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Inhibiting GSK3β enhances fracture healing without formation of endochondral bone



DOI:10.1038/bonekey.2013.54

The role of glycogen synthase kinase 3β (GSK3β), which regulates β-catenin degradation, may be important in fracture healing. To investigate, Sisask et al. used a rat femoral fracture model and AZD2858, an oral inhibitor of GSK3β and a global agonist for the Wnt/β-catenin pathway.

Young rats were treated with 30 μmol/kg of AZD2858 (20 mg/kg) or control vehicle every day for up to 21 days after femoral fracture. Histology was performed at day 4 and after 1, 2 and 3 weeks, and, at the latter two time points, X-rays, peripheral quantitative computed tomography scans and four-point bending tests were employed.

AZD2858-treated animals showed rapid fracture healing without pre-formation of cartilage. Bone calluses around the fracture site showed increased bone mineral density (28% at 2 weeks, 38% at 3 weeks) and bone mineral content (81% at 2 weeks, 93% at 3 weeks), compared to controls. The treated group also showed an increase in bone strength at weeks 2 and 3. The mechanism involved was independent of endochondral bone formation; the authors propose that inhibiting GSK3β promotes differentiation of mesenchymal stem cells into osteoblasts, driving bone repair.

Editor’s comment: The GSK3β inhibitor AZD2858 changed the characteristics of fracture repair in this rat model; endochondral ossification was inhibited, replaced by intramembranous ossification with a concomitant increase in mechanical properties. Further research using more severe fracture models will be required to demonstrate the safety of this attractive potential therapy.


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