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GSK-3 inhibition by...
GSK-3 inhibition by an orally active small molecule increases bone mass in rats
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- Marsell, Richard (författare)
- Uppsala universitet,Ortopedi
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- Sisask, Gregor (författare)
- Uppsala universitet,Ortopedi
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Nilsson, Yvonne (författare)
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Sundgren-Andersson, Anna K (författare)
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Andersson, Ulf (författare)
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- Larsson, Sune (författare)
- Uppsala universitet,Ortopedi
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- Nilsson, Olle (författare)
- Uppsala universitet,Ortopedi
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- Ljunggren, Östen (författare)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Metabola bensjukdomar
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- Jonsson, Kenneth B (författare)
- Uppsala universitet,Ortopedi
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(creator_code:org_t)
- Elsevier BV, 2012
- 2012
- Engelska.
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:3, s. 619-627
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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 (1μM) 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 20mg/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 20mg/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.
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