Hedgehog Activation Regulates Human Osteoblastogenesis

Stem Cell Reports. 2020 Jul 14;15(1):125-139. doi: 10.1016/j.stemcr.2020.05.008. Epub 2020 Jun 11.

Abstract

Two genetic diseases, Gorlin syndrome and McCune-Albright syndrome (MAS), show completely opposite symptoms in terms of bone mineral density and hedgehog (Hh) activity. In this study, we utilized human induced pluripotent stem cell (iPSC)-based models of the two diseases to understand the roles of Hh signaling in osteogenesis. Gorlin syndrome-derived iPSCs showed increased osteoblastogenesis and mineralization with Hh signaling activation and upregulation of a set of transcription factors in an osteogenic culture, compared with the isogenic control. MAS-specific iPSCs showed poor mineralization with low Hh signaling activity in the osteogenic culture; impaired osteoblastogenesis was restored to the normal level by treatment with an Hh signaling-activating small molecule. These data suggest that Hh signaling is a key controller for differentiation of osteoblasts from precursors. This study may pave a path to new drug therapies for genetic abnormalities in calcification caused by dysregulation of Hh signaling.

Keywords: Gorlin syndrome; McCune-Albright syndrome; calcification; fibrous dysplasia; hedgehog pathway; osteogenesis; patient-specific iPSC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basal Cell Nevus Syndrome / pathology
  • Cell Culture Techniques
  • Chromogranins / genetics
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • Gene Expression Profiling
  • Hedgehog Proteins / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Mutation / genetics
  • Osteoblasts / metabolism*
  • Osteogenesis*
  • Signal Transduction
  • Transcription Factors / metabolism
  • Transcriptome / genetics

Substances

  • Chromogranins
  • Hedgehog Proteins
  • Transcription Factors
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs