A Phe377del mutation in ANK leads to impaired osteoblastogenesis and osteoclastogenesis in a mouse model for craniometaphyseal dysplasia (CMD)

Hum Mol Genet. 2011 Mar 1;20(5):948-61. doi: 10.1093/hmg/ddq541. Epub 2010 Dec 13.


Craniometaphyseal dysplasia (CMD) is a rare genetic disorder with hyperostosis of craniofacial bones and widened metaphyses in long bones. Patients often suffer from neurological symptoms due to obstruction of cranial foramina. No proven treatment is available and the pathophysiology is largely unknown. A Phe377 (TTC(1130-1132)) deletion in exon 9 of the pyrophosphate (PPi) transporter ANK leads to CMD-like features in an Ank(KI/KI) mouse model. Here, we investigated the effects of CMD-mutant ANK on mineralization and bone mass at a cellular level. Ank(KI/KI) osteoblast cultures showed decreased mineral deposition. Expression of bone mineralization regulating genes Mmp13, Ocn, Osx and Phex was reduced in Ank(KI/KI) osteoblasts, while the Fgf23 mRNA level was highly elevated in Ank(KI/KI) calvarial and femoral bones. Since ANK is a known PPi transporter, we examined other regulators of Pi/PPi homeostasis Enpp1 and Tnap. Significantly increased ENPP1 activity may compensate for dysfunctional mutant ANK leading to comparable extracellular PPi levels in Ank(+/+) osteoblasts. Similar to Ank(KI/KI) bone marrow-derived macrophage cultures, peripheral blood cultures from CMD patients exhibited reduced osteoclastogenesis. Cell-autonomous effects in Ank(KI/KI) osteoclasts resulted in disrupted actin ring formation and cell fusion. In addition, Ank(KI/KI) osteoblasts failed to adequately support osteoclastogenesis. Increased bone mass could partially be rescued by bone marrow transplants supporting our hypothesis that reduced osteoclastogenesis contributes at least in part to hyperostosis. We conclude that the Phe377del mutation in ANK causes impaired osteoblastogenesis and osteoclastogenesis resulting in hypomineralization and a high bone mass phenotype.

Publication types

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

MeSH terms

  • Animals
  • Bone Diseases, Developmental / genetics
  • Bone Diseases, Developmental / metabolism
  • Calcification, Physiologic
  • Case-Control Studies
  • Cell Differentiation*
  • Cells, Cultured
  • Craniomandibular Disorders
  • Disease Models, Animal
  • Exons
  • Facial Paralysis / genetics
  • Facial Paralysis / metabolism
  • Female
  • Fibroblast Growth Factor-23
  • Gene Expression Regulation, Developmental
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL / abnormalities
  • Mutation
  • Osteoblasts / cytology*
  • Osteoblasts / metabolism
  • Osteoclasts / cytology*
  • Osteoclasts / metabolism
  • Osteogenesis
  • Osteoporosis / genetics
  • Osteoporosis / metabolism
  • Phosphate Transport Proteins / genetics*
  • Phosphate Transport Proteins / metabolism
  • Sequence Deletion*
  • Skull / abnormalities
  • Skull / metabolism


  • ANKH protein, human
  • FGF23 protein, human
  • Fgf23 protein, mouse
  • Membrane Proteins
  • Phosphate Transport Proteins
  • ank protein, mouse
  • Fibroblast Growth Factor-23

Supplementary concepts

  • Craniometaphyseal Dysplasia, Autosomal Dominant