IADR Abstract Archives

Molecular mechanisms of craniosynostosis in Apert syndrome.

Abstract: Apert syndrome(AS) is an inherited disorder caused by FGFR2 gene mutations and is characterized by craniosynostosis and osseous syndactyly, associated with enhanced osteoblast differentiation. However, no systemic excessive bone formation has been observed in AS patients, and the mechanisms of site-specific osteoblast hyper activation remains unclear. Here, we report that mechanical factors are related to the AS pathogenesis. To elucidate the molecular mechanisms of osteoblast activation in AS, we first established iPS cells from AS patients and analyzed osteoblast differentiation. However, no clear abnormalities were observed in AS-iPS cell derived osteoblasts. Since the bone abnormalities in AS are confined to cranial sutures and fingers, and mechanical stress causes craniofacial deformity in patients, we hypothesized that mechanical stimulation may trigger site-specific hypercalcification. Mechanical stress loading on normal human mesenchymal stem cells (hMSCs) using cell stretching system caused increased FGF2 gene expression and enhanced proliferation, which was offset by FGF2 neutralizing antibody. Furthermore, FGF2-dependent cell proliferation during the early stages of osteoblast differentiation caused cell condensation, which promoted subsequent osteoblast maturation and calcified nodule formation. This indicates that FGF2 gene expression is important for the mechanical stress-dependent bone formation. The induction of osteoblast differentiation in AS-iPS cells under mechanical stress showed increased calcification compared to wild-type iPS cells. Namely, mechanical cues increased the local concentration of FGF2, which, in concert with mutant FGFR2, may induce excessive bone formation in AS. These results suggest that the mechanical stress response may be a new therapeutic target for AS.
Japanese Division Meeting
2020 Japanese Division Meeting (Virtual)
Virtual, Japan
Future is now! Stem cell revolution in hard and soft tissue engineering
  • Nakamura, Takashi  ( Department of Biochemistry/Research Branding Project, Tokyo Dental College. )
  • Ogura, Hiroyuki  ( Department of Orthodontics, Tokyo Dental College. )
  • Azuma, Toshifumi  ( Department of Biochemistry/Oral Health Science Center/Research Branding Project, Tokyo Dental College. )
  • Symposium II