Inactivation of Osteoblast PKC Signaling Reduces Cortical Bone Mass and Density and Aggravates Renal Osteodystrophy in Mice with Chronic Kidney Disease on High Phosphate Diet.
Fiche publication
Date publication
juin 2022
Journal
International journal of molecular sciences
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BAHRAM Siamak
Tous les auteurs :
Zaloszyc A, Choquet P, Sayeh A, Bartosova M, Schaefer B, Huegel U, Aubertin-Kirch G, Healy C, Severac F, Rizzo S, Boivin G, Schaefer F, Fischbach M, Bacchetta J, Bahram S, Schmitt CP
Lien Pubmed
Résumé
Chronic kidney disease (CKD) frequently leads to hyperphosphatemia and hyperparathyroidism, mineral bone disorder (CKD-MBD), ectopic calcifications and cardiovascular mortality. PTH activates the osteoanabolic Gα/PKA and the Gα/PKC pathways in osteoblasts, the specific impact of the latter in CKD-MBD is unknown. We generated osteoblast specific Gα knockout (KO) mice and established CKD-MBD by subtotal nephrectomy and dietary phosphate load. Bone morphology was assessed by micro-CT, osteoblast function by bone planar scintigraphy at week 10 and 22 and by histomorphometry. Osteoblasts isolated from Gα KO mice increased cAMP but not IP3 in response to PTH 1-34, demonstrating the specific KO of the PKC signaling pathway. Osteoblast specific Gα KO mice exhibited increased serum calcium and reduced bone cortical thickness and mineral density at 24 weeks. CKD Gα KO mice had similar bone morphology compared to WT, while CKD Gα-KO on high phosphate diet developed decreased metaphyseal and diaphyseal cortical thickness and area, as well as a reduction in trabecular number. Gα-KO increased bone scintigraphic tracer uptake at week 10 and mitigated tracer uptake in CKD mice at week 22. Histological bone parameters indicated similar trends. Gα-KO in osteoblast modulates calcium homeostasis, bone formation rate, bone morphometry, and bone mineral density. In CKD and high dietary phosphate intake, osteoblast Gα/PKC KO further aggravates mineral bone disease.
Mots clés
CKD-MBD, bone scintigraphy, bone μCT, parathyroid related disorder, preclinical studies
Référence
Int J Mol Sci. 2022 06 8;23(12):