Mineral and Bone Biomarkers Associate with Adverse Cardiovascular Outcomes and Mortality Within the German Chronic Kidney Disease (GCKD) Cohort
Abstract
Background: Osteocytes are the master regulator of bone remodeling, and studies in CKD patients and animals show defective osteocyte function and maturation regardless of the PTH level suggesting other CKD specific factors may affect osteocytes. Indoxyl sulfate (IS) has been shown to have an effect on osteoclasts and osteoblasts, but the IS effect on osteocytes has not been evaluated. IS is a potent endogenous ligand for aryl hydrocarbon receptor (AhR) which is critical in the removal of toxins and can lead to inflammation, changes in steroid hormones and altered MAP kinase signaling. Methods: We therefore evaluated the effect of IS with and without PTH on differentiation, signaling, and mineralization in mature osteocytes (day 35) and in early osteocytes when mineralization is occurring (day 14) using IDG-SW3 cell line. Results: The results demonstrated that in mature osteocytes, the addition of IS for 24 hrs dose dependently increased the expression of bone forming genes SOST and Dkk1, bone resorbing genes RANKL/OPG ratio and oxidative stress genes NOX1 & NOX4 (all P<0.01) but no effect on FGF23. In contrast, PTH treatment for 24 hrs decreased SOST by 135 fold, Dkk1 by 155 fold (p<0.01) and increased RANKL/OPG ration by 1080 fold (p<0.001) with no effect on NOX. IS, but not PTH, inhibited MAP kinase activity (ERK1/2; p <0.002) and induced AhR activity assessed by downstream CYP1A1 (increased by10 fold) & CYP1B1 (increased by 4.5-fold) (p<0.001). Thus, in mature osteocytes,…
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Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
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