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Kidney Week

Abstract: TH-PO518

Increases in Osteocyte RANKL Correspond with Elevated Cortical Porosity in Adenine-Induced CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Metzger, Corinne E., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Swallow, Elizabeth A., Indiana University, Indianapolis, Indiana, United States
  • Allen, Matthew R., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Chronic kidney disease (CKD) increases bone fragility and fracture incidence. Bone loss in CKD preferentially occurs within the cortical bone through the development of porosity. For cortical pores to form, osteoclasts must be recruited into the cortex to locally induce bone resorption. Receptor activator of nuclear factor ΚB ligand (RANKL) is a key osteoclastogenesis regulator that is released by various cells within bone including osteocytes. We hypothesized that elevated cortical osteocyte RANKL coincides with the development of cortical pores in adenine-induced CKD.

Methods

Female C57BL/6J mice (8-wk-old) were fed a casein-based diet (0.9% P, 0.6% Ca) with 0.2% adenine (Ad) to induce CKD. Age-matched controls (Con) were fed the same casein-based diet without adenine. Mice were terminated after 2, 6, and 10 weeks.

Results

Serum blood urea nitrogen was elevated at all time points in Ad vs. Con confirming the induction of kidney disease. MicroCT of the distal 1/3 shaft of the femur demonstrated that Ad mice had porosity not different from Con at 2 weeks, mild cortical porosity at 6 weeks (1.9%; p<0.001 vs Con), and a greater average porosity at 10 weeks (4.1%, p=0.01 vs Con). At 2 weeks, the percentage of cortical osteocytes in the femoral shaft that stained positive for RANKL (%RANKL+) was 20% higher in Ad vs. Con while at 6 and 10 weeks %RANKL+ osteocytes were 115% higher and 277% higher, respectively, compared to Con. A time-by-treatment statistical analysis indicated significant impact of Ad treatment and a time-by-treatment interaction effect whereby Con groups had decreasing %RANKL+ osteocytes with age and Ad groups maintained high %RANKL+ osteocytes with age. This indicates adenine-induced CKD increased osteocyte RANKL in younger animals as well as prevented age-related declines in osteocyte RANKL as animals age in the presence of disease.

Conclusion

In conclusion, we determined that both osteocyte RANKL and cortical porosity are elevated over time in adenine-induced CKD. We hypothesize in CKD osteocytes release RANKL signaling osteoclasts into the cortical bone leading to the development of cortical porosity. Future research should address the factors altered in CKD, such as elevated parathyroid hormone, which are responsible for stimulating osteocytes to produce RANKL.

Funding

  • Veterans Affairs Support