title: Extracellular signal-related kinase and bone morphogenetic protein expression during distraction osteogenesis of the mandible: in vivo evidence of a mechanotransduction mechanism for differentiation and osteogenesis by mesenchymal precursor cells.
abstract: BACKGROUND
  The goal in this study was to investigate the role of extracellular signal-related kinase (ERK) 1/2, a central regulator of mesenchymal stem cell differentiation, and its temporal relationship to bone morphogenetic protein (BMP) 2/4, a potent osteogenic growth factor, during live model distraction osteogenesis.
  
  
  METHODS
  The authors examined histomorphometric expression through the early temporal sequence for both ERK 1/2 and BMP 2/4 during gradual distraction to 5.1 mm (n = 12 net). Comparison groups (group sizes, n = 12) included an acute critical-size defect of 5.1 mm and a subcritical-size defect of 2.1 mm.
  
  
  RESULTS
  In the group gradually distracted to 5.1 mm, immunohistochemical analysis demonstrated significant intranuclear expression of ERK 1/2 within mesenchymal precursor cells at the osteotomy edges early in distraction (postoperative days 6 and 9). ERK 1/2 became increasingly localized to hypertrophic chondrocytes within the distraction regenerate during the later stages of distraction (postoperative day 16). Adjacent sections examined for BMP 2/4 expression established a close temporal and spatial correlation with ERK 1/2. BMP 2/4 expression was initially present in the regions surrounding mesenchymal precursor cells expressing ERK 1/2, but then developed most prominently within the cytoplasm of hypertrophic chondrocytes expressing ERK 1/2 late in distraction. Comparison groups consistently demonstrated either fibrous nonunion or bony union typical in fracture healing, depending on defect size. However, even specimens with subcritical-size defects and complete bony union were consistently found to have minimal ERK 1/2 expression.
  
  
  CONCLUSIONS
  These data provide evidence that ERK 1/2 expression is present within mesenchymal precursor cells during distraction osteogenesis and that ERK expression correlates closely with BMP 2/4 expression. The presence of ERK 1/2 expression only during gradual distraction strongly implicates the concept that mechanical strain appears to be the key upregulating factor for ERK 1/2 expression, based on comparison with fracture-healing and critical-size defect specimens.
authors.affiliation: Section of Plastic Surgery, University of Michigan Medical Center, Ann Arbor, USA.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Rhee
authors.forename: Loai
authors.initials: L
authors.lastname: El-Bassiony
authors.forename: Steven R
authors.initials: SR
authors.lastname: Buchman
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis*; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis*; D017102:Fracture Healing / Q000502:physiology; D008297:Male; D008334:Mandible / Q000378:metabolism* / Q000502:physiology / Q000601:surgery; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis; D023421:Models, Animal; D010012:Osteogenesis / Q000502:physiology; D019857:Osteogenesis, Distraction; D010027:Osteotomy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019485:Bone Morphogenetic Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3