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CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis.

Ouellet V, Siegel PM - J Cell Commun Signal (2012)

Bottom Line: The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity.These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease.In contrast, CCN3 is known to promote chondrocyte differentiation.

View Article: PubMed Central - PubMed

Affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 513, Montreal, Quebec, Canada, H3A 1A3.

ABSTRACT
The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity. These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease. In this review, we focus on CCN3, a founding member of this family, and its role in regulating cells within the bone microenvironment. CCN3 impairs normal osteoblast differentiation through multiple mechanisms, which include the neutralization of pro-osteoblastogenic stimuli such as BMP and Wnt family signals or the activation of pathways that suppress osteoblastogenesis, such as Notch. In contrast, CCN3 is known to promote chondrocyte differentiation. Given these functions, it is not surprising that CCN3 has been implicated in the progression of primary bone cancers such as osteosarcoma, Ewing's sarcoma and chondrosarcoma. More recently, emerging evidence suggests that CCN3 may also influence the ability of metastatic cancers to colonize and grow in bone.

No MeSH data available.


Related in: MedlinePlus

CCN3 is a physiological regulator of osteoblast differentiation. a Schematic depicting the different stages during osteoblast differentiation. The prevailing data suggests that CCN3 can block the differentiation of mesenchymal stem cells and/or osteoprogenitors into committed pre-osteoblasts. As mesenchymal stem cells differentiate into mature osteoblasts, Receptor Activator of NF-κB Ligand (RANKL) expression decreases and the levels of Osteoprotegerin (OPG), a decoy receptor for RANKL, increase. Thus, CCN3 would have the indirect effect of elevating the RANKL/OPG ratio in pre-osteoblasts by impairing osteoblast differentiation. b Mechanisms underlying CCN3-mediated blockade of osteoblast differentiation. CCN3 can directly bind and neutralize BMP-2, a potent osteoblastic factor. In addition, CCN3 can indirectly inhibit BMP2 effect by increasing the level of Gremlin, a known antagonist of BMP2, by favoring the stabilization of Gremlin mRNA. CCN3 also counteracts the signaling of Wnt3, by causing a reduction of β-Catenin levels and a subsequent diminishment of Wnt3 target genes, through a mechanism that does not interfere with the ligand-receptor interaction. CCN3 can also bind and activate Notch, causing the release the Notch intracellular domain (NICD). The NICD induces the expression of Hairy/Enhancer of Split (HES) and Hairy/Enhancer of Split with YRPW motif 1 (HEY), which in turn physically interact with and repress Runx2 activity, a key transcription factor involved in osteoblast differentiation
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Fig2: CCN3 is a physiological regulator of osteoblast differentiation. a Schematic depicting the different stages during osteoblast differentiation. The prevailing data suggests that CCN3 can block the differentiation of mesenchymal stem cells and/or osteoprogenitors into committed pre-osteoblasts. As mesenchymal stem cells differentiate into mature osteoblasts, Receptor Activator of NF-κB Ligand (RANKL) expression decreases and the levels of Osteoprotegerin (OPG), a decoy receptor for RANKL, increase. Thus, CCN3 would have the indirect effect of elevating the RANKL/OPG ratio in pre-osteoblasts by impairing osteoblast differentiation. b Mechanisms underlying CCN3-mediated blockade of osteoblast differentiation. CCN3 can directly bind and neutralize BMP-2, a potent osteoblastic factor. In addition, CCN3 can indirectly inhibit BMP2 effect by increasing the level of Gremlin, a known antagonist of BMP2, by favoring the stabilization of Gremlin mRNA. CCN3 also counteracts the signaling of Wnt3, by causing a reduction of β-Catenin levels and a subsequent diminishment of Wnt3 target genes, through a mechanism that does not interfere with the ligand-receptor interaction. CCN3 can also bind and activate Notch, causing the release the Notch intracellular domain (NICD). The NICD induces the expression of Hairy/Enhancer of Split (HES) and Hairy/Enhancer of Split with YRPW motif 1 (HEY), which in turn physically interact with and repress Runx2 activity, a key transcription factor involved in osteoblast differentiation

Mentions: Of the cell types that reside in the bone microenvironment, osteoblasts are the bone forming cells and osteoclasts are responsible for resorbing bone. Mesenchymal stem cells differentiate into osteoblasts through a multi-step process (Fig. 2a) that is stimulated by BMP and Wnt family members and inhibited via Notch1 signaling (reviewed in (Krishnan et al. 2006; Canalis 2008; Long 2011)). The proper differentiation of precursors into osteoblasts requires expression of the Runx2 transcription factor, which acts as a master regulator of this process (Marie 2008).Fig. 2


CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis.

Ouellet V, Siegel PM - J Cell Commun Signal (2012)

CCN3 is a physiological regulator of osteoblast differentiation. a Schematic depicting the different stages during osteoblast differentiation. The prevailing data suggests that CCN3 can block the differentiation of mesenchymal stem cells and/or osteoprogenitors into committed pre-osteoblasts. As mesenchymal stem cells differentiate into mature osteoblasts, Receptor Activator of NF-κB Ligand (RANKL) expression decreases and the levels of Osteoprotegerin (OPG), a decoy receptor for RANKL, increase. Thus, CCN3 would have the indirect effect of elevating the RANKL/OPG ratio in pre-osteoblasts by impairing osteoblast differentiation. b Mechanisms underlying CCN3-mediated blockade of osteoblast differentiation. CCN3 can directly bind and neutralize BMP-2, a potent osteoblastic factor. In addition, CCN3 can indirectly inhibit BMP2 effect by increasing the level of Gremlin, a known antagonist of BMP2, by favoring the stabilization of Gremlin mRNA. CCN3 also counteracts the signaling of Wnt3, by causing a reduction of β-Catenin levels and a subsequent diminishment of Wnt3 target genes, through a mechanism that does not interfere with the ligand-receptor interaction. CCN3 can also bind and activate Notch, causing the release the Notch intracellular domain (NICD). The NICD induces the expression of Hairy/Enhancer of Split (HES) and Hairy/Enhancer of Split with YRPW motif 1 (HEY), which in turn physically interact with and repress Runx2 activity, a key transcription factor involved in osteoblast differentiation
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368020&req=5

Fig2: CCN3 is a physiological regulator of osteoblast differentiation. a Schematic depicting the different stages during osteoblast differentiation. The prevailing data suggests that CCN3 can block the differentiation of mesenchymal stem cells and/or osteoprogenitors into committed pre-osteoblasts. As mesenchymal stem cells differentiate into mature osteoblasts, Receptor Activator of NF-κB Ligand (RANKL) expression decreases and the levels of Osteoprotegerin (OPG), a decoy receptor for RANKL, increase. Thus, CCN3 would have the indirect effect of elevating the RANKL/OPG ratio in pre-osteoblasts by impairing osteoblast differentiation. b Mechanisms underlying CCN3-mediated blockade of osteoblast differentiation. CCN3 can directly bind and neutralize BMP-2, a potent osteoblastic factor. In addition, CCN3 can indirectly inhibit BMP2 effect by increasing the level of Gremlin, a known antagonist of BMP2, by favoring the stabilization of Gremlin mRNA. CCN3 also counteracts the signaling of Wnt3, by causing a reduction of β-Catenin levels and a subsequent diminishment of Wnt3 target genes, through a mechanism that does not interfere with the ligand-receptor interaction. CCN3 can also bind and activate Notch, causing the release the Notch intracellular domain (NICD). The NICD induces the expression of Hairy/Enhancer of Split (HES) and Hairy/Enhancer of Split with YRPW motif 1 (HEY), which in turn physically interact with and repress Runx2 activity, a key transcription factor involved in osteoblast differentiation
Mentions: Of the cell types that reside in the bone microenvironment, osteoblasts are the bone forming cells and osteoclasts are responsible for resorbing bone. Mesenchymal stem cells differentiate into osteoblasts through a multi-step process (Fig. 2a) that is stimulated by BMP and Wnt family members and inhibited via Notch1 signaling (reviewed in (Krishnan et al. 2006; Canalis 2008; Long 2011)). The proper differentiation of precursors into osteoblasts requires expression of the Runx2 transcription factor, which acts as a master regulator of this process (Marie 2008).Fig. 2

Bottom Line: The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity.These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease.In contrast, CCN3 is known to promote chondrocyte differentiation.

View Article: PubMed Central - PubMed

Affiliation: Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Room 513, Montreal, Quebec, Canada, H3A 1A3.

ABSTRACT
The CCN family of proteins is composed of six secreted proteins (CCN1-6), which are grouped together based on their structural similarity. These matricellular proteins are involved in a large spectrum of biological processes, ranging from development to disease. In this review, we focus on CCN3, a founding member of this family, and its role in regulating cells within the bone microenvironment. CCN3 impairs normal osteoblast differentiation through multiple mechanisms, which include the neutralization of pro-osteoblastogenic stimuli such as BMP and Wnt family signals or the activation of pathways that suppress osteoblastogenesis, such as Notch. In contrast, CCN3 is known to promote chondrocyte differentiation. Given these functions, it is not surprising that CCN3 has been implicated in the progression of primary bone cancers such as osteosarcoma, Ewing's sarcoma and chondrosarcoma. More recently, emerging evidence suggests that CCN3 may also influence the ability of metastatic cancers to colonize and grow in bone.

No MeSH data available.


Related in: MedlinePlus