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Introduction of a Phe377del Mutation in ANK Creates a Mouse Model for Craniometaphyseal Dysplasia
Author(s) -
Chen IPing,
Wang Chiachien J,
Strecker Sara,
KoczonJaremko Boguslawa,
Boskey Adele,
Reichenberger Ernst J
Publication year - 2009
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.090218
Subject(s) - mutation , genetics , computational biology , biology , medicine , evolutionary biology , gene
Craniometaphyseal dysplasia (CMD) is a monogenic human disorder characterized by thickening of craniofacial bones and flaring metaphyses of long bones. Mutations for autosomal dominant CMD have been identified in the progressive ankylosis gene ANKH . Previous studies of Ank loss‐of‐function models, Ank null/null and Ank ank/ank mice, suggest that Ank plays a role in the regulation of bone mineralization. However, the mechanism for Ank mutations leading to CMD remains unknown. We generated the first knockin (KI) mouse model for CMD expressing a human mutation (Phe377 deletion) in ANK. Homozygous Ank knockin mice ( Ank KI/KI ) replicate many typical features of human CMD including hyperostosis of craniofacial bones, massive jawbones, decreased diameters of cranial foramina, obliteration of nasal sinuses, fusion of middle ear bones, and club‐shaped femurs. In addition, Ank KI/KI mice have increased serum alkaline phosphatase and TRACP5b, as reported in CMD patients. Biochemical markers of bone formation and bone resorption, N‐terminal propeptide of type I procollagen and type I collagen cross‐linked C‐terminal telopeptide, are significantly increased in Ank KI/KI mice, suggesting increased bone turnover. Interestingly, Ank KI/KI bone marrow–derived macrophage cultures show decreased osteoclastogenesis. Despite the hyperostotic phenotype, bone matrix in Ank KI/KI mice is hypomineralized and less mature, indicating that biomechanical properties of bones may be compromised by the Ank mutation. We believe this new mouse model will facilitate studies of skeletal abnormalities in CMD at cellular and molecular levels.

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