Inhibition of tyrosine kinase receptor C-ROS-1 as novel treatment in alleviating TWIST-1 haploinsufficiency induced craniosynostosis in children — ASN Events
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Inhibition of tyrosine kinase receptor C-ROS-1 as novel treatment in alleviating TWIST-1 haploinsufficiency induced craniosynostosis in children (#48)

Esther Camp 1 2 , Peter Anderson 3 , Andrew Zannettino 1 2 , Stan Gronthos 1 2
  1. Adelaide Medical School, University of Adelaide, Adelaide, S.A, Australia
  2. South Australian Health and Medical Research Institute, Adelaide, S.A, Australia
  3. Australian Craniofacial Unit, Women’s and Children’s Hospital, Adelaide, South Australia, Australia

The c-ros-oncogene 1 (C-ROS-1) gene encodes a receptor, which belongs to the sevenless subfamily of tyrosine kinase insulin receptors and is conserved among vertebrates 1,2. We have, for the first time, identified C-ROS-1 expression in human bone marrow derived mesenchymal stem cells (BMSC) and cranial bone cells. Knock-down of C-ROS-1 in human BMSC and cranial bone cells resulted in a decreased capacity for osteogenic differentiation in vitro 3. Expression of C-ROS-1 is upregulated during osteogenic differentiation, but is suppressed by the basic helix loop helix transcription factor, TWIST-1 3. TWIST-1 is important in skeletal and cranial development, where Twist-1 mutant heterozygote mice display abnormal craniofacial and skeletal structures 4. These abnormalities are replicated in a human childhood disorder known as Saethre–Chotzen syndrome (SCS) which is caused by a mutation in the TWIST-1 gene. In both mice and humans, TWIST-1 happloinsuficiency results in the premature bony bridging between apposed skull plates in the cranium due to excessive intramembranous and endochondral ossification, leading to craniosynostosis. TWIST-1 haploinsufficient human and mouse cranial bone cells express higher levels of C-ROS-1 when compared to wild type cells. Knock-down of C-ROS-1 transcript using siRNA, or inhibition of C-ROS-1 function using the drug Crizotinib in TWIST-1 haploinsufficient cranial cells resulted in a decreased capacity for osteogenic differentiation. Furthermore, treatment of TWIST-1 haploinsufficient mouse cranial bone explants with Crizotinib induced a decrease in mineral deposition compared to untreated cranial explants. We have identified C-ROS-1 as a possible novel target in the treatment of SCS. Currently, the only treatment option available is major invasive cranial surgery. This procedure is traumatic for the children and their families, requiring substantial hospitalization and resources. The development of new approaches with therapeutic agents to prevent or minimise fusion could have a profound impact on an affected child’s management resulting in reduced cranial surgery.

  1. 1. Chen, J.M, et al. Oncogene. 6: 257-64, 1991. 2. Acquaviva, J., R, et al. Biochim Biophys Acta. 1795: 37-52, 2009. 3. Camp E.,et al. Bone. 94: 98-107, 2017. 4. Chen Z.F BRR. Genes Dev. 9: 689-699, 1995.