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

• Published in: Bone (New York, N.Y.) N.Y.), 2012-03, Vol.50 (3), p.619-627
• Main Authors: Marsell, Richard, Sisask, Gregor, Nilsson, Yvonne, Sundgren-Andersson, Anna K, Andersson, Ulf, Larsson, Sune, Nilsson, Olle, Ljunggren, Östen, Jonsson, Kenneth B
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - metabolism; Biological and medical sciences; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone Density - drug effects; Bone Remodeling - drug effects; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Female; Fundamental and applied biological sciences. Psychology; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Humans; Medical sciences; Orthopedics; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoporosis. Osteomalacia. Paget disease; Rats; Rats, Sprague-Dawley; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Wnt Signaling Pathway - drug effects
• ISSN: 8756-3282; 1873-2763; 1873-2763
• DOI: 10.1016/j.bone.2011.11.007

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.