Pivotal role of Twist in skeletal biology and pathology.

Basic Helix-loop-Helix (bHLH) factors play important roles in development and disease. Recent functional and genetic analyses revealed that the bHLH factor Twist1 is a critical modulator of mesenchymal cell fate during skeletal development. Specifically, studies in mice and humans showed that Twist1 controls mesenchymal stem cell differentiation into chondrocytes, osteoblasts or adipocytes via direct and indirect mechanisms. In a physiological context, Twist1 targets several molecular mechanisms to induce positive or negative effects on osteoblastic cell growth, differentiation and survival. In a pathological context, Twist1 loss-of-function mutations induce premature cranial suture fusion (craniosynostosis) in the Saethre-Chotzen syndrome. In this syndrome, expansion of cranial osteogenesis at the suture level results from alterations in the balance between osteoprogenitor cell proliferation, differentiation and apoptosis. These studies provide mechanisms by which Twist1 plays a pivotal role in skeletal cell fate in normal and pathologic conditions, which may offer therapeutic perspectives in conditions where mesenchymal cell behaviour is compromised.