Inhibition of GSK-3β increases trabecular bone volume but not cortical bone volume in adenine-induced uremic mice with severe hyperparathyroidism.
Patients with chronic kidney disease (CKD) are at increased risk for bone fractures compared with the general population. Repression of the Wnt/β-catenin signaling pathway is associated with bone abnormalities. Inhibition of glycogen synthase kinase (GSK)-3β, a critical component of the Wnt/β-catenin signaling pathway, increases bone volume through accumulation of β-catenin. It remains unknown whether inhibition of GSK-3β increases bone volume in CKD The present in vivo study examined the effects of GSK-3β inhibition on bone volume in CKD mice. Wild-type mice were divided into three groups. One group was fed a control diet (CNT) and the other two groups were fed a diet containing 0.2% adenine and given water with or without lithium chloride (LiCl), a GSK-3 inhibitor (CKD, CKD+LiCl, respectively). GSK-3β heterozygous knockout mice were fed a diet containing 0.2% adenine (CKD-GSK-3β+/-). After 6 weeks, trabecular and cortical bone volumes of the femur were analyzed using microcomputed tomography. CKD mice developed azotemia, hyperphosphatemia, and hyperparathyroidism, followed by a decrease in cortical bone volume without any change in trabecular bone volume. Serum levels of urea nitrogen, phosphate, and parathyroid hormone were comparable among the three groups of CKD mice. Trabecular bone volume increased in CKD-GSK-3β+/-and CKD+LiCl mice compared with CNT and CKD mice. However, there were no significant differences in cortical bone volume among the three groups of CKD mice. The results suggest that inhibition of GSK-3β increases trabecular bone volume but not cortical bone volume in adenine-induced uremic mice with uncontrolled hyperparathyroidism.
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.|Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Narihito
N
Tatsumoto
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan arioka@clipharm.med.kyushu-u.ac.jp.
Masaki
M
Arioka
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Shunsuke
S
Yamada
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.|Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Fumi
F
Takahashi-Yanaga
Department of Internal Medicine, Fukuoka Dental College, Fukuoka, Japan.
Masanori
M
Tokumoto
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.|Department of Integrated Therapy for Chronic Kidney Disease, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Kazuhiko
K
Tsuruya
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Takanari
T
Kitazono
Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Toshiyuki
T
Sasaguri
D000225:Adenine / Q000009:adverse effects*; D000818:Animals; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000254:growth & development; D000071538:Cortical Bone / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000254:growth & development; D050723:Fractures, Bone / Q000150:complications / Q000503:physiopathology; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006961:Hyperparathyroidism / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced* / Q000150:complications; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D055114:X-Ray Microtomography / Q000379:methods
D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000225:Adenine
Bone fracture; Wnt/β‐catenin signaling pathway; chronic kidney disease; glycogen synthase kinase‐3β