Introduction: Activation of Runt Related Transcription Factor 2 (RUNX2) is required for transdifferentiation of Vascular Smooth Muscle Cells (VSMCs) into a calcifying osteoblast-like phenotype. Our lab showed that deletion of Discoidin Domain Receptor 1 (Ddr1), decreased atherosclerotic vascular calcification in the Ldlr-/- mouse.
Hypothesis: DDR1 regulates RUNX2 activity by affecting microtubule organization during VSMC mediated calcification.
Results: Ddr1-/- VSMCs show reduced RUNX2 activity when compared to Ddr1+/+ VSMCs. Addition of the microtubule-destabilizing agent nocodazole inhibited both RUNX2 activity and nuclear localization in Ddr1+/+ VSMCs. Addition of the microtubule-stabilizing agent taxol rescued RUNX2 nuclear localization in Ddr1-/- VSMCs. Despite this, Taxol was unable to rescue RUNX2 activity as it eliminated activity in both genotypes.
Conclusion: These findings indicate that under osteogenic conditions, Ddr1 deletion impedes the dynamic instability required for the maintenance of microtubule architecture. This prevents RUNX2 nuclear localization and transcriptional activation in VSMCs.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/35146 |
| Date | 19 March 2013 |
| Creators | Wan, Mark H. |
| Contributors | Bendeck, Michelle |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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