NOTCHing the bone: Insights into multi-functionality

doi:10.1016/j.bone.2009.05.027

Bone

Volume 46, Issue 2, February 2010, Pages 274-280

https://doi.org/10.1016/j.bone.2009.05.027 Get rights and content

Abstract

Evolutionarily conserved Notch signaling plays a critical role during embryonic and postnatal life. The importance of Notch signaling in the determination of cell fate, and the spatio-temporal regulation of proliferation, differentiation and apoptosis has been demonstrated in various different organ systems. However, how Notch signaling affects the bone development was unknown until now. The in vivo effects of Notch signaling in lineage commitment, bone formation and bone resorption were demonstrated in recent studies. In addition to regulation of osteoblastogenesis, osteoblast directed osteoclastogenesis by Notch signaling revealed a dimorphic effect for this signaling pathway providing another example of such in bone development. Moreover, identification of the cross talk between the hematopoietic stem cell niche and osteoblasts through Notch signaling also suggested another important role for Notch signaling, i.e., the coupling of cellular components of the bone microenvironment. The association between the gain and loss of function of Notch activity in bone pathology highlights Notch as a potentially novel therapeutic target for the treatment of metabolic bone disease and bone cancer. In this review, we will focus primarily on the regulation of bone cells, i.e., osteoblasts and osteoclasts by Notch signaling. We will also review the importance of Notch in specifying bone–hematopoietic stem cell niche interactions within the bone microenvironment. Finally, we will discuss potential clinical implications and future directions for this field.

Section snippets

Mammalian Notch signaling

Evolutionarily conserved Notch signaling plays an important role in developmental processes and adult tissue homeostasis by regulating cell fate determination, proliferation, differentiation and apoptosis in a spatio-temporal manner. Altered Notch signaling has been associated with many different diseases including cancers of epithelial and hematopoietic origins. The Notch receptor and its ligands are transmembrane proteins whose signaling requires cell to cell contact between neighboring

Bone formation and remodeling

Skeleton forms through two different mechanisms; endochondral and intramembranous ossification [6], [7]. During endochondral ossification, cells located in the center of mesenchymal condensations differentiate into chondrocytes. Later, chondrocytes at the growth plate undergo well-ordered and controlled phases of cell proliferation, maturation, and apoptosis in order to form the future skeletal elements [8]. During intramembranous ossification, mesenchymal cells give rise to pre-osteoblasts to

Notch signaling during skeletogenesis

Until recently, the role of Notch signaling during skeletogenesis has mainly been limited to its role in patterning and somitogenesis. The involvement of the Notch-signaling pathway in somitogenesis was first revealed by the finding that Notch1 and its ligand Dll1 were highly expressed in the presomitic mesoderm (PSM) of mouse embryos. Subsequently, additional cycling genes, such as Lunatic fringe (Lfng), Hes7, and Hes1 were identified in different species to be components of this pathway [9],

Notch regulates osteoblast commitment, proliferation and differentiation

The importance of Notch function in osteoblast was demonstrated in vivo by studies in which tissue specific gain and loss of function mutants were generated. We generated an osteoblast specific over-expression of Notch1 ICD by using 2.3 kb collagen type 1 (Col1a1) promoter to drive the expression of activated Notch receptor specifically in committed osteoblasts [29]. These transgenic mice showed a dramatic increase in osteoblast number, proliferation and formation resulting in a severe

Notch regulates osteoclastogenesis directly and indirectly

The animal models generated above indicated that Notch could also regulate osteoblast dependent formation of osteoclasts. It has been shown that in PNN mice while RANKL expression was up-regulated, Opg levels were decreased. Osteoblast specific deletion of Presenilins via the 2.3 kb Col1a1-Cre resulted in decreased levels of Opg mRNA and protein as well. This demonstrates that Notch signaling may regulate osteoclastogenesis in a non-cell-autonomous manner through Opg regulation in osteoblasts (

Osteoblast regulation of hematopoietic stem cells via Notch signaling

In bone marrow, osteoblasts of the trabecular bone are in close physical association with hematopoietic stem cells and blood vessels, suggesting that the bone marrow microenvironment may provide regulatory signals for hematopoietic cells. Emerging data support the notion that osteoblasts lining the endosteal surface of trabecular bone can provide important cues to regulate/support the hematopoietic stem cell (HSC) niche. Transgenic mice expressing Parathyroid Hormone Receptor (PTH1R) under the

Notch as a therapeutic target for bone diseases

Loss of function studies of Notch signaling indicated an age dependent osteoporotic phenotype in mice. There are few anabolic bone agents for the treatment of osteoporosis, with most therapies targeted at inhibition of bone resorption. Up-regulation of Notch signaling may represent a potential approach for increasing bone formation over bone resorption as well as for inhibiting osteoclastogenesis. However, Notch's effects on other cellular compartments such as the mesenchymal stem cell pool

Future directions

Notch has a dual function in bone development in regulating both osteoblastogenesis and osteoclastogenesis. Cells in osteoclast and osteoblast lineages communicate with each other through cell to cell contact. Although osteoblast dependent activation of osteoclasts through Notch signaling has been demonstrated, whether there is reverse signaling between these two types of bone cells needs to be further investigated. Such cross talk and coupling might also exist within the bone marrow

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Cited by (70)

Notch4 affects the proliferation and differentiation of deer antler chondrocytes through the Smad3/lncRNA27785.1 axis
2022, Cellular Signalling
Long non-coding RNA play an importantr role in the differentiation of chondrocytes. This study aims to explore the role of long non-coding RNA in the transcriptional regulation of Notch4. In previous studies, it has been found that Notch signal can be used as the downstream of TGF-β signal to affect the proliferation and differentiation of deer antler chondrocytes, but the specific mechanism remains unclear. Here we found that lncRNA27785.1 was involved in the regulation of TGF-β/ Smad3 signal and Notch4 gene. The overexpression lncRNA27785.1 can negatively regulate the expression of Notch4 to inhibit cell proliferation and differentiation, while interference with lncRNA27785.1 can promote the expression of Notch4 gene to promote the proliferation and differentiation of chondrocytes. Subsequently, through luciferase experiment and CHIP experiment, we found that lncRNA27785.1 is regulated by Smad3 transcription, and Smad3 inhibited the expression of lncRNA27785.1. In addition, activated TGF-β signaling can reduce the inhibitory effect of lncRNA27785.1 on Notch4 signaling. In summary, we found that lncRNA27785.1 and TGF-β/Smad3 play an important role in Notch4 signaling. Our findings provided evidence to explain how TGF-β signaling regulate the Notch signaling pathway to influence chondrocyte proliferation and differentiation by a specific lncRNA27785.1.
Smad4 and γ-secretase knock-down effect on osteogenic differentiation mediated via Runx2 in canine mesenchymal stem cells
2022, Research in Veterinary Science
Cell lineage determination during mesenchymal stem cell (MSCs) differentiation is a highly orchestrated process involving diverse signaling pathways and distinct classes of regulatory molecules. Bone morphogenetic protein (BMP) signaling positively influence the osteoblast lineage determination, whereas the Notch signaling may have a dimorphic action. Effective regenerative therapy for repairing bone defects requires ample knowledge of the signaling pathways responsible for the differentiation of MSCs. To elucidate the signaling pathways that drives canine bone-marrow derived MSCs towards osteogenic lineage, the current work was focused on BMP and Notch signaling. Target genes of Runx2, Smad4 and γ-secretase were silenced by short hairpin RNA (shRNA) in canine MSCs. Evaluation of the effect of gene silencing on in-vitro osteogenic differentiation potential was done by quantitative polymerase chain reaction (qPCR) for osteoblastic markers (Osteocalcin and Osteopontin) and Alizarin red S staining for the extracellular deposition of calcium. Silencing of Runx2 significantly reduced the osteocalcin and osteopontin gene expression while a similar trend was observed in the case of smad 4 silencing and their combination groups, but there was no difference found in Hey 1 expression. Runx2 and Smad4 silencing groups showed very less positive staining with Alizarin red S staining, whereas knockdown of γ-secretase and its combination groups showed reverse results as that of Runx2 and Smad4. Runx2 plays an indispensable part in directing the canine mesenchymal stem cells towards osteogenic lineage. Also, Smad-mediated BMP signaling induced the osteoblast-specific gene expression, whereas the notch pathway negatively regulated the osteogenic differentiation of canine MSCs.
Differential expression of Notch related genes in dental pulp stem cells and stem cells isolated from apical papilla
2021, Journal of Oral Biology and Craniofacial Research
Although dental pulp and apical papilla are originated from neural crest cells, these tissues exhibit distinct characteristics. Notch signaling is one of the known signaling pathways regulating stemness and behaviors of stem cells. The aim of this study was to examine Notch signaling related gene expression profile comparing between coronal pulp tissues and apical pulp complex. Results demonstrated that coronal pulp tissue had higher expression levels of various genes in Notch pathway. However, NOTCH2, MAML2, DTX4, and NEDD4 mRNA levels were significantly lower in coronal pulp tissue than those of apical pulp complex. Furthermore, dental pulp stem cells (DPSCs) and stem cells isolated from apical papilla (SCAPs) were isolated and characterized. These two cell types exhibited similar mesenchymal stem cell surface markers. DPSCs expressed higher mRNA levels of NOTCH3, NOTCH4, DLL1, and HES1. In addition, SCAPs demonstrated higher colony formation and cell proliferation than DPSCs. In summary, cells and tissues from dental pulp and apical papilla exhibited the distinct gene expression profile of Notch related genes. This could be of one the signaling participated in control of DPSCs and SCAPs cells behaviors.
ADAM10 is indispensable for longitudinal bone growth in mice
2020, Bone
Citation Excerpt :
Consistently, our gene expression analysis revealed that the transcripts of molecules downstream of Notch signaling, including Hes1, Hey1, and Heyl, were all expressed at lower levels in Adam10ΔCol2 mice than those in Ctrl mice (Fig. 3). The role of Notch signaling in chondrogenesis and skeletal development has been widely investigated [24–27]. The manipulation of Notch signaling in vivo proves that Notch signaling plays a crucial role in skeletal development.
Skeletal development is a highly sophisticated process in which the expression of a variety of growth factors, signaling molecules, and extracellular matrix proteins is spatially and temporally orchestrated. In the present study, we show that ADAM10, a transmembrane protease that is critically involved in the functional regulation of various membrane-bound molecules, plays an essential role in the longitudinal growth of long bones and in skeletal development. We found that mutant mice lacking ADAM10 in osteochondroprogenitors exhibited marked growth retardation and had shorter long bones than the control mice. Histomorphometric analysis revealed that the mutant mice had a shorter hypertrophic zone and that their hypertrophic chondrocytes were smaller in size than those of the control mice. Unexpectedly, we found that the mRNA expression of the chemokine CXCL12 and its receptor CXCR4 were significantly reduced in cartilage tissues lacking ADAM10. Further, exogenous supplementation of recombinant CXCL12 rescued the defect in the ADAM10-deficient growth plate in an ex vivo culture model. Taken together, our data show a previously unknown role for ADAM10 in skeletal development that involves its regulation of the CXCL12 and CXCR4 signaling pathway.
The Role of Neuromodulation and Potential Mechanism in Regulating Heterotopic Ossification
2024, Neurochemical Research
Autophagy promoted neural differentiation of human placenta-derived mesenchymal stem cells
2021, In Vivo

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ReviewNOTCHing the bone: Insights into multi-functionality

Abstract

Section snippets

Mammalian Notch signaling

Bone formation and remodeling

Notch signaling during skeletogenesis

Notch regulates osteoblast commitment, proliferation and differentiation

Notch regulates osteoclastogenesis directly and indirectly

Osteoblast regulation of hematopoietic stem cells via Notch signaling

Notch as a therapeutic target for bone diseases

Future directions

Dev. Biol.

Neuron

Blood

Biochem. Biophys. Res. Commun.

Curr. Opin. Genet. Dev.

Dev. Biol.

Mech. Dev.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Blood

Mech. Dev.

J. Biol. Chem.

J. Biol. Chem.

Cell Metab.

Blood

Reconstitution of gamma-secretase activity

Nat. Cell Biol.

Critical role of notch signaling in osteosarcoma invasion and metastasis

Clin. Cancer Res.

Cellular and molecular interactions regulating skeletogenesis

J. Cell. Biochem.

Notch1 is required for the coordinate segmentation of somites

Development

Disruption of the mouse RBP-J kappa gene results in early embryonic death

Development

Abnormal vertebral segmentation and the notch signaling pathway in man

Dev. Dyn.

Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1

Nat. Genet.

Review
NOTCHing the bone: Insights into multi-functionality