IADR Abstract Archives
Enzyme Replacement Improves Socket Healing in a Mouse Modeling Hypophosphatasia Dentoalveolar Disease
Objectives: Hypophosphatasia (HPP) is an inherited skeletal dysplasia resulting from loss-of-function mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNAP). HPP causes a range of dental disorders contributing to premature tooth loss. The only current treatment is a mineralized tissue-targeted enzyme replacement therapy, asfotase alfa (TNAP-D10). Low alveolar bone quality and quantity in edentulous areas of patients with HPP may impact osseointegration following implant placement. There are a lack of studies testing effects of TNAP-D10 on alveolar bone socket healing in HPP. We hypothesized impaired socket healing from conditional TNAP deletion in a mouse model of HPP would be improved by TNAP-D10.
Methods: We generated Wnt1-Cre2; Alplfl/fl conditional knockout (cKO) mice to target Alpl deletion in neural crest-derived dentoalveolar tissues. First maxillary molars of cKO and control (CTR) mice were extracted at 42 days postnatal and allowed to heal for 21 days (n=5-7/group). For treatment, mice were subcutaneously injected with 8.2 mg/kg TNAP-D10 or saline starting 2 days prior to extraction and every other day until the end of the study (n=4 /group). Socket healing was assessed by micro-computed tomography and histology.
Results: Alpl cKO mice exhibited developmental defects including reduced dentin, cementum, and alveolar bone volumes and/or densities. After extraction, cKO mice exhibited dramatically reduced bone healing compared to CTR, including 50% or greater reduction in bone volume fraction (BV/TV) and bone mineral density (BMD), and 10% reduction in tissue mineral density (TMD) of new bone (p<0.001 for all). Compared to untreated cKO mice, those administered TNAP-D10 showed 50% increased BV/TV (p<0.05).
Conclusions: This dentoalveolar tissue-targeted mouse model of HPP exhibited alveolar bone socket healing defects. Even a short course of TNAP-D10 promoted increased alveolar bone healing. More studies are required to determine if implant osseointegration/stability in those affected by HPP would be improved by treatment.
Methods: We generated Wnt1-Cre2; Alplfl/fl conditional knockout (cKO) mice to target Alpl deletion in neural crest-derived dentoalveolar tissues. First maxillary molars of cKO and control (CTR) mice were extracted at 42 days postnatal and allowed to heal for 21 days (n=5-7/group). For treatment, mice were subcutaneously injected with 8.2 mg/kg TNAP-D10 or saline starting 2 days prior to extraction and every other day until the end of the study (n=4 /group). Socket healing was assessed by micro-computed tomography and histology.
Results: Alpl cKO mice exhibited developmental defects including reduced dentin, cementum, and alveolar bone volumes and/or densities. After extraction, cKO mice exhibited dramatically reduced bone healing compared to CTR, including 50% or greater reduction in bone volume fraction (BV/TV) and bone mineral density (BMD), and 10% reduction in tissue mineral density (TMD) of new bone (p<0.001 for all). Compared to untreated cKO mice, those administered TNAP-D10 showed 50% increased BV/TV (p<0.05).
Conclusions: This dentoalveolar tissue-targeted mouse model of HPP exhibited alveolar bone socket healing defects. Even a short course of TNAP-D10 promoted increased alveolar bone healing. More studies are required to determine if implant osseointegration/stability in those affected by HPP would be improved by treatment.