Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/113538
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Type: Journal article
Title: Tyrosine kinase receptor c-ros-oncogene 1 inhibition alleviates aberrant bone formation of TWIST-1 haploinsufficient calvarial cells from Saethre-Chotzen syndrome patients
Author: Camp, E.
Anderson, P.
Zannettino, A.
Glackin, C.
Gronthos, S.
Citation: Journal of Cellular Physiology, 2018; 233(9):7320-7332
Publisher: Wiley
Issue Date: 2018
ISSN: 0021-9541
1097-4652
Statement of
Responsibility: 
Esther Camp, Peter J. Anderson, Andrew C.W. Zannettino, Carlotta A. Glackin, Stan Gronthos
Abstract: Saethre-Chotzen syndrome (SCS), associated with TWIST-1 mutations, is characterized by premature fusion of cranial sutures. TWIST-1 haploinsufficiency, leads to alterations in suture mesenchyme cellular gene expression patterns, resulting in aberrant osteogenesis and craniosynostosis. We analyzed the expression of the TWIST-1 target, Tyrosine kinase receptor c-ros-oncogene 1 (C-ROS-1) in TWIST-1 haploinsufficient calvarial cells derived from SCS patients and calvaria of Twist-1del/+ mutant mice and found it to be highly expressed when compared to TWIST-1 wild-type controls. Knock-down of C-ROS-1 expression in TWIST-1 haploinsufficient calvarial cells derived from SCS patients was associated with decreased capacity for osteogenic differentiation in vitro. Furthermore, treatment of human SCS calvarial cells with the tyrosine kinase chemical inhibitor, Crizotinib, resulted in reduced C-ROS-1 activity and the osteogenic potential of human SCS calvarial cells with minor effects on cell viability or proliferation. Cultured human SCS calvarial cells treated with Crizotinib exhibited a dose-dependent decrease in alkaline phosphatase activity and mineral deposition, with an associated decrease in expression levels of Runt-related transcription factor 2 and OSTEOPONTIN, with reduced PI3K/Akt signalling in vitro. Furthermore, Crizotinib treatment resulted in reduced BMP-2 mediated bone formation potential of whole Twist-1del/+ mutant mouse calvaria organotypic cultures. Collectively, these results suggest that C-ROS-1 promotes osteogenic differentiation of TWIST-1 haploinsufficient calvarial osteogenic progenitor cells. Furthermore, the aberrant osteogenic potential of these cells is inhibited by the reduction of C-ROS-1. Therefore, targeting C-ROS-1 with a pharmacological agent, such as Crizotinib, may serve as a novel therapeutic strategy to alleviate craniosynostosis associated with aberrant TWIST-1 function.
Keywords: C-ROS-1; calvarial cells; osteoblasts; Saethre–Chotzen; TWIST-1; twist-1del/⁺-heterozygous mice
Rights: © 2018 Wiley Periodicals, Inc.
RMID: 0030085691
DOI: 10.1002/jcp.26563
Grant ID: http://purl.org/au-research/grants/nhmrc/1120989
http://purl.org/au-research/grants/nhmrc/1042677
Appears in Collections:Medicine publications

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