Pathogenic role of Fgf23 in Dmp1-null mice

Area of Science:

• Genetics and Molecular Biology
• Endocrinology and Metabolism
• Skeletal Biology

Background:

• Autosomal recessive hypophosphatemic rickets (ARHR) is linked to inactivating mutations in dentin matrix protein 1 (DMP1).
• ARHR shares features with X-linked hypophosphatemia (XLH) and autosomal dominant hypophosphatemic rickets (ADHR), both involving FGF23 dysregulation.
• Elevated FGF23 levels are observed in ARHR and Dmp1-null mice, indicating a potential role for FGF23.

Purpose of the Study:

• To investigate the causal role of FGF23 in the pathogenesis of ARHR.
• To elucidate the relationship between DMP1, FGF23, and phosphate/vitamin D metabolism.

Main Methods:

• Generation of double knockout mice lacking both Fgf23 and Dmp1 (Dmp1(-/-)/Fgf23(-/-)).
• Phenotypic analysis of single knockout (Dmp1(-/-) and Fgf23(-/-)) and double knockout mice.
• Measurement of serum phosphate, 1,25(OH)(2)D levels, and assessment of rickets and osteomalacia.

Main Results:

• Dmp1(-/-) mice exhibited hypophosphatemia, normal 1,25(OH)(2)D, rickets, osteomalacia, and elevated FGF23.
• Fgf23(-/-) mice showed hyperphosphatemia, elevated 1,25(OH)(2)D, growth retardation, and focal osteomalacia.
• Dmp1(-/-)/Fgf23(-/-) mice displayed FGF23 deficiency, normal phosphate and 1,25(OH)(2)D levels, and focal osteomalacia, with rickets ameliorated.

Conclusions:

• DMP1 regulates extracellular matrix mineralization and is linked to renal phosphate handling and vitamin D metabolism.
• These functions are mediated through DMP1's control over FGF23 production by osteocytes.
• FGF23 is a critical mediator in the pathophysiology of DMP1-associated hypophosphatemic rickets.