Unleashing β-catenin with a new anti-Alzheimer drug for bone tissue regeneration

被引:11
作者
Comeau-Gauthier, Marianne [1 ,2 ]
Tarchala, Magdalena [1 ,3 ]
Luna, Jose Luis Ramirez-Garcia [1 ,2 ,3 ]
Harvey, Edward [1 ,4 ]
Merle, Geraldine [5 ]
机构
[1] McGill Univ, Dept Surg, Div Orthoped Surg, Montreal, PQ, Canada
[2] McGill Univ, Fac Med, Expt Surg, Rue Montaigne, Montreal, PQ, Canada
[3] Montreal Gen Hosp, 1650 Cedar Ave,Room A10-110, Montreal, PQ H3G 1A4, Canada
[4] Montreal Gen Hosp, Bone Engn Labs, 1650 Cedar Ave,Room C10-124, Montreal, PQ H3G 1A4, Canada
[5] Chem Engn Dept, Polytech JA Bombardier Bldg Polytech Montreal, Montreal, PQ H3C 3A7, Canada
来源
INJURY-INTERNATIONAL JOURNAL OF THE CARE OF THE INJURED | 2020年 / 51卷 / 11期
关键词
Glycogen synthase kinase 3 beta; Osteoblast; Bone regeneration; Femur; Fracture; GSK-3 INHIBITOR TIDEGLUSIB; FRACTURE REPAIR; OSTEOTOMY MODEL; WNT; LITHIUM; OSTEOBLAST; MICE; QUANTIFICATION; ACTIVATION; PARAMETERS;
D O I
10.1016/j.injury.2020.07.035
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
The Wnt/beta-catenin signaling pathway is critical for bone differentiation and regeneration. Tideglusib, a selective FDA approved glycogen synthase kinase-3 beta(GSK-3 beta) inhibitor, has been shown to promote dentine formation, but its effect on bone has not been examined. Our objective was to study the effect of localized Tideglusib administration on bone repair. Bone healing between Tideglusib treated and control mice was analysed at 7, 14 and 28 days postoperative (PO) with microCT, dynamic histomorphometry and immunohistology. There was a local downregulation of GSK-3 beta in Tideglusib animals, resulting in a significant increase in the amount of new bone formation with both enhanced cortical bone bridging and medullary bone deposition. The bone formation in the Tideglusib group was characterized by early osteoblast differentiation with down-regulation of GSK-3 beta at day 7 and 14, and higher accumulation of active beta-catenin at day 14. Here, for the first time, we show a positive effect of Tideglusib on bone formation through the inactivation of GSK-3 beta. Furthermore, the findings suggest that Tideglusib does not interfere with precursor cell recruitment and commitment, contrary to other GSK-3 beta antagonists such as lithium chloride. Taken together, the results indicate that Tideglusib could be used directly at a fracture site during the initial intraoperative internal fixation without the need for further surgery, injection or drug delivery system. This FDA-approved drug may be useful in the future for the prevention of nonunion in patients presenting with a high risk for fracture-healing. (C) 2020 Elsevier Ltd. All rights reserved.
引用
收藏
页码:2449 / 2459
页数:11
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