Therapeutic Targeting Notch2 Protects Bone Micro-Vasculatures from Methotrexate Chemotherapy-Induced Adverse Effects in Rats
Intensive cancer chemotherapy is well known to cause bone vasculature disfunction and damage, but the mechanism is poorly understood and there is a lack of treatment. Using a rat model of methotrexate (MTX) chemotherapy (five once-daily dosses at 0.75 mg/kg), this study investigated the roles of the...
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MDPI AG
2022-08-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/15/2382 |
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| author | Yaser Peymanfar Yu-Wen Su Mohammadhossein Hassanshahi Cory J. Xian |
| author_facet | Yaser Peymanfar Yu-Wen Su Mohammadhossein Hassanshahi Cory J. Xian |
| author_sort | Yaser Peymanfar |
| collection | DOAJ |
| description | Intensive cancer chemotherapy is well known to cause bone vasculature disfunction and damage, but the mechanism is poorly understood and there is a lack of treatment. Using a rat model of methotrexate (MTX) chemotherapy (five once-daily dosses at 0.75 mg/kg), this study investigated the roles of the Notch2 signalling pathway in MTX chemotherapy-induced bone micro-vasculature impairment. Gene expression, histological and micro-computed tomography (micro-CT) analyses revealed that MTX-induced micro-vasculature dilation and regression is associated with the induction of Notch2 activity in endothelial cells and increased production of inflammatory cytokine tumour necrosis factor alpha (TNFα) from osteoblasts (bone forming cells) and bone marrow cells. Blockade of Notch2 by a neutralising antibody ameliorated MTX adverse effects on bone micro-vasculature, both directly by supressing Notch2 signalling in endothelial cells and indirectly via reducing TNFα production. Furthermore, in vitro studies using rat bone marrow-derived endothelial cell revealed that MTX treatment induces Notch2/Hey1 pathway and negatively affects their ability in migration and tube formation, and Notch2 blockade can partially protect endothelial cell functions from MTX damage. |
| first_indexed | 2024-03-09T12:42:36Z |
| format | Article |
| id | doaj.art-304ce7d87d9c49cdbf0a7a89b114978d |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T12:42:36Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-304ce7d87d9c49cdbf0a7a89b114978d2023-11-30T22:16:16ZengMDPI AGCells2073-44092022-08-011115238210.3390/cells11152382Therapeutic Targeting Notch2 Protects Bone Micro-Vasculatures from Methotrexate Chemotherapy-Induced Adverse Effects in RatsYaser Peymanfar0Yu-Wen Su1Mohammadhossein Hassanshahi2Cory J. Xian3UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5001, AustraliaUniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5001, AustraliaUniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5001, AustraliaUniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5001, AustraliaIntensive cancer chemotherapy is well known to cause bone vasculature disfunction and damage, but the mechanism is poorly understood and there is a lack of treatment. Using a rat model of methotrexate (MTX) chemotherapy (five once-daily dosses at 0.75 mg/kg), this study investigated the roles of the Notch2 signalling pathway in MTX chemotherapy-induced bone micro-vasculature impairment. Gene expression, histological and micro-computed tomography (micro-CT) analyses revealed that MTX-induced micro-vasculature dilation and regression is associated with the induction of Notch2 activity in endothelial cells and increased production of inflammatory cytokine tumour necrosis factor alpha (TNFα) from osteoblasts (bone forming cells) and bone marrow cells. Blockade of Notch2 by a neutralising antibody ameliorated MTX adverse effects on bone micro-vasculature, both directly by supressing Notch2 signalling in endothelial cells and indirectly via reducing TNFα production. Furthermore, in vitro studies using rat bone marrow-derived endothelial cell revealed that MTX treatment induces Notch2/Hey1 pathway and negatively affects their ability in migration and tube formation, and Notch2 blockade can partially protect endothelial cell functions from MTX damage.https://www.mdpi.com/2073-4409/11/15/2382methotrexatecancer chemotherapybone vasculaturenotch signalling |
| spellingShingle | Yaser Peymanfar Yu-Wen Su Mohammadhossein Hassanshahi Cory J. Xian Therapeutic Targeting Notch2 Protects Bone Micro-Vasculatures from Methotrexate Chemotherapy-Induced Adverse Effects in Rats Cells methotrexate cancer chemotherapy bone vasculature notch signalling |
| title | Therapeutic Targeting Notch2 Protects Bone Micro-Vasculatures from Methotrexate Chemotherapy-Induced Adverse Effects in Rats |
| title_full | Therapeutic Targeting Notch2 Protects Bone Micro-Vasculatures from Methotrexate Chemotherapy-Induced Adverse Effects in Rats |
| title_fullStr | Therapeutic Targeting Notch2 Protects Bone Micro-Vasculatures from Methotrexate Chemotherapy-Induced Adverse Effects in Rats |
| title_full_unstemmed | Therapeutic Targeting Notch2 Protects Bone Micro-Vasculatures from Methotrexate Chemotherapy-Induced Adverse Effects in Rats |
| title_short | Therapeutic Targeting Notch2 Protects Bone Micro-Vasculatures from Methotrexate Chemotherapy-Induced Adverse Effects in Rats |
| title_sort | therapeutic targeting notch2 protects bone micro vasculatures from methotrexate chemotherapy induced adverse effects in rats |
| topic | methotrexate cancer chemotherapy bone vasculature notch signalling |
| url | https://www.mdpi.com/2073-4409/11/15/2382 |
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