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

Marsell, Richard; Sisask, Gregor; Nilsson, Yvonne; Sundgren-Andersson, Anna K.; Andersson, Ulf; Larsson, Sune; Nilsson, Olle; Ljunggren, Östen; Jonsson, Kenneth B.

Affiliations

¹Department of Surgical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden

²AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden

³AstraZeneca R&D, Toxicology Sciences, Global Safety Assessment, Mölndal, SE-431 83 Mölndal, Sweden

⁴Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden

Abstract and keywords

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.

Keywords: GSK-3; Osteoporosis; BMD; Wnt; β-Catenin; Bone formation

Links

DOI: 10.1016/j.bone.2011.11.007

PubMed: 22142634

WoS: 000300650100006

History

Received: 2011-06-13

Revised: 2011-11-11

Accepted: 2011-11-15

Online: 2011-11-25

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Cited By (2)

Year	Entry
2020	Schupbach D, Comeau-Gauthier M, Harvey E, Merle G. Wnt modulation in bone healing. Bone. September 2020;138:115491.
2013	Morton JJ. An Investigation of Rat Vertebra Failure Behaviour Under Uniaxial Compression Through Time-Lapsed Micro-CT Imaging [Master's thesis]. Kingston, ON: Queen's University; 2013.