Aberrant Phex function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia

Area of Science:

• Genetics
• Biochemistry
• Bone Biology

Background:

• X-linked hypophosphatemia (XLH) is a genetic disorder characterized by low phosphate levels, renal phosphate wasting, and rickets.
• The Phex gene is implicated in XLH, with mutations in PHEX/Phex identified in affected individuals and the hyp-mouse model.
• Previous studies suggested Phex expression outside of osteoblasts might be crucial for XLH, as osteoblast-specific Phex expression failed to rescue the hyp-mouse phenotype.

Purpose of the Study:

• To investigate whether abnormal Phex function solely within osteoblasts and osteocytes is sufficient to cause the hypophosphatemic (HYP) phenotype.
• To differentiate the roles of Phex expression in different cell types in the pathogenesis of XLH.

Main Methods:

• Created global Phex knockout mice (Cre-PhexDeltaflox/y).
• Generated conditional knockout mice with osteocalcin-promoted Phex inactivation in osteoblasts and osteocytes (OC-Cre-PhexDeltaflox/y).
• Compared serum phosphorus, kidney phosphate transport, FGF-23 levels, type IIa sodium phosphate cotransporter protein expression, and osteomalacia in knockout mice and hyp-mice.

Main Results:

• Global and conditional Phex knockout mice exhibited reduced serum phosphorus and impaired kidney phosphate transport, similar to hyp-mice.
• These mice also showed increased bone production, elevated serum FGF-23, decreased kidney type IIa sodium phosphate cotransporter, and osteomalacia.
• The phenotype in OC-Cre-PhexDeltaflox/y mice closely mirrored that of global Phex knockout and hyp-mice.

Conclusions:

• Aberrant Phex function specifically in osteoblasts and/or osteocytes is sufficient to cause the hypophosphatemic phenotype observed in the hyp-mouse model.
• These findings challenge the previous notion that Phex expression at other sites is essential for the XLH phenotype.
• The study highlights the critical role of Phex in bone cells for phosphate homeostasis and skeletal integrity.