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Synergistic Crosstalk of PACAP and Notch Signaling Pathways in Bone Development
Vince Szegeczki1, Andrea Pálfi1, Csaba Fillér1
1Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
International Journal of Molecular Sciences
|June 13, 2025
Summary
Pituitary adenylate cyclase-activating polypeptide (PACAP) influences bone development. This study reveals PACAP and Notch signaling synergistically regulate osteogenesis, impacting bone formation and homeostasis.
Area of Science:
- Endocrinology
- Molecular Biology
- Developmental Biology
Background:
- Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide crucial for nervous system and organ differentiation.
- PACAP deficiency can cause long bone development abnormalities.
- The interplay between PACAP and Notch signaling in osteogenesis remains unexplored.
Purpose of the Study:
- To investigate the connection between PACAP and Notch signaling in osteogenesis.
- To elucidate the roles of these pathways in bone formation and homeostasis.
Main Methods:
- Analysis of long bones in PACAP-gene-deficient mice.
- In vitro studies using UMR-106 and MC3T3-E1 osteogenic cells treated with PACAP 1-38.
- Investigation of Notch signaling inhibition and its compensation by PACAP 1-38.
- Assessment of NFATc1 transcription factor expression and nuclear translocation.
Main Results:
- Notch signaling was elevated in PACAP-deficient mice and upon PACAP 1-38 treatment of osteogenic cells.
- PACAP 1-38 treatment compensated for Notch signaling inhibition in vitro.
- PACAP 1-38 enhanced inorganic and organic matrix production in UMR-106 cells under Notch inhibition.
- NFATc1 expression and nuclear translocation increased with PACAP and Notch signaling disturbances.
Conclusions:
- PACAP and Notch signaling likely act synergistically to regulate bone formation.
- The crosstalk between PACAP and Notch pathways is critical for bone development and homeostasis.
- NFATc1 may be a common target in the coordinated regulation of osteogenesis.
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