Abstract: TH-OR32
Bone Sialoprotein Regulates Phosphate Metabolism and Reduces Hyperparathyroidism in Mice with CKD
Session Information
- CKD-MBD and Kidney Stones: Novel Insights
October 24, 2024 | Location: Room 6D, Convention Center
Abstract Time: 05:10 PM - 05:20 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Lafage-Proust, Marie-Helene, Université J Monnet, Inserm U1059, Saint-Etienne, France
- Hivert, Lauriane, Université J Monnet, Inserm U1059, Saint-Etienne, Auvergne Rhone Alpes, France
- Soulage, Christophe O., Université Lyon 1, Lyon, France
- Beck, Laurent, UMR_S 1087 / UMR_C 6291 l'Unité de Recherche de l'Institut du Thorax, Nantes, France
- Malaval, Luc, Université J Monnet, Inserm U1059, Saint-Etienne, Auvergne Rhone Alpes, France
Group or Team Name
- Sainbiose Lab.
Background
Bone Sialoprotein (BSP), Osteopontin (OPN), DMP1 and MEPE, regulate bone mineralization and are closely co-regulated. While DMP1 and MEPE are known to impact phosphate (Pi) metabolism, we hypothesized that BSP might also influence body Pi handling.
Methods
Nine-week-old (WT) and BSP knockout (KO) mice fed a normal Pi diet (0.55% Pi, ND). We collected 24h urine, feces, blood, femur, kidneys and gut samples for biochemical and molecular analyses.
Results
WT and KO had normal Pi and FGF23 serum levels (s) but KO were hypophosphaturic (-75% vs WT). KO expressed lower NaPi2c renal transporter mRNA levels (p<0.006 vs WT) while NPT2b and Pit1/2 gut expression were similar to WT. We suspected impaired paracellular Pi gut absorption, a key pathway under ND. Indeed, KO exhibited significant higher water (200%), K+ (50%), Na+ and Pi levels in feces (p<0.01 vs WT). Multiplex gene expression analysis of gut revealed differential regulation of genes related to matrix remodeling, including higher DMP1, confirmed by RT-PCR (x10 in KO vs WT), BSP and MEPE mRNAs being undetectable. As Chronic kidney disease (CKD) raises systemic Pi load, increasing cardiovascular mortality, we hypothesized that lack of BSP could mitigate CKD-Mineral and Bone Disorders (CKD-MBD) by reducing Pi intestinal absorption. We performed 5/6 nephrectomy (Nx) or sham surgery on 20-wk-old WT and KO mice. After 3 months of CKD, both genotypes showed higher ureamia compared to their sham controls. However, FGF23 (s) rose less in Nx-KO compared to Nx-WT (p<0.05) while serum Pi remained normal. Fractional urine Pi excretion increased in both genotypes but remained twice lower in Nx-KO than in Nx-WT (p<0.05). After 3 months of high Pi diet (1.65% Pi, HP), Nx-KO were neither hypophosphaturic nor had lower FGF23 (s) compared to Nx-WT. In addition, KO displayed higher PTH serum levels (x1.5) and cortical porosity (µCT) compared to Nx-WT.
Conclusion
Deletion of BSP, a bone-specific protein, decreased gut paracellular Pi absorption, possibly involving DMP1, known to regulate Blood Brain Barrier permeability. In CKD and under ND, the blunting of FGF23 increase in KO suggests an adverse role of BSP in Pi homeostasis, while, under HP, BSP might protect against CKD-MBD by reducing secondary hyperparathyroidism and its harmful effects on cortical bone.
Funding
- Commercial Support – KIOWA-KRIRIN