Strain-specific alterations in the skeletal response to adenine-induced chronic kidney disease are associated with differences in parathyroid hormone levels.

Abstract

Female C57BL/6J (B6) and C3H/Hej (C3H) at 16-weeks of age were given a diet with 0.2% adenine to induce CKD for 6weeks followed by a control diet for 4weeks. Age- and strain-matched controls were fed the control diet without adenine for the 10-week period (n=8 per group per strain). Both strains of adenine-fed mice had elevated blood urea nitrogen, demonstrating compromised kidney function, compared to strain-matched controls, but only B6 adenine mice had statistically higher parathyroid hormone (PTH), greater cortical porosity, high bone turnover rate, a greater percentage of osteocytes positive for RANKL and IL-17, and lower osteocyte apoptosis compared to B6 controls. C3H mice had intracortical remodeling present in both control and adenine mice, while B6 mice had intracortical remodeling present only in adenine mice. Adenine mice of both strains had lower cortical thickness and a higher percentage of osteocytes positive for TNF-α compared to controls. While both strains of mice had biochemical markers of kidney disease, only B6 mice developed a phenotype with significantly elevated PTH, high bone turnover, and cortical porosity development. This work, in a model of progressive CKD, further confirms the role of chronically elevated PTH in the development of cortical porosity and demonstrates adenine-induced increases in PTH contribute to intracortical remodeling in B6 mice. Adenine-induced changes that occurred in both strains of mice, notably lower cortical thickness and a higher percentage of osteocytes expressing TNF-α, indicate potential PTH-independent responses to CKD.