title: Jagged1 immobilization to an osteoconductive polymer activates the Notch signaling pathway and induces osteogenesis.
abstract: Treatment of nonunion fractures is a significant problem. Common therapeutics, including autologous bone grafts and bone morphogenetic proteins, show well-established limitations. Therefore, a need persists for the identification of novel clinical therapies to promote healing. The Notch signaling pathway regulates bone development. Clinically, loss-of-function mutations to the Notch ligand Jagged1 decrease bone mass and increase fracture risk. Jagged1 is also the most highly upregulated ligand during fracture repair, identifying it as a potential target to promote bone formation. Therefore, the objective of this study was to develop a clinically translatable construct comprised of Jagged1 and an osteoconductive scaffold, and characterize its activity in human mesenchymal stem cells (hMSC). We first evaluated the effects of Jagged1 directly immobilized to a novel poly(β-amino ester) relative to indirect coupling via antibody. Direct was more effective at activating hMSC Notch target gene expression and osteogenic activity. We then found that directly immobilized Jagged1 constructs induced osteoblast differentiation. This is the first study to demonstrate that Jagged1 delivery transiently activates Notch signaling and increases osteogenesis. A positive correlation was found between Jagged1-induced Notch and osteogenic expression. Collectively, these results indicate that Jagged1 coupled to an osteogenic biomaterial could promote bone tissue formation during fracture healing.
authors.affiliation: Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Dishowitz
authors.forename: Fengchang
authors.initials: F
authors.lastname: Zhu
authors.forename: Harini G
authors.initials: HG
authors.lastname: Sundararaghavan
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Ifkovits
authors.forename: Jason A
authors.initials: JA
authors.lastname: Burdick
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Hankenson
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001672:Biocompatible Materials / Q000494:pharmacology; D002113:Calcification, Physiologic / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D055767:Immobilized Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016348:Osseointegration / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D010641:Phenotype; D011108:Polymers / Q000494:pharmacology*; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects*; D054457:Tissue Scaffolds / Q000737:chemistry
chemical_list: D000469:Alkaline Phosphatase; D051792:Basic Helix-Loop-Helix Proteins; D001672:Biocompatible Materials; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D055767:Immobilized Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011108:Polymers; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; C485631:HEY1 protein, human; C000606273:JAG1 protein, human; C000606275:Jag1 protein, rat
keywords: Jagged1; Notch signaling; osteoblast differentiation; osteoinduction; translational medicine