Unit:
Faculty of MedicineLibrary of the School of Health Sciences
Dissertation committee:
Αθανάσιος Γ. Παπαβασιλείου Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ευθυμία Κ. Μπάσδρα Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Χριστίνα Πιπέρη Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μυρσίνη Κουλούκουσα- Γιαννιού Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αναστάσιος Φιλίππου Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μαρία Πιάγκου Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Ελένη Βασταρδή Αναπληρώτρια Καθηγήτρια, Οδοντιατρική Σχολή, ΕΚΠΑ
Original Title:
Ο ρόλος της πολυκυστίνης 1 και 2 στη σύγκλειση των ραφών
Translated title:
The role of polycystins 1 and 2 in cranial suture fusion
Summary:
Craniosynostosis refers to the premature fusion of one or more cranial sutures leading to skull shape deformities and brain growth restriction. It is the second most clinically significant craniofacial disorder and, to date, management of this disease is limited to complicated surgical procedures. Among the many factors that contribute to abnormal suture fusion, mechanical forces seem to play a major role. Nevertheless, the underlying mechanobiology-related mechanisms of craniosynostosis still remain unknown.
Understanding how aberrant mechanosensation and mechanotransduction pathways drive premature suture fusion will offer important insights into the pathophysiology of craniosynostosis and result in the development of new therapies, which can be used to intervene at an early stage, preventing premature suture fusion.
The present study aimed to investigate the implication of PC1 in the pathogenesis of non-syndromic craniosynostosis and elucidate the underlying molecular mechanisms. This thesis provides evidence for the first time on the implication of a key mechanosensory protein, polycystin-1 (PC1) in the pathogenesis of craniosynostosis. Protein expression of PC1 and PC2 was detected in bone fragments and primary cranial suture cells derived from craniosynostosis patients with trigonocephaly and dolichocephaly, two common non-syndromic subtypes. The cleaved cytoplasmic tail of PC1 (PC1-CT) that mediates mechanotransduction was detected in cranial suture cells indicating putative PC1 activation and possible interaction with intracellular pathways and transcription factors to regulate cell function.
By using cranial suture cells isolated from patients with trigonocephaly and dolichocephaly, the two common types of craniosynostosis, we have performed mechanistic studies. Τo investigate the functional role of PC1 in cranial suture cells, we blocked the PC1 extracellular mechanosensing domain using a specific IgPKD1 antibody. PC1 inhibition induced elevation of p-AKT (Ser473) and PTEN levels. This was followed by an activation of mTOR signalling pathway which resulted in increased proliferation and migration of cranial suture cells. At the same time, inhibition of PC1 increased RUNX2, a transcription factor associated with osteoblast differentiation, in cranial suture cells as well as osteocalcin an osteogenesis marker demonstrating that PC1 regulates the runt-related transcription factor 2 (RUNX2) activation and osteocalcin gene expression via activation of extracellular signal-regulated kinase (ERK) signaling.
Altogether, our study reveals a novel mechanotransduction signaling axis, PC1-ERK- RUNX2, which affects osteoblastic differentiation in cranial suture cells from trigonocephaly and dolichocephaly patients. All the above, will contribute to the identification of new therapeutic targets or prognostic markers in non-syndromic craniosynostosis as well as identifying the key role of PC1 in a new therapeutic scheme against craniosynostosis at a diagnosis level, advancing our knowledge of craniosynostosis biology.
Main subject category:
Health Sciences
Keywords:
Craniosynostosis, Dolichocephaly, ERK, Mechanosensation, Mechano-transduction, Osteoblast differentiation, Osteocalcin, PC1, RUNX2, Trigonocephaly
Number of references:
268
File:
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MARIA KATSIANOU PhD.pdf
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