title: Rats treated with AZD2858, a GSK3 inhibitor, heal fractures rapidly without endochondral bone formation.
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 30 μmol/kg (20mg/kg) daily for up to 3 weeks, while control animals were administered vehicle. At 4days, and at 1, 2 and 3 weeks, histological analysis was performed, and at the 2 and 3 week 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 2 weeks and 38% at 3weeks) and mineral content (of 81% at 2 weeks and 93% at 3 weeks) 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 3 weeks 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.
authors: Department of Surgical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden. Gregor.Sisask@akademiska.se
authors: Gregor
authors: G
authors: Sisask
authors: Richard
authors: R
authors: Marsell
authors: Anna
authors: A
authors: Sundgren-Andersson
authors: Sune
authors: S
authors: Larsson
authors: Olle
authors: O
authors: Nilsson
authors: Osten
authors: O
authors: Ljunggren
authors: Kenneth B
authors: KB
authors: Jonsson
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D002146:Bony Callus / Q000187:drug effects / Q000473:pathology; D005260:Female; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology*; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D017102:Fracture Healing / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D011859:Radiography; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: C583189:AZD2858; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D013449:Sulfonamides; D038362:Glycogen Synthase Kinase 3