-type (WT) littermates at three weeks following femoral osteotomy. METHODS: Zucker rats, WT and homozygous for leptin receptor mutation (ZDF), were fed a moderately high-fat diet to induce T2DM only in the ZDF animals. At ten weeks of age, open femoral fractures were simulated using a unilateral osteotomy stabilized with an external fixator. At three weeks post-surgery, the fractured femur from each animal was retrieved for analysis. Callus formation and the extent of healing were assessed by radiograph and histology. Bone tissue was processed for total RNA extraction and messenger RNA (mRNA) sequencing (mRNA-Seq). RESULTS: Radiographs and histology demonstrated impaired fracture healing in ZDF rats with incomplete bony bridge formation and an influx of intramedullary inflammatory tissue. In comparison, near-complete bridging between cortices was observed in Sham WT animals. Of 13,160 genes, mRNA-Seq analysis identified 13 that were differentially expressed in ZDF rat callus, using a false discovery rate (FDR) threshold of 10%. Seven genes were upregulated with high confidence (FDR = 0.05) in ZDF fracture callus, most with known roles in inflammation. CONCLUSION: These findings suggest that elevated or prolonged inflammation contributes to delayed fracture healing in T2DM. The identified genes may be used as biomarkers to monitor and treat delayed fracture healing in diabetic patients. Cite this article: Bone Joint Res 2023;12(10):657–666. The British Editorial Society of Bone & Joint Surgery 2023-10-17 /pmc/articles/PMC10578971/ /pubmed/37844909 http://dx.doi.org/10.1302/2046-3758.1210.BJR-2023-0062.R1 Text en © 2023 Author(s) et al. https://creativecommons.org/licenses/by-nc-nd/4.0/https://online.boneandjoint.org.uk/TDMThis is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND 4.0) licence, which permits the copying and redistribution of the work only, and provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Bone Fracture Sung, Jonghoo Barratt, Kate R. Pederson, Stephen M. Chenu, Chantal Reichert, Ines Atkins, Gerald J. Anderson, Paul H. Smitham, Peter J. Unbiased gene expression analysis of the delayed fracture healing observed in Zucker diabetic fatty rats |
title | Unbiased gene expression analysis of the delayed fracture healing observed in Zucker diabetic fatty rats |
title_full | Unbiased gene expression analysis of the delayed fracture healing observed in Zucker diabetic fatty rats |
title_fullStr | Unbiased gene expression analysis of the delayed fracture healing observed in Zucker diabetic fatty rats |
title_full_unstemmed | Unbiased gene expression analysis of the delayed fracture healing observed in Zucker diabetic fatty rats |
title_short | Unbiased gene expression analysis of the delayed fracture healing observed in Zucker diabetic fatty rats |
title_sort | unbiased gene expression analysis of the delayed fracture healing observed in zucker diabetic fatty rats |
topic | Bone Fracture |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10578971/ https://www.ncbi.nlm.nih.gov/pubmed/37844909 http://dx.doi.org/10.1302/2046-3758.1210.BJR-2023-0062.R1 |
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