• Molecules and Cells
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• v.43 no.6
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• pp.517-529
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• 2020

Carboxyl-terminal binding proteins (CtBPs) are transcription regulators that control gene expression in multiple cellular processes. Our recent findings indicated that overexpression of CtBP2 caused the repression of multiple bone development and differentiation genes, resulting in atrophic nonunion. Therefore, disrupting the CtBP2-associated transcriptional complex with small molecules may be an effective strategy to prevent nonunion. In the present study, we developed an in vitro screening system in yeast cells to identify small molecules capable of disrupting the CtBP2-p300 interaction. Herein, we focus our studies on revealing the in vitro and in vivo effects of a small molecule NSM00158, which showed the strongest inhibition of the CtBP2-p300 interaction in vitro. Our results indicated that NSM00158 could specifically disrupt CtBP2 function and cause the disassociation of the CtBP2-p300-Runx2 complex. The impairment of this complex led to failed binding of Runx2 to its downstream targets, causing their upregulation. Using a mouse fracture model, we evaluated the in vivo effect of NSM00158 on preventing nonunion. Consistent with the in vitro results, the NSM00158 treatment resulted in the upregulation of Runx2 downstream targets. Importantly, we found that the administration of NSM00158 could prevent the occurrence of nonunion. Our results suggest that NSM00158 represents a new potential compound to prevent the occurrence of nonunion by disrupting CtBP2 function and impairing the assembly of the CtBP2-p300-Runx2 transcriptional complex.

• Journal of Korean Foot and Ankle Society
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• v.22 no.3
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• pp.95-99
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• 2018

Purpose: The purpose of this study was to evaluate the radiologic outcomes of distal fibular fractures and to analyze the risk factors associated with nonunion. Materials and Methods: Between January 2009 and March 2016, 13 patients who had final nonunion with ankle fracture were included. In the control group, 370 patients who had undergone bony union and removed metal implants were included. All patients underwent the same surgical procedure and had the same treatment method, ultimately achieving satisfactory open reduction results with less than 2 mm fracture gap. Surgical treatment of fracture was considered to have the same effect on nonunion, and factors that might be associated with nonunion were evaluated. SPSS ver. 13.0 (SPSS Inc., USA) was used for all statistical analyses. Pearson's chi-square test and multi-variate regression analysis were performed to determine the factors affecting nonunion of distal fibular fracture. A p-value less than 0.05 was considered statistically significant, and relative risk was assessed. Results: The mean age of 13 patients was 46.9 years (range, 16~57 years); there were 8 men and 5 women. Among the 13 patients with nonunion, atrophic was the most common (12 cases). The association between the injury mechanism and the Lauge-Hansen classification and diabetes mellitus was not statistically significant. Distal fibular fractures with tibia shaft fracture (p=0.015) and Danis-Weber type C fracture (p=0.023), open fracture (p=0.011), and smoking (p=0.023) were significantly associated with nonunion. Conclusion: In this study, the combined injury of the ipsilateral tibia shaft fracture, open fracture, and Danis-Weber type C fracture may increase the possibility of nonunion. Therefore, caution is advised to prevent nonunion.