Increased Phospho1 Expression Mediates Cortical Bone Mineral Density in Renal Osteodystrophy
| Autor: | Shun-Neng Hsu, Louise A Stephen, Scott Dillon, Elspeth Milne, Behzad Javaheri, Andrew A Pitsillides, Amanda Novak, Jose Luis Millán, Vicky E Macrae, Katherine A Staines, Colin Farquharson |
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| Rok vydání: | 2022 |
| Předmět: |
medicine.medical_specialty
History Polymers and Plastics Endocrinology Diabetes and Metabolism urologic and male genital diseases Industrial and Manufacturing Engineering Phosphates Bone remodeling Mice Hyperphosphatemia Endocrinology Bone Density Internal medicine medicine Animals Renal Insufficiency Chronic Business and International Management Klotho Chronic Kidney Disease-Mineral and Bone Disorder Mice Knockout Hyperparathyroidism business.industry ALPL Osteoblast medicine.disease Phosphoric Monoester Hydrolases female genital diseases and pregnancy complications medicine.anatomical_structure Alkaline phosphatase Cortical bone business |
| Zdroj: | Hsu, S-N, Stephen, L, Dillon, S, Milne, E, Javaheri, B, Pitsillides, A A, Novak, A, Millán, J L, MacRae, V, Staines, K & Farquharson, C 2022, ' Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy ', Journal of Endocrinology, vol. 254, no. 3, pp. 153-167 . https://doi.org/10.1530/JOE-22-0097 |
| ISSN: | 1556-5068 |
| DOI: | 10.2139/ssrn.4069614 |
| Popis: | 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 recognized to be 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. While matrix mineralization was increased with phosphate (Pi), it decreased with PTH and FGF23 had no effect. 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 in an attempt to protect the bone from hypomineralization. We propose that increased PHOSPHO1 expression in ROD may contribute to the disordered skeletal mineralization characteristic of this progressive disorder. |
| Databáze: | OpenAIRE |
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