Abstract
Patients with advanced chronic kidney disease (CKD) often present with skeletal abnormalities; a condition known as renal osteodystrophy (ROD). While Tissue-nonspecific alkaline phosphatase (TNAP) and PHOSPHO1 are critical for bone mineralization, their role in the etiology of ROD is unclear. To address this, ROD was induced in both wild-type and Phospho1 knockout (P1KO) mice using dietary adenine supplementation. The mice presented with hyperphosphatemia, hyperparathyroidism, and elevated levels of FGF23 and bone turnover markers. In particular, we noted that in CKD mice, bone mineral density (BMD) was increased in cortical bone (p < 0.05) but decreased in trabecular bone (p < 0.05). These changes were accompanied by decreased TNAP (p < 0.01) and increased PHOSPHO1 (p < 0.001) expression in wild-type CKD bones. In P1KO CKD mice, the cortical BMD phenotype was rescued, suggesting that the increased cortical BMD of CKD mice was driven by increased PHOSPHO1 expression. Other structural parameters were also improved in P1KO CKD mice. We further investigated the driver of the mineralization defects, by studying the effects of FGF23, PTH, and phosphate administration on PHOSPHO1 and TNAP expression by primary murine osteoblasts. We found both PHOSPHO1 and TNAP expression to be down-regulated in response to phosphate and PTH. The in vitro data suggest that the TNAP reduction in CKD-MBD is driven by the hyperphosphatemia and/or hyperparathyroidism noted in these mice, while the higher PHOSPHO1 expression may be a compensatory mechanism. Increased PHOSPHO1 expression in ROD may contribute to the disordered skeletal mineralization characteristic of this progressive disorder.
| Original language | English |
|---|---|
| Pages (from-to) | 153-167 |
| Number of pages | 15 |
| Journal | Journal of Endocrinology |
| Volume | 254 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 12 Aug 2022 |
Bibliographical note
Funding Information:This work was funded by the Tri-Service General Hospital (TSGH), National Defense Medical Center (NDMC), Taiwan, through a Ph.D. scholarship award to S-N H. The authors are also grateful to the Biotechnology and Biological Sciences Research Council (BBSRC) for Institute Strategic Programme Grant Funding BB/J004316/1 to C F, L A S and V E M, grant DE12889 from the National Institute of Dental and Craniofacial Research (NIDCR) to J L M and Versus Arthritis (grant 20581) awarded to A A P to support B J. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The authors thank Elaine Seawright and Yao-Tang Lin for technical assistance; Darren Smith, Tricia Mathieson, Heather Warnock, Lorraine Blackford, Lee Mcmanus, and the staff of the animal care facility at Biological Research Facility (BRF) providing animal support; Colin Wood and the staff at Easter Bush Pathology, Royal (Dick) School of Veterinary Studies, University of Edinburgh for conducting mouse serum biochemistries.
Funding Information:
This work was funded by the Tri-Service General Hospital (TSGH), National Defense Medical Center (NDMC), Taiwan, through a Ph.D. scholarship award to S-N H. The authors are also grateful to the Biotechnology and Biological Sciences Research Council (BBSRC) for Institute Strategic Programme Grant Funding BB/J004316/1 to C F, L A S and V E M, grant DE12889 from the National 阀nstitute of Dental and Craniofacial Research (N 阀DCR) to J L M and Versus Arthritis (grant 20581) awarded to A A P to support B J. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2022 The authors Published by Bioscientifica Ltd.
Keywords
- bone mineralization
- bone mineral density
- chronic kidney disease-mineral bone disorder
- renal osteodystrophy
- PHOSPHO1
- TNAP