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Abstract: FR-PO314

Uremic Toxin Indoxyl Sulfate (IS) and Parathyroid Hormone (PTH) Interact and Affect Osteocyte Signaling and Function

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Chen, Neal X., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • O'Neill, Kalisha, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States
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, PTH and IS have opposing effects on osteocyte genes, oxidative stress, mediated by different mechanisms. To assess the impact of IS and PTH on mineralization, osteocytes were treated with IS or PTH alone or together for 14 days. IS and PTH both decreased alkaline phosphatase activity and together reduced further. IS also reduced mineralization but PTH had no effect. PTH increased cAMP secretion by 90%, whereas IS decreased cAMP secretion by 60% alone and significantly reduced PTH induced cAMP secretion in osteocytes (p<0.002).

Conclusion

In conclusion, IS and PTH have additive effects to inhibit early osteocyte mineralization, and opposing effects on mature osteocyte signaling and the gene expression involved in regulation of bone remodeling and differentiation. These results indicate IS is a major uremic toxin affecting osteocytes.

Funding

  • Private Foundation Support