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Elevations in Cortical Porosity Occur Prior to Significant Rise in Serum Parathyroid Hormone in Young Female Mice with Adenine-Induced CKD

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Abstract

Chronic kidney disease (CKD) leads to significant bone loss primarily through the development of cortical porosity. In both patients and animal models of CKD, sustained elevations in serum parathyroid hormone (PTH) are associated with cortical porosity. In this study, we aimed to track the progression of cortical porosity and increased PTH utilizing the adenine-induced CKD model. Young female mice (8 weeks) were given 0.2% adenine to induce CKD. Tissues were collected from groups of adenine and age-matched control mice after 2, 6, and 10 weeks. Serum blood urea nitrogen was elevated at all time points in adenine mice, but serum PTH was only statistically elevated at the 10-week time point. Cortical porosity was sevenfold higher in 6-week adenine mice compared to age-matched controls and 14-fold higher in 10-week adenine mice vs. controls. Additionally, osteocyte receptor activator of nuclear factor κB ligand (RANKL) was elevated in adenine-fed mice, while annexin V, an early marker of cellular apoptosis, was mildly decreased in osteocytes in adenine-fed mice. Based on these results, we hypothesize high serum PTH signals to osteocytes prolonging their lifespan resulting in sustained RANKL which drives osteoclastic bone resorption in the cortex. In conclusion, our data show time-dependent elevations in serum PTH and cortical porosity in adenine-induced CKD mice and demonstrate changes in osteocyte RANKL and apoptosis which may contribute to the development of cortical pores.

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Acknowledgements

This work was supported by VA Merit Award (BX003025) from the United States (US Department of Veterans Affairs [Biomedical Laboratory Research and Development Service]) and the NIH (F32DK122731).

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Correspondence to Matthew R. Allen.

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CEM, EAS, and MRA have no conflicts of interest to disclose.

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All animal procedures were approved by the Indiana University School of Medicine Animal Use and Care Committee prior to any experiments being initiated.

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Metzger, C.E., Swallow, E.A. & Allen, M.R. Elevations in Cortical Porosity Occur Prior to Significant Rise in Serum Parathyroid Hormone in Young Female Mice with Adenine-Induced CKD. Calcif Tissue Int 106, 392–400 (2020). https://doi.org/10.1007/s00223-019-00642-w

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