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

Plast Reconstr Surg. 2006 Jun;117(7):2243-9. doi: 10.1097/01.prs.0000224298.93486.1b.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / biosynthesis*
  • Cell Differentiation
  • Chondrocytes / metabolism
  • Extracellular Signal-Regulated MAP Kinases / biosynthesis*
  • Fracture Healing / physiology
  • Male
  • Mandible / metabolism*
  • Mandible / physiology
  • Mandible / surgery
  • Mechanotransduction, Cellular / physiology*
  • Mesenchymal Stem Cells / physiology
  • Mitogen-Activated Protein Kinase 1 / biosynthesis
  • Mitogen-Activated Protein Kinase 3 / biosynthesis
  • Models, Animal
  • Osteogenesis / physiology
  • Osteogenesis, Distraction*
  • Osteotomy
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Bone Morphogenetic Proteins
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3