title: The role of bioactive nanofibers in enamel regeneration mediated through integrin signals acting upon C/EBPα and c-Jun.
abstract: Enamel formation involves highly orchestrated intracellular and extracellular events; following development, the tissue is unable to regenerate, making it a challenging target for tissue engineering. We previously demonstrated the ability to trigger enamel differentiation and regeneration in the embryonic mouse incisor using a self-assembling matrix that displayed the integrin-binding epitope RGDS (Arg-Gly-Asp-Ser). To further elucidate the intracellular signaling pathways responsible for this phenomenon, we explore here the coupling response of integrin receptors to the biomaterial and subsequent downstream gene expression profiles. We demonstrate that the artificial matrix activates focal adhesion kinase (FAK) to increase phosphorylation of both c-Jun N-terminal kinase (JNK) and its downstream transcription factor c-Jun (c-Jun). Inhibition of FAK blocked activation of the identified matrix-mediated pathways, while independent inhibition of JNK nearly abolished phosphorylated-c-Jun (p-c-Jun) and attenuated the pathways identified to promote enamel regeneration. Cognate binding sites in the amelogenin promoter were identified to be transcriptionally up-regulated in response to p-c-Jun. Furthermore, the artificial matrix induced gene expression as evidenced by an increased abundance of amelogenin, the main protein expressed during enamel formation, and the CCAAT enhancer binding protein alpha (C/EBPα), which is the known activator of amelogenin expression. Elucidating these cues not only provides guidelines for the design of synthetic regenerative strategies and opportunities to manipulate pathways to regulate enamel regeneration, but can provide insight into the molecular mechanisms involved in tissue formation.
authors: The Center for Craniofacial Molecular Biology, The Herman Ostrow School of Dentistry of the University of Southern California, Los Angeles, CA, USA.
authors: Z
authors: Z
authors: Huang
authors: C J
authors: CJ
authors: Newcomb
authors: Y
authors: Y
authors: Zhou
authors: Y P
authors: YP
authors: Lei
authors: P
authors: P
authors: Bringas
authors: S I
authors: SI
authors: Stupp
authors: M L
authors: ML
authors: Snead
mesh_terms: D053523:Amelogenin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001672:Biocompatible Materials / Q000494:pharmacology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003743:Dental Enamel / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D057139:Nanofibers / Q000737:chemistry*; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013501:Surface-Active Agents / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D053523:Amelogenin; D001672:Biocompatible Materials; D022763:CCAAT-Enhancer-Binding Protein-alpha; D016023:Integrins; D009842:Oligopeptides; D010455:Peptides; D016755:Proto-Oncogene Proteins c-jun; D013501:Surface-Active Agents; C046617:arginyl-glycyl-aspartyl-serine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases
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