Introduction of a Phe377del mutation in ANK creates a mouse model for craniometaphyseal dysplasia

J Bone Miner Res. 2009 Jul;24(7):1206-15. doi: 10.1359/jbmr.090218.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acid Phosphatase / blood
  • Alkaline Phosphatase / blood
  • Animals
  • Bone Diseases, Developmental / blood*
  • Bone Diseases, Developmental / genetics*
  • Bone Diseases, Developmental / pathology
  • Collagen Type I / metabolism
  • Disease Models, Animal*
  • Humans
  • Isoenzymes / blood
  • Macrophages / metabolism
  • Macrophages / pathology
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Transgenic
  • Phosphate Transport Proteins
  • Sequence Deletion*
  • Skull / metabolism
  • Skull / pathology
  • Tartrate-Resistant Acid Phosphatase


  • Collagen Type I
  • Isoenzymes
  • Membrane Proteins
  • Phosphate Transport Proteins
  • ank protein, mouse
  • Alkaline Phosphatase
  • Acid Phosphatase
  • Tartrate-Resistant Acid Phosphatase