GSK-3 inhibition by an orally active small molecule increases bone mass in rats

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.

► The Wnt-signaling pathway, which includes GSK-3, is important in bone metabolism.
► The small molecule drug AZ2858 inhibits GSK-3.
► Oral administration of AZD2858 increases bone mineral density and content in rats.
► This increase enhances both vertebral compression and diaphyseal bending strength.
► AZD2858 is a potent anabolic drug candidate for future treatment of bone disease.