LAUSR

Background: X-linked hypophosphatemia (XLH) is the most common form of familial phosphate-wasting disorders, due to an inactivating mutation in the phosphate-regulating neutral endopeptidase, X-linked gene. Persistent osteomalacia, enthesophytes, osteophytes, degenerative arthritis and dental abscesses/periodontal disease dominate the adult disorder. However, the impact of insufficient phosphate on hydroxyapatite composition, the major inorganic component of bone and teeth, is unknown in individuals with XLH. Methods: Using Raman spectroscopy, the carbonate (CO32−) to phosphate (PO43−) ion ratio was measured in HYP and wild-type mice and in primary and permanent teeth from XLH individuals and unaffected controls. Results: There was a significant difference in carbonate ion substitution between the HYP and wild-type femoral cortical bone (0.36 ± 0.08 versus 0.24 ± 0.04; p < 0.001). Carbonate ion substitution levels were also higher in permanent XLH teeth compared with unaffected individuals (0.39 ± 0.12 versus 0.23 ± 0.04; p < 0.001), but not in primary teeth (0.29 ± 0.11 versus 0.26 ± 0.02; p = 0.29). Complementary Fourier transform infrared analyses demonstrated higher relative intensities of the four major vibrational bands originating from the carbonate anion in XLH teeth compared with unaffected controls. Conclusion: Ionic substitution within the crystal lattice is a common feature of hydroxyapatite and one that confers the physiological properties of bone that impact mechanical strength and the process of bone remodeling. Our data demonstrating anionic substitution in human dentin from individuals with XLH validate the use of dentin as a proxy for bone and to better understand the molecular adaptations that occur in the biochemical milieu of XLH.