Jagged1 is essential for osteoblast development during maxillary ossification

Hill, Cynthia R.; Yuasa, Masato; Schoenecker, Jonathan G.; Goudy, Steven L.

doi:10.1016/j.bone.2014.01.019

Cited by 42 publications

(49 citation statements)

References 30 publications

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“…ARS was quantified as described. (15) The samples were read on a Flex Station 3 microplate reader (Molecular Devices, Sunnyvale, CA, USA) at 405 nm in 96-well opaque-walled transparent-bottomed plates. Data were collected with Soft Max Pro (Molecular Devices) software.…”

Section: Methodsmentioning

confidence: 99%

The Selective Serotonin Reuptake Inhibitor Fluoxetine Directly Inhibits Osteoblast Differentiation and Mineralization During Fracture Healing in Mice

Bradaschia-Corrêa

Josephson

Mehta

et al. 2016

Journal of Bone and Mineral Research

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Chronic use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression has been linked to osteoporosis. In this study, we investigated the effect of chronic SSRI use on fracture healing in two murine models of bone regeneration. First, we performed a comprehensive analysis of endochondral bone healing in a femur fracture model. C57/BL6 mice treated with fluoxetine, the most commonly prescribed SSRI, developed a normal cartilaginous soft-callus at 14 days after fracture and demonstrated a significantly smaller and biomechanically weaker bony hard-callus at 28 days. In order to further dissect the mechanism that resulted in a smaller bony regenerate, we used an intramembranous model of bone healing and revealed that fluoxetine treatment resulted in a significantly smaller bony callus at 7 and 14 days postinjury. In order to test whether the smaller bony regenerate following fluoxetine treatment was caused by an inhibition of osteogenic differentiation and/or mineralization, we employed in vitro experiments, which established that fluoxetine treatment decreases osteogenic differentiation and mineralization and that this effect is serotonin-independent. Finally, in a translational approach, we tested whether cessation of the medication would result in restoration of the regenerative potential. However, histologic and µCT analysis revealed non-union formation in these animals with fibrous tissue interposition within the callus. In conclusion, fluoxetine exerts a direct, inhibitory effect on osteoblast differentiation and mineralization, shown in two disparate murine models of bone repair. Discontinuation of the drug did not result in restoration of the healing potential, but rather led to complete arrest of the repair process. Besides the well-established effect of SSRIs on bone homeostasis, our study provides strong evidence that fluoxetine use negatively impacts fracture healing.

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Section: Methodsmentioning

confidence: 99%

The Selective Serotonin Reuptake Inhibitor Fluoxetine Directly Inhibits Osteoblast Differentiation and Mineralization During Fracture Healing in Mice

Bradaschia-Corrêa

Josephson

Mehta

et al. 2016

Journal of Bone and Mineral Research

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Liao

Wei

Zou

et al. 2017

Cell Physiol Biochem

1,991

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Background/Aims: Mesenchymal stem cells (MSCs) are multipotent progenitors that can differentiate into several lineages including bone. Successful bone formation requires osteogenesis and angiogenesis coupling of MSCs. Here, we investigate if simultaneous activation of BMP9 and Notch signaling yields effective osteogenesis-angiogenesis coupling in MSCs. Methods: Recently-characterized immortalized mouse adipose-derived progenitors (iMADs) were used as MSC source. Transgenes BMP9, NICD and dnNotch1 were expressed by adenoviral vectors. Gene expression was determined by qPCR and immunohistochem¡stry. Osteogenic activity was assessed by in vitro assays and in vivo ectopic bone formation model. Results: BMP9 upregulated expression of Notch receptors and ligands in iMADs. Constitutively-active form of Notch1 NICD1 enhanced BMP9-induced osteogenic differentiation both in vitro and in vivo, which was effectively inhibited by dominant-negative form of Notch1 dnNotch1. BMP9- and NICD1-transduced MSCs implanted with a biocompatible scaffold yielded highly mature bone with extensive vascularization. NICD1 enhanced BMP9-induced expression of key angiogenic regulators in iMADs and Vegfa in ectopic bone, which was blunted by dnNotch1. Conclusion: Notch signaling may play an important role in BMP9-induced osteogenesis and angiogenesis. It’s conceivable that simultaneous activation of the BMP9 and Notch pathways should efficiently couple osteogenesis and angiogenesis of MSCs for successful bone tissue engineering.

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“…Formation of this complex was observed and found to be important for endothelial function and neuroepithelial cell differentiation [118, 119]. Follow up work has now determined that crosstalk between Notch and BMP is important for a wide variety of cellular responses including osteoblastic differentiation [120-122] and vascular biology/angiogenesis [123, 124]. Finally, besides TGF-β and BMP, little is known regarding crosstalk between other TGF-β superfamily members and Notch.…”

Section: Notch and Tgf-βmentioning

confidence: 99%

Notch: A multi-functional integrating system of microenvironmental signals

LaFoya

Munroe

Mia

et al. 2016

Developmental Biology

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The Notch signaling cascade is an evolutionarily ancient system that allows cells to interact with their microenvironmental neighbors through direct cell-cell interactions, thereby directing a variety of developmental processes. Recent research is discovering that Notch signaling is also responsive to a broad variety of stimuli beyond cell-cell interactions, including: ECM composition, crosstalk with other signaling systems, shear stress, hypoxia, and hyperglycemia. Given this emerging understanding of Notch responsiveness to microenvironmental conditions, it appears that the classical view of Notch as a mechanism enabling cell-cell interactions, is only a part of a broader function to integrate microenvironmental cues. In this review, we summarize and discuss published data supporting the idea that the full function of Notch signaling is to serve as an integrator of microenvironmental signals thus allowing cells to sense and respond to a multitude of conditions around them.

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Jagged1 is essential for osteoblast development during maxillary ossification

Cited by 42 publications

References 30 publications

The Selective Serotonin Reuptake Inhibitor Fluoxetine Directly Inhibits Osteoblast Differentiation and Mineralization During Fracture Healing in Mice

The Selective Serotonin Reuptake Inhibitor Fluoxetine Directly Inhibits Osteoblast Differentiation and Mineralization During Fracture Healing in Mice

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

Notch: A multi-functional integrating system of microenvironmental signals

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