Craniometaphyseal Dysplasia Mutations in ANKH Negatively Affect Human Induced Pluripotent Stem Cell Differentiation into Osteoclasts

Stem Cell Reports. 2017 Nov 14;9(5):1369-1376. doi: 10.1016/j.stemcr.2017.09.016. Epub 2017 Oct 19.


We identified osteoclast defects in craniometaphyseal dysplasia (CMD) using an easy-to-use protocol for differentiating osteoclasts from human induced pluripotent stem cells (hiPSCs). CMD is a rare genetic bone disorder, characterized by life-long progressive thickening of craniofacial bones and abnormal shape of long bones. hiPSCs from CMD patients with an in-frame deletion of Phe377 or Ser375 in ANKH are more refractory to in vitro osteoclast differentiation than control hiPSCs. To exclude differentiation effects due to genetic variability, we generated isogenic hiPSCs, which have identical genetic background except for the ANKH mutation. Isogenic hiPSCs with ANKH mutations formed fewer osteoclasts, resorbed less bone, expressed lower levels of osteoclast marker genes, and showed decreased protein levels of ANKH and vacuolar proton pump v-ATP6v0d2. This proof-of-concept study demonstrates that efficient and reproducible differentiation of isogenic hiPSCs into osteoclasts is possible and a promising tool for investigating mechanisms of CMD or other osteoclast-related disorders.

Keywords: craniometaphyseal dysplasia; hiPSC differentiated osteoclasts; osteoclastogenesis; rare genetic bone disorder.

Publication types

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

MeSH terms

  • Adult
  • Bone Diseases, Developmental / genetics*
  • Cell Differentiation*
  • Cells, Cultured
  • Child
  • Craniofacial Abnormalities / genetics*
  • Female
  • Humans
  • Hyperostosis / genetics*
  • Hypertelorism / genetics*
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Male
  • Mutation
  • Osteoclasts / cytology*
  • Osteoclasts / metabolism
  • Phosphate Transport Proteins / genetics*


  • ANKH protein, human
  • Phosphate Transport Proteins

Supplementary concepts

  • Schwartz-Lelek syndrome