{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPHEX is a zinc‐dependent endopeptidase belonging to the M13 family that is predominantly expressed in osteoblasts. Although early studies anticipated that PHEX might directly cleave circulating phosphatonins such as FGF23, experimental evidence instead shows that PHEX does not process FGF23 directly. Rather, it appears to modulate the local bone microenvironment by influencing the transcriptional regulation of fgf23 and by affecting the metabolism of extracellular matrix proteins (including MEPE, osteopontin, DMP1, and others). In addition, PHEX expression is regulated indirectly by factors such as 1α,25‐dihydroxyvitamin D₃ via transcriptional repression mechanisms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThrough its regulatory actions, PHEX is central to the bone–kidney hormonal axis that governs systemic phosphate homeostasis. In normal physiology, PHEX activity in bone limits fgf23 transcript expression so that adequate phosphate reabsorption in the kidney is maintained and proper mineralization occurs in the skeleton. When PHEX function is diminished, increased fgf23 expression leads to renal phosphate wasting, hypophosphatemia, and defective mineralization. Moreover, the enzyme’s interplay with extracellular matrix regulators underscores its role in integrating signals from vitamin D and other phosphatonins to finely tune phosphate balance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "18"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLoss‐of‐function mutations in PHEX cause X‐linked hypophosphatemia (XLH), a disorder characterized by hypophosphatemia, rickets/osteomalacia, dental abnormalities, and skeletal deformities. Extensive mutational analyses in diverse populations have revealed a wide spectrum of PHEX defects—including truncating mutations, missense changes, splice‐site alterations, and even noncoding 3′‐UTR variants—all of which disturb normal PHEX function and contribute to the complex genotype–phenotype relationships seen in affected individuals. In both human subjects and animal models, impaired PHEX activity results in dysregulated fgf23 expression and aberrant processing of local matrix proteins, thereby providing critical insights into the molecular pathogenesis of XLH and highlighting potential targets for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "45"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marcelo Campos, Constance Couture, Izaura Y Hirata, et al. 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