CCN3 modulates bone turnover and is a novel regulator of skeletal metastasis - PubMed (original) (raw)

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

Véronique Ouellet et al. J Cell Commun Signal. 2012 Jun.

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.

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Figures

Fig. 1

Fig. 1

Schematic diagram depicting the modular domains of CCN3. CCN3 shares a similar overall structural organization with the remaining CCN family members, including a secretory signal peptide (SP), an insulin-like growth factor binding protein domain (IGFBP), a von Willebrand factor type C domain (VWC), a Thrombospondin-1 type repeat (TSP-1) and a carboxyl-terminal domain (CT) that contains a cysteine knot. Known binding proteins are listed in black underneath the particular domain through which they interact with CCN3. Proteins denoted in grey are those for which the precise CCN3 domain responsible for the interaction remains unknown, but has been defined in other CCN family members. IGFs: Insulin-like Growth Factors, BMP: Bone Morphogenetic Protein; Rbp7: Retinol Binding Protein 7; HSPG: Heparan Sulfate Proteoglycan

Fig. 2

Fig. 2

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

Fig. 3

Fig. 3

Potential roles for CCN3 in promoting the formation of osteolytic breast cancer metastases. CCN3 expressed by breast cancer cells can block the differentiation of mature osteoblasts, utilizing the mechanisms outlined in Fig. 2. This would result in a tip towards higher levels of Receptor Activator of NF-κB Ligand (RANKL) produced by pre-osteoblasts and less Osteoprotegerin (OPG). The higher levels of RANKL would serve to induce the differentiation of monocytes into osteoclasts. In concert with its negative effects on osteoblast differentiation, CCN3 can also sensitize osteoclast precursors to respond to RANKL, enhancing osteoclastogenesis and bone resorption

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