Enzyme replacement for craniofacial skeletal defects and craniosynostosis in murine hypophosphatasia.
Hypophosphatasia (HPP) is an inborn-error-of-metabolism disorder characterized by deficient bone and tooth mineralization due to loss-of function mutations in the gene (Alpl) encoding tissue-nonspecific alkaline phosphatase (TNAP). Alpl(-/-) mice exhibit many characteristics seen in infantile HPP including long bone and tooth defects, vitamin B6 responsive seizures and craniosynostosis. Previous reports demonstrated that a mineral-targeted form of TNAP rescues long bone, vertebral and tooth mineralization defects in Alpl(-/-) mice. Here we report that enzyme replacement with mineral-targeted TNAP (asfotase-alfa) also prevents craniosynostosis (the premature fusion of cranial bones) and additional craniofacial skeletal abnormalities in Alpl(-/-) mice. Craniosynostosis, cranial bone volume and density, and craniofacial shape abnormalities were assessed by microscopy, histology, digital caliper measurements and micro CT. We found that craniofacial shape defects, cranial bone mineralization and craniosynostosis were corrected in Alpl(-/-) mice injected daily subcutaneously starting at birth with recombinant enzyme. Analysis of Alpl(-/-) calvarial cells indicates that TNAP deficiency leads to aberrant osteoblastic gene expression and diminished proliferation. Some but not all of these cellular abnormalities were rescued by treatment with inorganic phosphate. These results confirm an essential role for TNAP in craniofacial skeletal development and demonstrate the efficacy of early postnatal mineral-targeted enzyme replacement for preventing craniofacial abnormalities including craniosynostosis in murine infantile HPP.
['Liu|Jin|J|', 'Campbell|Cassie|C|', 'Nam|Hwa Kyung|HK|', 'Caron|Alexandre|A|', 'Yadav|Manisha C|MC|', 'Millán|José Luis|JL|', 'Hatch|Nan E|NE|']
D016475:3T3 Cells D000469:Alkaline Phosphatase D000818:Animals D001842:Bone and Bones D002113:Calcification, Physiologic D049109:Cell Proliferation D019465:Craniofacial Abnormalities D003398:Craniosynostoses D003433:Crosses, Genetic D004195:Disease Models, Animal D056947:Enzyme Replacement Therapy D057487:Enzyme Therapy D007014:Hypophosphatasia D007074:Immunoglobulin G D051379:Mice D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D010710:Phosphates D011993:Recombinant Fusion Proteins D055114:X-Ray Microtomography
Craniofacial Craniosynostosis Mineralization Animal models Disorders of calcium/phosphate Micro computed tomography (micro CT, μCT)