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.

Jagged1 is essential for osteoblast development during maxillary ossification

“…Conversely, inhibition of NOTCH signaling in MC3T3 cells was shown to result in decreased regulators of bone development: RUNX2, Alkaline Phosphatase, Collagen1 , and Osteocalcin [7]. Several recent studies demonstrated that JAG1 acts to induce mesenchymal stem cells to differentiate into osteoblasts and undergo mineralization [5, 30]. In these studies, JAG1 induced expression of bone sialoprotein and Alkaline Phosphatase , demonstrating the role of JAGGED1 during the induction of mesenchymal cells into osteoblasts [30].…”

“…Several recent studies demonstrated that JAG1 acts to induce mesenchymal stem cells to differentiate into osteoblasts and undergo mineralization [5, 30]. In these studies, JAG1 induced expression of bone sialoprotein and Alkaline Phosphatase , demonstrating the role of JAGGED1 during the induction of mesenchymal cells into osteoblasts [30]. In addition, mutations in Jag1 cause Alagille syndrome in humans which is associated with craniofacial defects, butterfly vertebrae, digit abnormalities, osteoporosis, and pediatric bone fractures, suggesting that JAG1 plays an important role in human bone development and maintenance [31].…”

Notch Signaling Augments BMP9-Induced Bone Formation by Promoting the Osteogenesis-Angiogenesis Coupling Process in Mesenchymal Stem Cells (MSCs)

“…While endothelial Notch activity was reported as an essential source for the coordinated osteogenesis and angiogenesis during the bone development [44], it is not clear if it's necessary to include endothelial progenitors in engineered bone tissues to achieve Notch-induced angiogenesis. It was reported that the expression of Notch ligand Jaggedl was able to induce osteogenesis [78], whereas the genetic deletion of Jaggedl resulted in defects in osteoblast development and differentiation during maxillary ossification [79]. We previously found that the downstream target gene of Notch signaling Heyl was upregulated by BMP9 [28], suggesting BMP9 may act upstream of Notch signaling.…”

Notch signaling partly regulates the osteogenic differentiation of retinoic acid-treated murine induced pluripotent stem cells

“…3,[405][406][407][408][409][410][411][412][413]2017 Original Notch signaling partly regulates the osteogenic differentiation of retinoic acid-treated murine induced pluripotent stem cells Thanaphum Osathanon 1) , Jeeranan Manokawinchoke 1) , Hiroshi Egusa 2) , and Prasit Pavasant 1) must be clarified in order to ensure that their complete differentiation results in bone regeneration, without the development of teratomas. Notch signaling regulates several differentiation processes (5)(6)(7)(8)(9), including bone healing. Increased expression of various Notch signaling components has been observed in healing tibial and calvarial fractures (10).…”