Increased PHOSPHO1 expression mediates cortical bone mineral density in renal osteodystrophy

Area of Science:

• Bone Biology
• Mineral Metabolism
• Renal Osteodystrophy

Background:

• Advanced chronic kidney disease (CKD) frequently causes skeletal abnormalities, termed renal osteodystrophy (ROD).
• Tissue non-specific alkaline phosphatase (TNAP) and PHOSPHO1 are crucial for bone mineralization, but their specific roles in ROD pathogenesis remain unclear.

Purpose of the Study:

• To investigate the roles of TNAP and PHOSPHO1 in the development of ROD.
• To elucidate the molecular mechanisms underlying skeletal mineralization defects in CKD.

Main Methods:

• Rodent models of CKD were established using dietary adenine supplementation in wild-type (WT) and Phospho1 knockout (P1KO) mice.
• Bone mineral density (BMD), bone turnover markers, and gene expression of TNAP and PHOSPHO1 were analyzed.
• Primary murine osteoblasts were treated with FGF23, parathyroid hormone (PTH), and phosphate to assess effects on PHOSPHO1 and TNAP expression.

Main Results:

• CKD mice exhibited hyperphosphatemia, hyperparathyroidism, and altered BMD (increased cortical, decreased trabecular).
• WT CKD bones showed decreased TNAP and increased PHOSPHO1 expression; P1KO CKD mice had rescued cortical BMD.
• In vitro studies indicated that phosphate and PTH downregulated both PHOSPHO1 and TNAP expression in osteoblasts.

Conclusions:

• Increased PHOSPHO1 expression in CKD mice contributes to elevated cortical bone mineral density.
• The observed TNAP reduction in CKD-related mineral and bone disorder (CKD-MBD) is likely driven by hyperphosphatemia and/or hyperparathyroidism.
• Elevated PHOSPHO1 may represent a compensatory response to disordered mineralization in ROD.