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Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
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2013 (English)In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 54, no 1, 126-132 p.Article in journal (Refereed) Published
Abstract [en]

Fracture healing is a complex interplay between endochondral and intramembranous bone formation processes. The canonical Wnt/β-catenin pathway enhances new bone formation and may play a role in fracture healing. Glycogen synthase kinase 3β (GSK3β) is a key regulator of β-catenin degradation. In this study, we investigate the effects of AZD2858, an orally bioactive GSK3 inhibitor, on fracture healing. Femoral fractures were produced in rats after the insertion of a femoral nail. The rats were treated with oral administration of AZD2858 at a dose of 30μmol/kg (20mg/kg) daily for up to 3weeks, while control animals were administered vehicle. At 4days, and at 1, 2 and 3weeks, histological analysis was performed, and at the 2 and 3week time points, we performed peripheral quantitative computed tomography (pQCT), X-rays, and four-point bending tests. Peripheral QCT showed an increase in both mineral density (of 28% at 2weeks and 38% at 3weeks) and mineral content (of 81% at 2weeks and 93% at 3weeks) in the calluses from AZD2858 treated animals as compared to vehicle treated animals. Histological analysis demonstrated that rats treated with GSK3 inhibitor healed their fractures rapidly, but without the pre-formation of cartilage tissue. Furthermore, four-point bending tests of fractured femora from animals treated for 2 and 3weeks showed an increase in strength in treated animals compared to their vehicle-treated controls. In conclusion, AZD2858, a potent GSK3 inhibitor, has a substantial impact on fracture healing. The fractures healed with a bony callus without an obvious endochondral component, suggesting that AZD2858 drives mesenchymal cells into the osteoblastic pathway. This leads to direct bone repair in an unstable fracture milieu.

Place, publisher, year, edition, pages
2013. Vol. 54, no 1, 126-132 p.
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Medical and Health Sciences
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URN: urn:nbn:se:uu:diva-193321DOI: 10.1016/j.bone.2013.01.019ISI: 000316839800017PubMedID: 23337038OAI: oai:DiVA.org:uu-193321DiVA: diva2:602012
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De två första författarna delar förstaförfattarskapet.

Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2017-12-06Bibliographically approved

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Sisask, GregorMarsell, RichardLarsson, SuneNilsson, OlleLjunggren, ÖstenJonsson, Kenneth B

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