Pharmacological targeting of KDM6A and KDM6B, as a novel therapeutic strategy for treating craniosynostosis in Saethre-Chotzen syndrome.

摘要: During development, excessive osteogenic differentiation of mesenchymal progenitor cells (MPC) within the cranial sutures can lead to premature suture fusion or craniosynostosis, leading craniofacial and cognitive issues. Saethre-Chotzen syndrome (SCS) is a common form caused by TWIST-1 gene mutations. Currently, only treatment option for craniosynostosis involves multiple invasive surgeries, which serious complications. The present study utilized Twist-1 haploinsufficient (Twist-1del/+) mice as SCS mouse model investigate inhibition Kdm6a Kdm6b activity using pharmacological inhibitor, GSK-J4, on calvarial cell potential. This showed that histone methyltransferase EZH2, an osteogenesis downregulated in derived from Twist-1del/+ mice, whereas counter demethylases, Kdm6b, known promoters osteogenesis, were upregulated. In vitro studies confirmed siRNA-mediated expression suppressed cells. Moreover, targeting activity, with dose-dependent suppression reduced mineralized bone formation explant cultures. Chromatin immunoprecipitation Western blot analyses found GSK-J4 elevated levels epigenetic target, repressive mark tri-methylated lysine 27 3, genes repression Runx2 Alkaline Phosphatase expression. Pre-clinical vivo local administration calvaria prevented kept open up postnatal day 20. could be used potential non-invasive therapeutic strategy preventing children SCS. Pharmacological Kdm6a/b alleviate syndrome. Aberrant mutant occurs via deregulation modifiers Ezh2 Kdm6a/Kdm6b. Suppression Kdm6a- Kdm6b-mediated inhibitor prevent prefusion sutures.