Diabetes impairs fracture healing through Foxo1 mediated disruption of ciliogenesis
Abstract Foxo1 upregulation is linked to defective fracture healing under diabetic conditions. Previous studies demonstrated that diabetes upregulates Foxo1 expression and activation and diabetes impairs ciliogenesis resulting in defective fracture repair. However, the mechanism by which diabetes ca...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
|
| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01562-3 |
| _version_ | 1797578070294528000 |
|---|---|
| author | Zahra Chinipardaz Gongsheng Yuan Min Liu Dana T. Graves Shuying Yang |
| author_facet | Zahra Chinipardaz Gongsheng Yuan Min Liu Dana T. Graves Shuying Yang |
| author_sort | Zahra Chinipardaz |
| collection | DOAJ |
| description | Abstract Foxo1 upregulation is linked to defective fracture healing under diabetic conditions. Previous studies demonstrated that diabetes upregulates Foxo1 expression and activation and diabetes impairs ciliogenesis resulting in defective fracture repair. However, the mechanism by which diabetes causes cilia loss during fracture healing remains elusive. We report here that streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) dramatically increased Foxo1 expression in femoral fracture calluses, which thereby caused a significant decrease in the expression of IFT80 and primary cilia number. Ablation of Foxo1 in osteoblasts in OSX cretTA Foxo1 f/f mice rescued IFT80 expression and ciliogenesis and restored bone formation and mechanical strength in diabetic fracture calluses. In vitro, advanced glycation end products (AGEs) impaired cilia formation in osteoblasts and reduced the production of a mineralizing matrix, which were rescued by Foxo1 deletion. Mechanistically, AGEs increased Foxo1 expression and transcriptional activity to inhibit IFT80 expression causing impaired cilia formation. Thus, our findings demonstrate that diabetes impairs fracture healing through Foxo1 mediated inhibition of ciliary IFT80 expression and primary cilia formation, resulting in impaired osteogenesis. Inhibition of Foxo1 and/or restoration of cilia formation has the potential to promote diabetes-impaired fracture healing. |
| first_indexed | 2024-03-10T22:18:02Z |
| format | Article |
| id | doaj.art-0bd42a1be2e54b4e9d3b91d023402d68 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-10T22:18:02Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-0bd42a1be2e54b4e9d3b91d023402d682023-11-19T12:22:42ZengNature Publishing GroupCell Death Discovery2058-77162023-08-01911810.1038/s41420-023-01562-3Diabetes impairs fracture healing through Foxo1 mediated disruption of ciliogenesisZahra Chinipardaz0Gongsheng Yuan1Min Liu2Dana T. Graves3Shuying Yang4Department of Basic and Translation Sciences, School of Dental Medicine, University of PennsylvaniaDepartment of Basic and Translation Sciences, School of Dental Medicine, University of PennsylvaniaDepartment of Periodontics, School of Dental Medicine, University of PennsylvaniaDepartment of Periodontics, School of Dental Medicine, University of PennsylvaniaDepartment of Basic and Translation Sciences, School of Dental Medicine, University of PennsylvaniaAbstract Foxo1 upregulation is linked to defective fracture healing under diabetic conditions. Previous studies demonstrated that diabetes upregulates Foxo1 expression and activation and diabetes impairs ciliogenesis resulting in defective fracture repair. However, the mechanism by which diabetes causes cilia loss during fracture healing remains elusive. We report here that streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) dramatically increased Foxo1 expression in femoral fracture calluses, which thereby caused a significant decrease in the expression of IFT80 and primary cilia number. Ablation of Foxo1 in osteoblasts in OSX cretTA Foxo1 f/f mice rescued IFT80 expression and ciliogenesis and restored bone formation and mechanical strength in diabetic fracture calluses. In vitro, advanced glycation end products (AGEs) impaired cilia formation in osteoblasts and reduced the production of a mineralizing matrix, which were rescued by Foxo1 deletion. Mechanistically, AGEs increased Foxo1 expression and transcriptional activity to inhibit IFT80 expression causing impaired cilia formation. Thus, our findings demonstrate that diabetes impairs fracture healing through Foxo1 mediated inhibition of ciliary IFT80 expression and primary cilia formation, resulting in impaired osteogenesis. Inhibition of Foxo1 and/or restoration of cilia formation has the potential to promote diabetes-impaired fracture healing.https://doi.org/10.1038/s41420-023-01562-3 |
| spellingShingle | Zahra Chinipardaz Gongsheng Yuan Min Liu Dana T. Graves Shuying Yang Diabetes impairs fracture healing through Foxo1 mediated disruption of ciliogenesis Cell Death Discovery |
| title | Diabetes impairs fracture healing through Foxo1 mediated disruption of ciliogenesis |
| title_full | Diabetes impairs fracture healing through Foxo1 mediated disruption of ciliogenesis |
| title_fullStr | Diabetes impairs fracture healing through Foxo1 mediated disruption of ciliogenesis |
| title_full_unstemmed | Diabetes impairs fracture healing through Foxo1 mediated disruption of ciliogenesis |
| title_short | Diabetes impairs fracture healing through Foxo1 mediated disruption of ciliogenesis |
| title_sort | diabetes impairs fracture healing through foxo1 mediated disruption of ciliogenesis |
| url | https://doi.org/10.1038/s41420-023-01562-3 |
| work_keys_str_mv | AT zahrachinipardaz diabetesimpairsfracturehealingthroughfoxo1mediateddisruptionofciliogenesis AT gongshengyuan diabetesimpairsfracturehealingthroughfoxo1mediateddisruptionofciliogenesis AT minliu diabetesimpairsfracturehealingthroughfoxo1mediateddisruptionofciliogenesis AT danatgraves diabetesimpairsfracturehealingthroughfoxo1mediateddisruptionofciliogenesis AT shuyingyang diabetesimpairsfracturehealingthroughfoxo1mediateddisruptionofciliogenesis |