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The effects of tissue-non-specific alkaline phosphatase gene therapy on craniosynostosis and craniofacial morphology in the FGFR2C342Y/+ mouse model of Crouzon craniosynostosis.
Orthod Craniofac Res. 2015 Apr; 18 Suppl 1:196-206.OC

Abstract

OBJECTIVES

Craniosynostosis, the premature fusion of cranial bones, has traditionally been described as a disease of increased bone mineralization. However, multiple mouse models of craniosynostosis display craniosynostosis simultaneously with diminished cranial bone volume and/or density. We propose an alternative hypothesis that craniosynostosis results from abnormal tissue mineralization through the downregulation of tissue-non-specific alkaline phosphatase (TNAP) enzyme downstream of activating mutations in FGFRs.

MATERIAL AND METHODS

Neonatal Crouzon (FGFRC342Y/+) and wild-type (FGFR+/+) mice were injected with lentivirus to deliver a recombinant form of TNAP. Mice were sacrificed at 4 weeks postnatal. Serum was collected to test for alkaline phosphatase (AP), phosphorus, and calcium levels. Craniofacial bone fusion and morphology were assessed by micro-computed tomography.

RESULTS

Injection with the TNAP lentivirus significantly increased serum AP levels (increased serum AP levels are indicative of efficient transduction and production of the recombinant protein), but results were variable and dependent upon viral lot and the litter of mice injected. Morphological analysis revealed craniofacial form differences for inferior surface (p=0.023) and cranial height (p=0.014) regions between TNAP lentivirus-injected and vehicle-injected Crouzon mice. With each unit increase in AP level, the odds of lambdoid suture fusion decreased by 84.2% and these results came close to statistical significance (p=0.068).

CONCLUSION

These results suggest that TNAP deficiency may mediate FGFR2-associated craniosynostosis. Future studies should incorporate injection of recombinant TNAP protein, to avoid potential side effects and variable efficacy of lentiviral gene delivery.

Authors+Show Affiliations

Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25865549

Citation

Wang, E, et al. "The Effects of Tissue-non-specific Alkaline Phosphatase Gene Therapy On Craniosynostosis and Craniofacial Morphology in the FGFR2C342Y/+ Mouse Model of Crouzon Craniosynostosis." Orthodontics & Craniofacial Research, vol. 18 Suppl 1, 2015, pp. 196-206.
Wang E, Nam HK, Liu J, et al. The effects of tissue-non-specific alkaline phosphatase gene therapy on craniosynostosis and craniofacial morphology in the FGFR2C342Y/+ mouse model of Crouzon craniosynostosis. Orthod Craniofac Res. 2015;18 Suppl 1:196-206.
Wang, E., Nam, H. K., Liu, J., & Hatch, N. E. (2015). The effects of tissue-non-specific alkaline phosphatase gene therapy on craniosynostosis and craniofacial morphology in the FGFR2C342Y/+ mouse model of Crouzon craniosynostosis. Orthodontics & Craniofacial Research, 18 Suppl 1, 196-206. https://doi.org/10.1111/ocr.12080
Wang E, et al. The Effects of Tissue-non-specific Alkaline Phosphatase Gene Therapy On Craniosynostosis and Craniofacial Morphology in the FGFR2C342Y/+ Mouse Model of Crouzon Craniosynostosis. Orthod Craniofac Res. 2015;18 Suppl 1:196-206. PubMed PMID: 25865549.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effects of tissue-non-specific alkaline phosphatase gene therapy on craniosynostosis and craniofacial morphology in the FGFR2C342Y/+ mouse model of Crouzon craniosynostosis. AU - Wang,E, AU - Nam,H K, AU - Liu,J, AU - Hatch,N E, PY - 2014/12/11/accepted PY - 2015/4/14/entrez PY - 2015/4/14/pubmed PY - 2016/7/21/medline KW - bone KW - craniofacial KW - craniosynostosis KW - mineralization KW - mouse model SP - 196 EP - 206 JF - Orthodontics & craniofacial research JO - Orthod Craniofac Res VL - 18 Suppl 1 N2 - OBJECTIVES: Craniosynostosis, the premature fusion of cranial bones, has traditionally been described as a disease of increased bone mineralization. However, multiple mouse models of craniosynostosis display craniosynostosis simultaneously with diminished cranial bone volume and/or density. We propose an alternative hypothesis that craniosynostosis results from abnormal tissue mineralization through the downregulation of tissue-non-specific alkaline phosphatase (TNAP) enzyme downstream of activating mutations in FGFRs. MATERIAL AND METHODS: Neonatal Crouzon (FGFRC342Y/+) and wild-type (FGFR+/+) mice were injected with lentivirus to deliver a recombinant form of TNAP. Mice were sacrificed at 4 weeks postnatal. Serum was collected to test for alkaline phosphatase (AP), phosphorus, and calcium levels. Craniofacial bone fusion and morphology were assessed by micro-computed tomography. RESULTS: Injection with the TNAP lentivirus significantly increased serum AP levels (increased serum AP levels are indicative of efficient transduction and production of the recombinant protein), but results were variable and dependent upon viral lot and the litter of mice injected. Morphological analysis revealed craniofacial form differences for inferior surface (p=0.023) and cranial height (p=0.014) regions between TNAP lentivirus-injected and vehicle-injected Crouzon mice. With each unit increase in AP level, the odds of lambdoid suture fusion decreased by 84.2% and these results came close to statistical significance (p=0.068). CONCLUSION: These results suggest that TNAP deficiency may mediate FGFR2-associated craniosynostosis. Future studies should incorporate injection of recombinant TNAP protein, to avoid potential side effects and variable efficacy of lentiviral gene delivery. SN - 1601-6343 UR - https://www.unboundmedicine.com/medline/citation/25865549/The_effects_of_tissue_non_specific_alkaline_phosphatase_gene_therapy_on_craniosynostosis_and_craniofacial_morphology_in_the_FGFR2C342Y/+_mouse_model_of_Crouzon_craniosynostosis_ L2 - https://doi.org/10.1111/ocr.12080 DB - PRIME DP - Unbound Medicine ER -