Retinoic acid modulates chondrogenesis in the developing mouse cranial base

J Exp Zool B Mol Dev Evol. 2011 Dec 15;316(8):574-83. doi: 10.1002/jez.b.21432. Epub 2011 Aug 8.


The retinoic acid (RA) signaling pathway is known to play important roles during craniofacial development and skeletogenesis. However, the specific mechanism involving RA in cranial base development has not yet been clearly described. This study investigated how RA modulates endochondral bone development of the cranial base by monitoring the RA receptor RARγ, BMP4, and markers of proliferation, programmed cell death, chondrogenesis, and osteogenesis. We first examined the dynamic morphological and molecular changes in the sphenooccipital synchondrosis-forming region in the mouse embryo cranial bases at E12-E16. In vitro organ cultures employing beads soaked in RA and retinoid-signaling inhibitor citral were compared. In the RA study, the sphenooccipital synchondrosis showed reduced cartilage matrix and lower BMP4 expression while hypertrophic chondrocytes were replaced with proliferating chondrocytes. Retardation of chondrocyte hypertrophy was exhibited in citral-treated specimens, while BMP4 expression was slightly increased and programmed cell death was induced within the sphenooccipital synchondrosis. Our results demonstrate that RA modulates chondrocytes to proliferate, differentiate, or undergo programmed cell death during endochondral bone formation in the developing cranial base.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyclic Monoterpenes
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Bone Morphogenetic Protein 4 / drug effects
  • Bone Morphogenetic Protein 4 / metabolism*
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Proliferation / drug effects
  • Chondrocytes / cytology*
  • Chondrocytes / drug effects
  • Chondrogenesis / drug effects
  • Chondrogenesis / physiology*
  • Integrin-Binding Sialoprotein / drug effects
  • Integrin-Binding Sialoprotein / metabolism*
  • Ki-67 Antigen / drug effects
  • Ki-67 Antigen / metabolism
  • Mice
  • Monoterpenes / pharmacology
  • Organ Culture Techniques
  • Osteogenesis / drug effects
  • Osteogenesis / physiology
  • Receptors, Retinoic Acid / metabolism
  • Signal Transduction
  • Skull Base / cytology
  • Skull Base / drug effects
  • Skull Base / embryology*
  • Skull Base / metabolism
  • Tretinoin / metabolism*
  • Tretinoin / pharmacology


  • Acyclic Monoterpenes
  • Bone Morphogenetic Protein 4
  • Integrin-Binding Sialoprotein
  • Ki-67 Antigen
  • Monoterpenes
  • Receptors, Retinoic Acid
  • retinoic acid receptor gamma
  • Tretinoin
  • citral