Abstract
AIM: X-linked Hypophosphatemia (XLH), caused by PHEX mutations, hinders skeletal and dental mineralization and contributes to tooth loss. While XLH is associated with dental implant-related complications, no clinical or preclinical studies have investigated socket healing. XLH secondarily disrupts local mineral metabolism by increasing levels of the mineralization inhibitors, osteopontin (OPN) and inorganic pyrophosphate (PP(i)). Tissue-nonspecific alkaline phosphatase (TNAP) promotes mineralization by dephosphorylating OPN and hydrolyzing PP(i). In this proof-of-principle study, we hypothesized that alveolar bone socket healing defects in the Hyp mouse model of XLH would be improved by exogenous TNAP. METHODS: Maxillary first molars were extracted from wild-type (WT) and Hyp mice at 6 weeks, and collagen gel ± mineral-targeted TNAP (TNAP-Fc-D(10); asfotase alfa) was placed in sockets. Submucosal injections of TNAP-Fc-D(10) or saline were delivered at 7 and 14 days post-procedure (dpp) in some mice. Maxillae were collected at 21 dpp for micro-computed tomography, histology, and RT-qPCR. RESULTS: Untreated Hyp mice showed impaired socket healing compared to WT mice in bone volume and density. TNAP delivered at the time of extraction was unable to improve healing in Hyp mice. However, additional local TNAP delivery increased both alveolar bone volume and density in Hyp mice. Histology indicated repeated TNAP increased both woven and mature bone in Hyp mouse sockets. Immunostaining for osteopontin and bone sialoprotein suggested partial resolution of osteoid accumulation. CONCLUSION: TNAP enhanced socket healing in Hyp mice, overcoming inherent bone healing defects in XLH. These results provide new insights into bone healing with implications beyond alveolar bone in XLH.