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- Marsell, Richard, et al.
(författare)
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GSK-3 inhibition by an orally active small molecule increases bone mass in rats
- 2012
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:3, s. 619-627
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Tidskriftsartikel (refereegranskat)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 (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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| 2. |
- Silfverswärd, Carl-Johan, et al.
(författare)
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Bone formation in interleukin-4 and interleukin-13 depleted mice.
- 2008
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Ingår i: Acta orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 79:3, s. 410-20
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Cytokines play an important role in the complex process of bone formation. We have previously found an altered skeletal phenotype with reduction of cortical bone mass in mice depleted of the 2 cytokines interleukin-4 (IL-4) and interleukin-13 (IL 13). The present study was performed to investigate a potential role of IL-4 and IL-13 in fracture healing and bone induction by demineralized xenogenic bone matrix (DXBM). METHODS: Callus formation in IL-4-(/)-IL-13-(/)- (IL-4/13 knockout) and wild-type (WT) male mice was compared using a standardized fracture model. The capacity of IL-4(-/-)IL-13(-/-) and WT male and female mice to form heterotopic bone was compared using intramuscular implants of DXBM. Bone formation and mechanical properties were evaluated by pQCT, ash weight, 3-point bending, radiology, and immunohistology. RESULTS: In the fracture investigation substantial amounts of new bone formation by 5 weeks were found, but no differences in radiographical healing, callus volume, BMD, BMC, or mechanical properties were detected between IL-4(-/-)IL-13(-/-) and WT mice. In the DXBM investigation radiographic analysis confirmed mineralization of implants in both groups, but no difference in the amount of mineral deposition (net bone formation) between IL-4(-/-)IL-13(-/-) and WT mice was found. Immunohistology showed inhibition of autonomic nerves in the capsule of the IL-4(-/-)IL-13(-/-) group along with a lack of vascularization within the implants. INTERPRETATION: Depletion of IL-4 and IL-13 does not cause any major alteration in fracture healing or heterotopic bone formation in mice. The pattern of autonomous nerve expression and expression of markers of neovascularization is, however, altered to some extent by the absence of IL-4 and IL-13.
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| 3. |
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| 4. |
- Sisask, Gregor, et al.
(författare)
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Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation
- 2013
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 54:1, s. 126-132
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Tidskriftsartikel (refereegranskat)abstract
- Fracture healing is a complex interplay between endochondral and intramembranous bone formation processes. The canonical Wnt/β-catenin pathway enhances new bone formation and may play a role in fracture healing. Glycogen synthase kinase 3β (GSK3β) is a key regulator of β-catenin degradation. In this study, we investigate the effects of AZD2858, an orally bioactive GSK3 inhibitor, on fracture healing. Femoral fractures were produced in rats after the insertion of a femoral nail. The rats were treated with oral administration of AZD2858 at a dose of 30μmol/kg (20mg/kg) daily for up to 3weeks, while control animals were administered vehicle. At 4days, and at 1, 2 and 3weeks, histological analysis was performed, and at the 2 and 3week time points, we performed peripheral quantitative computed tomography (pQCT), X-rays, and four-point bending tests. Peripheral QCT showed an increase in both mineral density (of 28% at 2weeks and 38% at 3weeks) and mineral content (of 81% at 2weeks and 93% at 3weeks) in the calluses from AZD2858 treated animals as compared to vehicle treated animals. Histological analysis demonstrated that rats treated with GSK3 inhibitor healed their fractures rapidly, but without the pre-formation of cartilage tissue. Furthermore, four-point bending tests of fractured femora from animals treated for 2 and 3weeks showed an increase in strength in treated animals compared to their vehicle-treated controls. In conclusion, AZD2858, a potent GSK3 inhibitor, has a substantial impact on fracture healing. The fractures healed with a bony callus without an obvious endochondral component, suggesting that AZD2858 drives mesenchymal cells into the osteoblastic pathway. This leads to direct bone repair in an unstable fracture milieu.
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