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Published on: May 9, 2019
GSK-3 inhibition by an orally active small molecule increases bone mass in rats
Richard Marsell1, Gregor Sisask, Yvonne Nilsson
1Department of Surgical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden. Richard.Marsell@surgsci.uu.se
Abstract:
Glycogen synthase kinase 3β (GSK-3β) actions are central in the canonical Wnt pathway, important in many biological processes and a potential drug target for treating several diseases. It is appreciated that a balanced Wnt canonical signaling is crucial for the maintenance of normal bone mass. In this study we investigated the effects of a potent orally active GSK-3 inhibitor, AZD2858, on bone mass in rats. Treatment (1 μM) of human osteoblast cells with AZD2858 in vitro increased β-catenin levels after a short period of time. In rats, oral AZD2858 treatment caused a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20 mg/kg once daily (total BMC: 172% of control; p<0.001). A small but significant effect was also seen at cortical sites (total BMC: 111% of control; p<0.001). Biomechanical testing demonstrated an increase in both vertebral compression strength at a dose of 20 mg/kg once daily (Load at failure: 370% of control, p<0.001) and diaphyseal strength of femora subjected to a three point bending test (Load at failure: 115% of control; p<0.01). Furthermore, histomorphometry showed a dramatic increase in bone formation indices, and serum markers of both bone formation (Osteocalcin, 146% of control; p<0.001) and resorption (CTX, 189% of control; p<0.001) were elevated. Our conclusion is that a GSK-3 inhibitor drug may prove effective as an anabolic strategy in the treatment of diseases characterized by low bone mass, since AZD2858 has extensive bone building effects at predominantly trabecular sites.
Insights
A potent GSK-3 inhibitor, AZD2858, significantly increased bone mass and strength in rats. This drug shows promise for treating bone diseases by promoting bone building.
Area of Science:
- Pharmacology
- Bone Biology
- Drug Discovery
Background:
- Glycogen synthase kinase 3 beta (GSK-3β) is integral to the Wnt pathway, crucial for bone mass regulation.
- Imbalances in Wnt signaling are implicated in various bone diseases, making GSK-3β a potential therapeutic target.
Purpose of the Study:
- To evaluate the efficacy of AZD2858, an orally active GSK-3 inhibitor, in increasing bone mass in a rat model.
- To investigate the effects of AZD2858 on bone formation, resorption, and biomechanical properties.
Main Methods:
- In vitro treatment of human osteoblast cells with AZD2858 to assess effects on β-catenin levels.
- In vivo oral administration of AZD2858 to rats at various doses for two weeks.
- Analysis of bone mineral content (BMC), biomechanical strength (vertebral compression and femoral bending tests), histomorphometry, and serum bone markers (Osteocalcin, CTX).
Main Results:
- AZD2858 treatment increased β-catenin levels in osteoblasts in vitro.
- Oral AZD2858 dose-dependently increased trabecular bone mass (up to 172% of control) and cortical bone mass (up to 111% of control) in rats.
- Significant improvements in vertebral compression strength (370% of control) and femoral strength (115% of control) were observed.
- Histomorphometry revealed increased bone formation, and elevated serum markers for both bone formation and resorption were noted.
Conclusions:
- AZD2858 demonstrates significant anabolic effects on bone, particularly in trabecular sites.
- GSK-3 inhibition represents a potential therapeutic strategy for conditions characterized by low bone mass.
- Further investigation into GSK-3 inhibitors like AZD2858 for treating bone diseases is warranted.
