FGF23 is processed by proprotein convertases but not by PHEX

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• X-linked hypophosphatemia (XLH) and autosomal dominant hypophosphatemic rickets (ADHR) involve renal phosphate wasting and bone abnormalities.
• Gain-of-function mutations in fibroblast growth factor 23 (FGF23) cause ADHR, linked to impaired FGF23 processing.
• Loss-of-function mutations in the PHEX gene cause XLH, with its role in FGF23 processing remaining unclear.

Purpose of the Study:

• To investigate the enzymes responsible for processing FGF23.
• To determine if PHEX cleaves FGF23, and to identify the enzyme that cleaves FGF23 in ADHR.

Main Methods:

• Co-incubation of FGF23 constructs with subtilisin-like proprotein convertases (SPCs) and PHEX in HEK293 cells.
• Inhibition of FGF23 cleavage using a specific SPC inhibitor.
• Use of secreted PHEX (secPHEX) and various FGF23 fragments (intact, N-terminal, C-terminal).

Main Results:

• FGF23 cleavage in HEK293 cells was inhibited by a specific SPC inhibitor, suggesting SPCs are involved.
• SPCs are expressed in HEK293 cells and osteoblasts.
• Experiments provided evidence against PHEX cleaving intact FGF23 or its fragments.

Conclusions:

• Subtilisin-like proprotein convertases (SPCs) likely process FGF23.
• PHEX does not appear to cleave FGF23, challenging previous hypotheses.
• Findings contribute to understanding the molecular mechanisms of hypophosphatemic disorders.