BoneKEy-Osteovision | Commentary

Notching up bone


Since the original identification of the Notch cell-cell signalling pathway in Drosophila embryogenesis, the role of this important component of cell fate determination has been found to be highly evolutionarily conserved and involved in many different cell contexts (). That it has taken until now to firmly link this pathway with bone cell differentiation seems unusual but the identification of a likely role for Notch signalling in osteoblast differentiation by Tezuka et al. () will hopefully provide the impetus for further studies.

Notch signalling controls cell fate commitment through local cell interactions during development of a wide range of tissues. Notch is a transmembrane receptor that binds membrane-bound ligands (Delta, Jagged/Serrate). Upon binding, Notch undergoes proteolytic cleavage and the resulting translocation of the intracellular domain to the nucleus associates with DNA-binding transcription factors such as CBF1/RJBk ().

Tezuka et al. report a number of different results linking Notch with osteoblast differentiation, but for me, the most interesting and compelling is the finding that activation of Notch in multipotent mesenchyme cells, C3H10T1/2, results in stimulation of osteoblast differentiation at the expense of adipocyte differentiation. This result parallels that previously reported in Cell by Morrison et al. () showing that activation of Notch in neural crest cells directs them towards a glial cell fate at the expense of neurogenesis. The role of Notch in osteoblast differentiation may thus be another example of a classic role in cell fate determination, whereby Notch regulates mesenchymal stem cell differentiation into osteoblasts and adipocytes. Such a suggested role does, however, mean that the expression of Notch and its ligands in marrow stem cells in vivo must be analyzed and outstanding questions such as how Notch activation is triggered and regulated to create the correct balance between osteoblasts and adipocytes must be investigated.

As is always the case with in vitro data based entirely on cell lines and overexpression using viruses, the data also need to be supported by loss of function experiments and in vivo investigations. Moreover, the effects of Notch activation in marrow have not been demonstrated. Conditional inactivation of Notch signalling in marrow stem cells surely awaits.

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