title: GSK-3 inhibition by an orally active small molecule increases bone mass in rats.
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.
authors.affiliation: Department of Surgical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden. Richard.Marsell@surgsci.uu.se
authors.forename: Richard
authors.initials: R
authors.lastname: Marsell
authors.forename: Gregor
authors.initials: G
authors.lastname: Sisask
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Nilsson
authors.forename: Anna K
authors.initials: AK
authors.lastname: Sundgren-Andersson
authors.forename: Ulf
authors.initials: U
authors.lastname: Andersson
authors.forename: Sune
authors.initials: S
authors.lastname: Larsson
authors.forename: Olle
authors.initials: O
authors.lastname: Nilsson
authors.forename: Osten
authors.initials: O
authors.lastname: Ljunggren
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Jonsson
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3