Pro-osteogenic topographical cues promote early activation of osteoprogenitor differentiation via enhanced TGFβ, Wnt, and Notch signaling

Clin Oral Implants Res. 2014 Apr;25(4):475-86. doi: 10.1111/clr.12178. Epub 2013 Apr 21.


Objectives: Titanium implant surfaces with modified topographies have improved osteogenic properties in vivo. However, the molecular mechanisms remain obscure. This study explored the signaling pathways responsible for the pro-osteogenic properties of micro-roughened (SLA) and chemically/nanostructurally (modSLA) modified titanium surfaces on human alveolar bone-derived osteoprogenitor cells (BCs) in vitro.

Materials and methods: The activation of stem cell signaling pathways (TGFβ/BMP, Wnt, FGF, Hedgehog, Notch) was investigated following early exposure (24 and 72 h) of BCs to SLA and modSLA surfaces in the absence of osteogenic cell culture supplements.

Results: Key regulatory genes from the TGFβ/BMP (TGFBR2, BMPR2, BMPR1B, ACVR1B, SMAD1, SMAD5), Wnt (Wnt/β-catenin and Wnt/Ca(2+) ) (FZD1, FZD3, FZD5, LRP5, NFATC1, NFATC2, NFATC4, PYGO2, LEF1) and Notch (NOTCH1, NOTCH2, NOTCH4, PSEN1, PSEN2, PSENEN) pathways were upregulated on the modified surfaces. These findings correlated with a higher expression of osteogenic markers bone sialoprotein (IBSP) and osteocalcin (BGLAP), and bone differentiation factors BMP2, BMP6, and GDF15, as observed on the modified surfaces.

Conclusions: These findings demonstrate that the activation of the pro-osteogenic cell signaling pathways by modSLA and SLA surfaces leads to enhanced osteogenic differentiation as evidenced after 7 and 14 days culture in osteogenic media and provides a mechanistic insight into the superior osseointegration on the modified surfaces observed in vivo.

Keywords: cell signaling; osteoprogenitor differentiation; titanium surface modification; topography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Proteins / metabolism
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Cues
  • Gene Expression Profiling
  • Growth Differentiation Factor 15 / metabolism
  • Humans
  • In Vitro Techniques
  • Microscopy, Atomic Force
  • Microscopy, Electron, Scanning
  • Osteocalcin / metabolism
  • Osteogenesis / physiology*
  • Real-Time Polymerase Chain Reaction
  • Receptors, Notch / metabolism*
  • Sialoglycoproteins / metabolism
  • Signal Transduction
  • Surface Properties
  • Titanium
  • Transforming Growth Factor beta / metabolism*
  • Wnt Proteins / metabolism*


  • Bone Morphogenetic Proteins
  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • Receptors, Notch
  • Sialoglycoproteins
  • Transforming Growth Factor beta
  • Wnt Proteins
  • Osteocalcin
  • Titanium