Transient Inhibition of the Hedgehog Pathway in Young Mice Causes Permanent Defects in Bone Structure

Cancer Cell. 2008 Mar;13(3):249-60. doi: 10.1016/j.ccr.2008.01.027.

Abstract

The Hedgehog (Hh) pathway plays critical roles in normal development and in tumorigenesis. We generated Gli-luciferase transgenic mice to evaluate the Smo inhibitor, HhAntag, by whole animal functional imaging. HhAntag rapidly reduced systemic luciferase activity in 10- to 14-day-old mice following oral dosing. Although pathway activity was restored 2 days after drug removal, brief inhibition caused permanent defects in bone growth. HhAntag inhibited proliferation and promoted differentiation of chondrocytes, leading to dramatic expansion of the hypertrophic zone. After drug removal, osteoblasts invaded the cartilage plate, mineralization occurred, and there was premature fusion of the growth plate resulting in permanent disruption of bone epiphyses.

Publication types

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

MeSH terms

  • Administration, Oral
  • Aging / metabolism
  • Animals
  • Animals, Newborn
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / toxicity*
  • Bone Remodeling / drug effects
  • Bone and Bones / drug effects*
  • Bone and Bones / embryology
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Calcification, Physiologic / drug effects
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cerebellar Neoplasms / drug therapy
  • Chondrocytes / drug effects*
  • Chondrocytes / metabolism
  • Chondrocytes / pathology
  • Dose-Response Relationship, Drug
  • Growth Plate / drug effects
  • Growth Plate / pathology
  • Hedgehog Proteins* / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Luciferases / genetics
  • Luciferases / metabolism
  • Medulloblastoma / drug therapy
  • Mice
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Microscopy, Video
  • Osteogenesis / drug effects
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / drug effects*
  • Smoothened Receptor
  • Time Factors
  • Zinc Finger Protein GLI1

Substances

  • Antineoplastic Agents
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins
  • Smo protein, mouse
  • Smoothened Receptor
  • Zinc Finger Protein GLI1
  • Luciferases