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GSK-3 inhibition by...
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Marsell, RichardUppsala universitet,Ortopedi
(author)
GSK-3 inhibition by an orally active small molecule increases bone mass in rats
- Article/chapterEnglish2012
Publisher, publication year, extent ...
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Elsevier BV,2012
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-164308
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-164308URI
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https://doi.org/10.1016/j.bone.2011.11.007DOI
Supplementary language notes
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Language:English
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Summary in:English
Part of subdatabase
Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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.
Added entries (persons, corporate bodies, meetings, titles ...)
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Sisask, GregorUppsala universitet,Ortopedi(Swepub:uu)gregsisa
(author)
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Nilsson, Yvonne
(author)
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Sundgren-Andersson, Anna K
(author)
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Andersson, Ulf
(author)
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Larsson, SuneUppsala universitet,Ortopedi(Swepub:uu)sunelars
(author)
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Nilsson, OlleUppsala universitet,Ortopedi(Swepub:uu)olnil677
(author)
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Ljunggren, ÖstenUppsala universitet,Institutionen för medicinska vetenskaper,Metabola bensjukdomar(Swepub:uu)osteljun
(author)
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Jonsson, Kenneth BUppsala universitet,Ortopedi(Swepub:uu)kennjons
(author)
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Uppsala universitetOrtopedi
(creator_code:org_t)
Related titles
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In:Bone: Elsevier BV50:3, s. 619-6278756-32821873-2763
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