Title: High Molecular Weight FGF2 in Dentin and Alveolar Bone Mineralization
Grethel Millington (Presenter)
University of Connecticut School of Dental Medicine
Johnny Joseph, University of Connecticut School of Dental Medicine
Liping Xiao, University of Connecticut Health Center
Anushree Vijaykumar, University of Connecticut health Center
Mina Mina, University of Connecticut health Center
Marja Hurley, University of Connecticut Health Center
Objectives: Our unpublished work showed that transgenic mice overexpressing the High Molecular Weight FGF2 isoforms in osteoblast lineage (HMWTg) exhibited decreased dentin and alveolar bone mineralization with increased FGF23 expression in mandibular molars. To examine if the alveolar bone and dentin mineralization defects were caused by the increased FGF23 expression, we aimed to rescue the dentin and alveolar bone mineralization defects by utilizing a neutralizing antibody against FGF23
Methods: HMWTg and VectorTg control mice were given subcutaneous injections of FGF23 neutralizing antibody (FGF23Ab, 10mg/kg, twice/week) starting at postnatal day21 for 6weeks. In addition, since Vitamin-D have direct effects in promoting bone mineralization, we aimed to determine if Vitamin-D protects against the defective dentin and alveolar bone mineralization in HMWTg mice. Therefore, HMWTg mice were given subcutaneous injections of Calcitriol (175pg/g daily) alone for 6 weeks or both Calcitriol and FGF23Ab. Mice were sacrificed and X-ray, Micro-CT, histological, and immunohistochemistry analyses were performed.
Results: Our results showed that similar to human X-Linked Hypophosphatemia (XLH) and the Hyp mouse homologue of XLH, HMWTg mice exhibited an enlarged pulp chamber. When we neutralized FGF23 activity in HMWTg mice we partially rescued the enlarged pulp chamber phenotype. Additionally, histological analyses show that the FGF23 neutralizing antibody also rescued the dentin and alveolar bone mineralization defects observed in HMWTg mice. Interestingly, we found that Calcitriol has a summative effect in promoting dentin and alveolar bone mineralization, in which HMWTg mice treated with both the FGF23 neutralizing antibody and Calcitriol further rescues the enlarged pulp chamber, dentin, and alveolar bone mineralization defect phenotypes
Conclusions: Together, our data suggest that the dentin and alveolar bone mineralization defects in HMWTg mice are caused by the increase in FGF23 expression. Our results further indicate that the HMW nuclear isoforms of FGF2 play a critical role in dentin and alveolar bone mineralization by regulating FGF23 activity.