NOTCH1 Regulates Osteoclastogenesis Directly in Osteoclast Precursors and Indirectly via Osteoblast Lineage Cells

Bai, Shuting; Kopan, Raphael; Zou, Wei; Hilton, Matthew J.; Ong, Chin‐Tong; Long, Fanxin; Ross, F. Patrick; Teitelbaum, Steven L.

doi:10.1074/jbc.m707000200

Cited by 204 publications

(203 citation statements)

References 49 publications

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“…This discrepancy could be due to changes in other genes in the absence of Cx37 or to the temporal preosteoclast-specific elevation of Notch1-3 signaling in our studies. The expression of the Notch signaling target Hey-1 is highly increased in mature osteoclasts from Cx37-deficient mice, consistent with evidence that the Notch/RBPJk signaling pathway inhibits osteoclast differentiation (34,35). Further studies are required to establish the mechanism by which Cx37 modulates cell number and osteoclast differentiation through the Notch signaling pathway.…”

Section: Discussionmentioning

confidence: 72%

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High Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiation

Pacheco‐Costa

Hassan

Reginato

et al. 2014

Journal of Biological Chemistry

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Background: Connexin proteins are essential for cell differentiation, function, and survival. Results: Global deletion of Cx37 results in increased bone mass caused by reduced osteoclast maturation. Conclusion: Our findings demonstrate a previously unrecognized role of Cx37 in bone homeostasis in vivo. Significance: Therapeutic approaches to increase bone mass might be developed by interfering with Cx37 function.

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Section: Discussionmentioning

confidence: 72%

“…Recent evidence indicates that the Notch signaling pathway negatively modulates osteoclast differentiation (34,35). We therefore investigated whether deleting Cx37 altered regulation of Notch signaling.…”

Section: Deletion Of Cx37 Decreases Osteoclast Fusion and Differentiamentioning

confidence: 99%

High Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiation

Pacheco‐Costa

Hassan

Reginato

et al. 2014

Journal of Biological Chemistry

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“…The Wnt/β-catenin pathway also regulates osteoblastic bone formation and the commitment of mesenchymal cells to the osteoblast lineage (72). Jagged1/Notch1 signaling negatively regulates osteoclast formation both directly in osteoclast precursors and indirectly by affecting the OPG/RANKL expression ratio in stromal cells (73). Thus, bone mass is determined by many influences on osteoblasts and osteoclasts and is regulated by osteoblasts through three major signaling pathways: RANKL/RANK, Wnt/β-catenin and Jagged1/Notch1.…”

Section: Opgmentioning

confidence: 99%

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Boyce

Xing

2008

Archives of Biochemistry and Biophysics

1,386

1,012

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The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-κB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/ OPG system in bone modeling and remodeling. KeywordsBone resorption; osteoclasts; RANKL; RANK; OPG Normal bone modelingWith the exception of the bones of the calvaria, all bones in the mammalian skeleton are preformed in cartilage moulds from mesenchymal progenitors, which under appropriate stimuli also have the potential to differentiate into a variety of tissue types, including fibrous tissue, fat and muscle. Chondrocytes proliferate near the ends of the cartilage moulds to drive their longitudinal growth, while others in the centers of undergo hypertrophic differentiation. The hypertrophic chondrocytes at the periphery of the centers of these moulds are invaded by blood vessels and undergo apoptosis. Some of this hypertrophic cartilage survives as thin islands of cartilage in the centers of ossification in growing bones. Osteoblasts, which differentiate from progenitors in a collar of connective tissue around the middle of the bones where vascular invasion takes place, follow the endothelial cells and lay down bone matrix on the surfaces of these islands of cartilage to form bone struts or trabeculae (1). Osteoclast precursors (OCPs), derived from progenitors in the spleen and liver are attracted from blood in the invading blood vessels close to newly formed bone trabeculae. These osteoclast precursors fuse with one

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“…Dll1 is able to activate the Notch1 receptor, leading to the activation of endogenous Hes1 genes (25) and several studies have demonstrated the inhibitory effects of Notch1 on osteoblastic cell differentiation (26)(27)(28). In the present study, the Dll1 overexpression vector was used to activate Notch signaling and the results revealed that the activation of Notch signaling attenuated the effects of OSM on MC3T3-E1 cell proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 76%

OSM is overexpressed in knee osteoarthritis and Notch signaling is involved in the effects of OSM on MC3T3-E1 cell proliferation and differentiation

Yuan

Yao

et al. 2015

International Journal of Molecular Medicine

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Abstract. Knee osteoarthritis (OA) is the most prevalent type of OA and the cytokine, oncostatin M (OSM), may contribute to the pathogenesis of OA. However, the exact role of OSM in the development of knee OA and the underlying mechanisms are not yet fully understood. This study was designed to detect the expression of OSM in the synovial tissue of patients with knee OA. Furthermore, we investigated whether Notch signaling is involved in the effects of OSM on MC3T3-E1 cell proliferation and differentiation. The synovial tissue of the knee joint was collected from 32 patients with knee OA. We detected OSM mRNA and protein expression (by RT-qPCR and western blot analysis, respectively) in the synovial tissue of the knee joint, and the expression level of OSM was higher in the patients with knee OA compared with the controls. MTT assay was used in the in vitro experiments to determine MC3T3-E1 cell proliferation, and cell differentiation was determined by measuring alkaline phosphatase (ALP) activity and osteocalcin (OCN) expression. The results from our in vitro experiments revealed that OSM induced bone formation by increasing osteoblast cell proliferation and differentiation. In addition, the expression levels of Notch ligand, receptor and target gene, including Delta-like 1 (Dll1), Notch homolog 1 (Notch1) and Hes family bHLH transcription factor 1 (Hes1) were decreased following treatment with OSM in a time-dependent manner in the MC3T3-E1 cells. A Dll1 overexpression vector was transfected into the cells to activate Notch signaling, and the results revealed that the activation of Notch signaling attenuated the effects of OSM on MC3T3-E1 cell proliferation and differentiation. In conclusion, our data demonstrate that elevated levels of OSM in synovial tissue induce bone formation by increasing osteoblast cell proliferation and differentiation. The Notch signaling pathway was found to be one of the signaling pathways that inhibit OSM-induced MC3T3-E1 cell proliferation and differentiation. The findings of this study may broaden our understanding of the mechanisms behing the role of OSM in the development of knee OA.

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NOTCH1 Regulates Osteoclastogenesis Directly in Osteoclast Precursors and Indirectly via Osteoblast Lineage Cells

Cited by 204 publications

References 49 publications

High Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiation

High Bone Mass in Mice Lacking Cx37 Because of Defective Osteoclast Differentiation

Functions of RANKL/RANK/OPG in bone modeling and remodeling

OSM is overexpressed in knee osteoarthritis and Notch signaling is involved in the effects of OSM on MC3T3-E1 cell proliferation and differentiation

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