Abstract
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.
Highlights
The incidence of bone fractures is high in patients with chronic kidney disease (CKD) (Alem et al 2000; Nickolas et al 2006; Ensrud et al 2007; Fried et al 2007), and this increased incidence is associated with high rates of hospitalization, disability, and mortality in patients with CKD (Mittalhenkle et al 2004; Nitsch et al 2009; Tentori et al 2014)
Body weight at week 6 was significantly lower in CKD, CKD-glycogen synthase kinase (GSK)-3b+/À, and CKD+LiCl mice than in control diet (CNT) mice
Food intake was significantly lower in CKD mice than in CNT mice, while there were no significant differences in food intake among the three CKD groups (Table 1)
Summary
The incidence of bone fractures is high in patients with chronic kidney disease (CKD) (Alem et al 2000; Nickolas et al 2006; Ensrud et al 2007; Fried et al 2007), and this increased incidence is associated with high rates of hospitalization, disability, and mortality in patients with CKD (Mittalhenkle et al 2004; Nitsch et al 2009; Tentori et al 2014). Studies have shown that impaired bone quality and quantity in CKD are ascribed to decreased bone strength, which enhances the risk for bone fractures Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society Retention of uremic toxins, acidemia, hypogonadism, increased oxidative stress and inflammation, and malnutrition may partly contribute to impairment in bone quality and quantity (Nickolas et al 2008; Kazama et al 2013; Dru€eke and Massy 2016). The pathogenesis behind the increased incidence of bone fractures among the CKD population still remains unclear. Identification of pathways that critically regulate bone pathology in CKD patients is required to prevent uremia-related bone fractures
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