Diverse functions of secreted frizzled-related proteins in the osteoblastogenesis of human multipotent mesenchymal stromal cells

Biomaterials. 2013 Apr;34(13):3270-8. doi: 10.1016/j.biomaterials.2013.01.066. Epub 2013 Feb 4.


Osteoinductive pretreatment of human mesenchymal stromal cells (hMSCs) has been widely accepted in bone tissue engineering before the use of cell transplantation; however, the mechanisms by which osteoinductive medium (OIM) enhances osteoblastic differentiation are not well understood. Using periodontal ligament-derived hMSCs, we identified key signalling molecules for osteoblastogenesis. Alkaline phosphatase activity induced by OIM, which contains ascorbic acid, β-glycerophosphate, and dexamethasone, was decreased by XAV939, which is an inhibitor of canonical WNT signalling, in a dose-dependent manner. A quantitative RT-PCR array demonstrated the upregulation of secreted frizzled-related protein (SFRP) 3 and the downregulation of SFRP4 during osteoinduction. Functional studies showed that SFRP3 promoted and SFRP4 suppressed the osteoblastic differentiation of hMSCs. In addition, SFRP3 inhibited non-canonical WNT signalling by binding WNT5A, which is a representative non-canonical WNT protein. These results indicate the involvement of the WNT signalling pathway during the osteoblastic differentiation of hMSCs. SFRPs oppositely control osteoblastogenesis through canonical and non-canonical pathways and may be useful for directing the lineage of hMSCs in cytotherapeutic use.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Culture Media / pharmacology
  • Flow Cytometry
  • Frizzled Receptors / genetics
  • Frizzled Receptors / metabolism*
  • Gene Expression Regulation / drug effects
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • Models, Biological
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism*
  • Osteogenesis* / drug effects
  • Osteogenesis* / genetics
  • Polymerase Chain Reaction
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • RNA, Small Interfering / metabolism
  • Transcriptome / drug effects
  • Transcriptome / genetics
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway / drug effects
  • Wnt Signaling Pathway / genetics


  • Culture Media
  • Frizzled Receptors
  • Heterocyclic Compounds, 3-Ring
  • RNA, Small Interfering
  • Wnt Proteins
  • XAV939