IRE1α Regulates the Formation of Craniofacial Bones and Dentin
Objective: Osteoblasts and odontoblasts are professional secretory cells that produce extracellular matrix of bone and dentin, respectively. The endoplasmic reticulum (ER) stress response signaling is a fundamental cellular adaptive mechanism required for the maintenance of intracellular protein homeostasis. Inositol requiring enzyme 1α (IRE1α) is an ER transmembrane protein that is associated with the evolutionarily conserved ER stress signaling branch-IRE1/X-binding protein 1s (XBP1s) signaling. However, the roles of IRE1α in regulating the formation of bone and dentin remain essentially unknown.
Method: The transgenic mice that carry genetic deletion of IRE1α in cells that express osterix, an essential transcription factor of both osteoblast and odontoblast lineage cells, were generated and characterized by histology, immunohistochemistry, microCT and TEM.
Result: Firstly, the IRE1 conditional knockout (CKO) mice displayed compromised formation of craniofacial bones, such as mandibular and skull bones, compared with their age- and gender-matched wild type (WT) counterparts. The calcein double labeling assay indicated a reduced formation rate of both bone and dentin in the CKO mice compared with the WT littermates. TEM demonstrated that primary osteoblasts of the CKO mice have reduced amount and fragmented ER compared with their WT counterparts. Furthermore, BrdU immunostaining revealed reduced cell proliferation in the CKO bone compared with the WT counterparts. Secondly, the CKO mice displayed approximately 10% reduction in the mineral density and 50% reduction in the thickness of the root dentin of mandibular molars compared with their WT counterparts. A similar trend, but to a less extent, is observed for the crown dentin between the CKO and WT littermates. Finally, the CKO mice exhibited delayed tooth eruption compared with the WT littermates.
Conclusion: Our studies, for the first time, revealed that the ER stress signaling molecule IRE1α is an essential physiological regulator for the formation of craniofacial bones and dentin and tooth eruption.
Division: AADR/CADR Annual Meeting
Meeting:2014 AADR/CADR Annual Meeting (Charlotte, North Carolina) Location: Charlotte, North Carolina
Year: 2014 Final Presentation ID:43 Abstract Category|Abstract Category(s):Mineralized Tissue
Authors
Revu, Shankar
( School of Dental Medicine, Pittsburgh, PA, USA
)
Shen, Hsiao-ling
( School of Dental Medicine, Pittsburgh, PA, USA
)
Liu, Kai
( School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
)
Riebe, Rebecca
( School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
)
Franks, Jonathan
( School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
)
Stolz, Donna
( School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
)
Ray, Herbert
( School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
)
Verdelis, Konstantinos
( University of Pittsburgh School of Dental Medicine, Pittsburgh, PA, USA
)
Ouyang, Hongjiao
( The University of Pittsburgh, Pittsburgh, PA, USA
; School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
; Comprehensive Care, Restorative Dentistry and Endodontics, Pittsburgh, PA, USA
)