CCN family protein 2 (CCN2), also widely known as connective tissue growth factor (CTGF), is one of the founding members of the CCN family of matricellular proteins. Extensive investigation on CCN2 over decades has revealed the novel molecular action and functional properties of this unique signalling modulator. By its interaction with multiple molecular counterparts, CCN2 yields highly diverse and context-dependent biological outcomes in a variety of microenvironments. Nowadays, CCN2 is recognized to conduct the harmonized development of relevant tissues, such as cartilage and bone, in the skeletal system, by manipulating extracellular signalling molecules involved therein by acting as a hub through a web. However, on the other hand, CCN2 occasionally plays profound roles in major human biological disorders, including fibrosis and malignancies in major organs and tissues, by modulating the actions of key molecules involved in these clinical entities. In this review, the physiological and pathological roles of this unique protein are comprehensively summarized from a molecular network-based viewpoint of CCN2 functionalities.

INTRODUCTION: CCN2/CTGF IN THE CCN FAMILY

The name of a biomolecule is generally given based on a particular functional aspect that happened to be revealed immediately after its discovery. Nevertheless, such an initial name sometimes does not well represent the entire functionality of the molecule under a variety of biological conditions. This also applies to the case of CCN family protein 2 (CCN2), the initial name of which was connective tissue growth factor (CTGF). CCN2 was discovered as a platelet-derived growth factor-related protein with mitogenic activity towards fibroblasts, thus prompting the designation of this protein as CTGF [1,2]. However, the versatile functionality of CCN2 in a variety of tissues and organs obviously goes beyond the one imagined based on this classical name.

CCN2 is the second member of the CCN family, which includes six members in the human body [36]. This family name originates from the acronym of the initial letters of the first names of the classical members found in the early days of research in this field: cysteine-rich protein 61 (CYR61), CTGF and nephroblastoma-overexpressed (NOV) gene product, a designation representing no functional aspect. This family was established based on the prominent structural characteristics shared by these proteins. All of them are composed of four distinct modules, i.e., insulin-like growth factor binding protein-like (IGFBP), von Willebrand factor type C repeat (VWC), thrombospondin type 1 repeat (TSP1) and C-terminal cystine-knot (CT) modules [36]. After the establishment of this family, three additional members were discovered by independent research groups and were widely known as Wnt-inducible secretory proteins (WISP)-1, -2 and -3 [36]. However, at least three other names were also used to represent the same WISP-2 protein. It may also be noted that as many as eight names were eventually given to CCN2, which afforded significant confusion in the relevant research communities. As such, in order to address this issue, a unified nomenclature was proposed, in which all of the family members were renamed in a numerical order according to the history of their discovery [7]. The newly assigned name, CCN2, seems to be more feasible than any other former name, since it gives no prejudice or constraint in understanding its functional versatility. Therefore, researchers are encouraged to use this unified terminology, instead of sticking to a particular name based on a particular biological interest.

GENE STRUCTURE AND REGULATION

The human genome contains six CCN family member genes on four different chromosomes (Figure 1). Among them three classical members, CCN1, CCN2 and CCN3, are commonly characterized by relatively compact genomic structure. The transcribed area of the human CCN2 gene is as short as 3.2 kb, containing five exons interrupted by four short introns (Figure 2). The boundary of exons corresponds to that of modules, indicating that the CCN family of genes evolved through exon shuffling events [6,8]. The structure of CCN2 mRNA is characterized by the presence of a relatively long 3′-untranslated region (UTR), which plays critical roles in CCN2 post-transcriptional regulation, as detailed below [1,3].

Genomic context of the human CCN family of genes and their products

Figure 1
Genomic context of the human CCN family of genes and their products

Approximate locations of the CCN family member genes are mapped on human chromosomes. In the centre, the modular structures of their translational products are also illustrated: I, insulin-like growth factor-binding protein-like module; V, von Willebrand factor type C repeat module; T, thrombospondin type 1 repeat module; C, C-terminal cystine-knot module.

Figure 1
Genomic context of the human CCN family of genes and their products

Approximate locations of the CCN family member genes are mapped on human chromosomes. In the centre, the modular structures of their translational products are also illustrated: I, insulin-like growth factor-binding protein-like module; V, von Willebrand factor type C repeat module; T, thrombospondin type 1 repeat module; C, C-terminal cystine-knot module.

Transcriptional and post-transcriptional regulation of the CCN2 gene

Figure 2
Transcriptional and post-transcriptional regulation of the CCN2 gene

At the centre, the structures of the CCN2 gene and its mRNA are illustrated. Solid boxes and solid lines in the CCN2 gene represent exons and introns, respectively. The mRNA, with the coding region shown in black, is characterized by the 5′-cap structure (circle) and 3′-polyadenyl tail (AAAAA). Above and below them, transcription factors and post-transcriptional regulatory molecules that are known to directly regulate CCN2 expression [11,24,27,125128] are summarized, respectively.

Figure 2
Transcriptional and post-transcriptional regulation of the CCN2 gene

At the centre, the structures of the CCN2 gene and its mRNA are illustrated. Solid boxes and solid lines in the CCN2 gene represent exons and introns, respectively. The mRNA, with the coding region shown in black, is characterized by the 5′-cap structure (circle) and 3′-polyadenyl tail (AAAAA). Above and below them, transcription factors and post-transcriptional regulatory molecules that are known to directly regulate CCN2 expression [11,24,27,125128] are summarized, respectively.

CCN2 is not ubiquitously or constitutively expressed, but is under sharp regulation by a number of extracellular stimuli. As a result of combinatory regulation by these stimuli, highly restricted spatiotemporal CCN2 expression is observed in vivo. Growth factors, cytokines and hormones are classical regulators of CCN2, which include transforming growth factor (TGF)-β, bone morphogenetic protein (BMP)-2, angiotensin II, glucocorticoids, monocyte chemotactic protein (MCP)-1 and interferon (IFN)-γ [911]. Among these regulators, TGF-β induces CCN2 expression and is known to play profound roles in certain biological aspects including the development of fibrosis and the epithelial–mesenchymal transition (EMT) [5,11,12]. In this point of view, one should note that induced CCN2 directly interacts with TGF-β molecules, which modulates its signalling [5]. In addition, it is also known that the expression of CCN3 and CCN4 are under the regulation of TGF-β [13]. Other extracellular signalling molecules, such as haemodynamic endothelin (ET)-1, secreted frizzled-like protein (sFRP)-2, anti-proliferative factor and thrombins are also reported to up-regulate CCN2 production [11,14,15]. Modulation of CCN2 expression by histamine, serotonin and prostaglandins emphasizes the involvement of CCN2 in the inflammatory process [11,13]. Natural compounds such as adenosine, α-tocopherol, nicotine and harmine are inducers of CCN2 expression, whereas curcumin represses it [1620]. Statins, representative inhibitors of cholesterol synthesis, were reported to repress CCN2 expression as well [21,22]. These findings suggest the utility of these compounds in controlling CCN2-related biological events. Small gas molecules are also involved in the regulation of CCN2. Hypoxia is a common microenvironmental condition that affects CCN2 expression, whereas nitric oxide (NO) is known to down-regulate it [11]. Interestingly, hypoxia-inducible factor (HIF) 1α, which partly mediates the hypoxic induction of CCN2, is suppressed by CCN2, forming a regulatory circuit [23]. Considering the clinical impact, it is noteworthy that metabolic factors, such as hyperglycaemia [24,25], reactive oxygen species (ROS) [26], advanced glycation end-products (AGE) and free fatty acids [25], all induce CCN2 production in the affected tissues, as also discussed later on.

In addition to these biochemical stimuli, certain physical events are also known to be inducing factors of CCN2. Distinct types of mechanical stresses, such as mechanical stretch and fluid flow shear stress, cause CCN2 expression in different types of the cells [27,28]. Application of low-intensity pulsed ultrasound (LIPUS) is a therapeutic intervention already utilized in orthopaedic clinics, and it also increases CCN2 expression in gingival epithelial cells [29].

Signals emitted by the stimulation from outside of cells are transmitted by intracellular messengers of signal transduction and eventually drive transcriptional and post-transcriptional regulators. A number of well-known secondary messengers and transcription factors have been found to mediate the transcriptional regulation of CCN2. As summarized in Figure 2, these molecules include Smads, mediating TGF-β signals and signal transducer and activator of transcription (STATs), involved in cytokine signalling [11,30]; Rho family members for mechanotransduction; certain isoforms of protein kinase C (PKC) [31,32] and other transcription factors driving a variety of human genes [5,11]. Among these molecules, a novel functional aspect was discovered for matrix metalloproteinase (MMP)-3 in relation to CCN2 regulation [33,34]. MMP-3 is a member of a family of extracellular proteases involved in extracellular matrix (ECM) remodelling, and thus it is found outside of the cell. However, surprisingly, MMP-3 was found taken up into the cell nucleus, where it directly interacts with CCN2 in chromatin and, indeed, activates its transcription. This regulation of CCN2 by an ECM-associated enzyme may further strengthen the view of CCN2 as being a matricellular protein.

As a post-transcriptional regulator, a new functional aspect of glyceraldehyde-3-dehydrogenase (GAPDH) as a molecular counterpart of the cis-acting element of structure-anchored repression (CAESAR) in the 3′-UTR was unveiled (Figure 2) [1,3,11,35]. CAESAR is located near the 5′-border of the CCN2 3′-UTR, repressing the translation of CCN2 mRNA in cis fashion. Another post-transcriptional regulatory protein driving CCN2 expression is nucleophosmin (NPM), a protein that shuttles between the nucleus and cytoplasm and acts as a histone chaperon. NPM also directly binds to a distinct RNA element in the 3′-UTR and accelerates its degradation, which results in the repression of CCN2 [11,36]. microRNAs (miRNAs) are small RNAs that promote degradation and repress translation of target mRNAs via hybridization with the target sequences by base-pair formation. Concerning this non-coding regulatory RNA family, at least seven members of it were found to control the fate of CCN2 mRNA (Figure 2) [11,3742]. Interestingly, the targets of miR-26a and miR-145 are located in the major loop structure in CAESAR [11,39,42]. A thousand human miRNAs have been identified, and each is anticipated to regulate thousands of targets. Therefore, a significant number of CCN2-targeting miRNAs are assumed to remain uncharacterized to date. A huge molecular network comprising post-transcriptional protein and RNA regulators should be active towards the CCN2 3′-UTR, which network still remains to be clarified.

PROTEIN STRUCTURE AND MOLECULAR ACTION

Usually, the biological role of the CCN family members is hard to define, since each family member may exert even apparently opposite biological effects, depending upon the microenvironmental context. It becomes clear how CCN family proteins produce such diverse outcomes, when one takes a close look into the molecular structure and behaviour of these unique proteins.

As stated in the previous section, every CCN family protein consists of IGFBP, VWC, TSP1 and CT modules, with the exception of CCN5, which lacks the CT module (Figure 1). The retention of the N-terminal signal peptide for secretion indicates the principal nature of these proteins as secretory molecules. The full-length CCN2 is thus a 38-kDa protein with a tetramodular structure, whereas several reports indicate the presence of monomodular or dimodular fragments, which are possibly formed by enzymatic cleavage [4,43,44]. These modules are commonly characterized by the conserved cysteine-rich primary structure and are all highly interactive with a number of molecular counterparts. These cofactors include cell surface receptors, extracellular signalling molecules such as growth factors, cytokines and ECM components [1,5,11]. In light of their intimate relationship with ECM molecules, CCN family members may be viewed as matricellular proteins [5]. Consequently, CCN2 manipulates the behaviour of these molecules, forming a proper molecular network (Figure 3A). Thus, the net effect given by CCN2 is highly variable and dependent on what kind of molecular counterparts are around it. In other words, one should interpret the biological role of CCN2 by always first taking into account the behaviour of the molecules surrounding it.

Molecular action of CCN2

Figure 3
Molecular action of CCN2

(A) Schematic representation of the multiple interactions of CCN2 (large coloured spheres) with another CCN family member (small coloured spheres) and cofactors in the microenvironment, which support its multiple functionality. Under the direct binding to ECM components, growth factors (GFs) and cell-surface receptors and related molecules (cylinder on the cell), a CCN family member manipulates and integrates the extracellular information network, under direct or indirect collaboration with other family members. (B) Interaction network among all of the CCN family members. Direct interaction between CCN family members has been confirmed only between CCN2 and CCN3. Nevertheless, all of the members are able to constitute an integrated molecular network under the collaboration with representative cofactors, such as integrins, VEGF and BMPs.

Figure 3
Molecular action of CCN2

(A) Schematic representation of the multiple interactions of CCN2 (large coloured spheres) with another CCN family member (small coloured spheres) and cofactors in the microenvironment, which support its multiple functionality. Under the direct binding to ECM components, growth factors (GFs) and cell-surface receptors and related molecules (cylinder on the cell), a CCN family member manipulates and integrates the extracellular information network, under direct or indirect collaboration with other family members. (B) Interaction network among all of the CCN family members. Direct interaction between CCN family members has been confirmed only between CCN2 and CCN3. Nevertheless, all of the members are able to constitute an integrated molecular network under the collaboration with representative cofactors, such as integrins, VEGF and BMPs.

Furthermore, whenever the role of CCN2 is discussed, one may not overlook the direct and indirect interplay between CCN2 and other CCN family members as well (Figure 3B). Several CCN family members coexist in vivo, for example, chondrocytes produce both CCN2 and CCN3 at a particular stage of their differentiation, and importantly, CCN3 is known to occasionally counteract CCN2 [11,45]. It should also be noted that CCN3 directly binds to CCN2 and modulates its function [46]. In certain fibrotic disorders, both CCN2 and CCN4 are overproduced, showing comparable cell biological effects on relevant cells [5,11,47,48]. Therefore, it is critical to obtain comprehensive knowledge on all of the CCN family members, even if the molecule of major interest is CCN2, in order to understand the true role of CCN2 under any biological situation.

ROLES UNDER PHYSIOLOGICAL CONDITIONS

Skeletal development

The mammalian skeletal system develops basically through two distinct biological processes entitled endochondral ossification and intramembranous ossification. The former process was established during the relatively later stages of animal evolution, after emergence of the vertebra prototype. In this developmental procedure, bones are primarily formed as small cartilaginous anlagen that develop from condensed mesenchymal cells. Afterwards, the anlagen grow from the inside, and the cartilaginous tissues are gradually replaced with bony tissues. Growth plate chondrocytes are the central players to conduct the endochondral ossification in collaboration with osteoblasts, vascular endothelial cells and osteo/chondroclasts. These chondrocytes proliferate, forming columnar structures, mature to produce cartilage ECM for growth and finally undergo terminal differentiation called hypertrophy. Thereafter, the chondrocytes are removed, and the bone tissue is constructed therein by osteo/chondroclasts, osteoblasts and vascular endothelial cells [1,49].

CCN2 is principally produced by chondrocytes immediately before their hypertrophic differentiation, is transported from the chondrocytes to target cells and indeed promotes all of the processes that operate for endochondral ossification [1,49,50], which is typically represented by the phenotype observed in Ccn2-null mice with remarkable skeletal defects [1,49,51]. Two other recent reports indicate such a role of CCN2 in intervertebral disc development and palatogenesis as well [52,53]. Supporting these notions, previous findings conducted in vitro indicate that CCN2 promotes the proliferation, maturation and hypertrophy of growth-plate chondrocytes [1,49]. Recently, it was revealed that CCN2 promotes these apparently opposite cell biological events, i.e., proliferation and differentiation, at least in part by supporting the energy metabolism in chondrocytes [54]. Proliferation, migration, adhesion and tube formation of vascular endothelial cells are also enhanced by CCN2 [4].

In a number of in vitro experiments, CCN2 was found to enhance the proliferation and differentiation of osteoblasts [49,55], whereas a recent in vivo study with CCN2-overexpressing osteoblasts suggests depressed osteogenesis [56]. This apparent discrepancy between these results is anticipated to be due to the peculiar experimental conditions employed in the latter report [56]. During endochondral ossification, the major supplier of CCN2 is not osteoblasts, but pre-hypertrophic chondrocytes [1,49]. Thus, overexpression of CCN2 in osteoblasts represents an unusual situation rather than a physiological one, causing a pathological response by the osteoblasts. In terms of bone formation, it should also be noted that osteoclastogenesis is promoted as a result of interaction of CCN2 with dendritic cell-specific transmembrane protein (DC-STAMP), receptor-activator of nuclear factor κB (RANK) and osteoprotegerin [57,58]. These findings are in accordance with the enlarged hypertrophic layer of chondrocytes observed in the growth plate of Ccn2-null mice [45,51], suggesting a role for CCN2 in the removal of hypertrophic chondrocytes by osteo/chondroclasts. Additionally, simultaneous positive effects of CCN2 on both bone formation and bone resorption suggest a critical role of CCN2 in physiological bone remodelling and maintenance [59].

The other mode of bone formation for construction of the human skeleton is the classical intramembranous ossification, in which bone is directly formed by osteoblasts. Significant parts of the craniofacial bones protecting the brain are formed through this process, indicating the origin of this process in ancient exoskeletal development. The requirement of a physiological level of CCN2 in this form of ossification is also suggested in a study on Ccn2-null mice [55].

Finally, a significant number of these skeletal parts are connected by flexible joints, in which CCN2 has been revealed to play a critical role in harmonizing its development in collaboration with CCN3 [11]. Collectively, CCN2 contributes to human skeletal development in total, which statement is firmly supported by the fact that CCN2 and its derivatives have been even shown to regenerate both damaged articular cartilage and bone in vivo [1,60]. As stated above, such multiple functionality is exerted by forming a molecular network with collaborative moieties in mesenchymal microenvironments, as is summarized in Figure 4.

Molecular action of CCN2 in physiological skeletal development

Figure 4
Molecular action of CCN2 in physiological skeletal development

Molecular counterparts of CCN2 involved in distinct aspects (shaded and specified in italicized words) of bone and cartilage development are summarized. Ellipses, trapezoids and rounded-corner rectangles represent growth factors and related molecules, cell-surface receptors and extracellular matrix components, respectively. Abbreviations: FGF, fibroblast growth factor; FGFR, FGF receptor [129]; OPG, osteoprotegerin; DC-STAMP, dendritic cell-specific transmembrane protein; RANK, receptor activator of nuclear factor κB; LRP1, low-density lipoprotein receptor-related protein 1. The red arrow between CCN2 and CCN3 indicates both direct interaction and functional counteraction between the two.

Figure 4
Molecular action of CCN2 in physiological skeletal development

Molecular counterparts of CCN2 involved in distinct aspects (shaded and specified in italicized words) of bone and cartilage development are summarized. Ellipses, trapezoids and rounded-corner rectangles represent growth factors and related molecules, cell-surface receptors and extracellular matrix components, respectively. Abbreviations: FGF, fibroblast growth factor; FGFR, FGF receptor [129]; OPG, osteoprotegerin; DC-STAMP, dendritic cell-specific transmembrane protein; RANK, receptor activator of nuclear factor κB; LRP1, low-density lipoprotein receptor-related protein 1. The red arrow between CCN2 and CCN3 indicates both direct interaction and functional counteraction between the two.

Central nervous system development

Histological examination of Ccn2-null mouse embryos has found no obvious defect in their central nervous system, suggesting no major role of CCN2 during development of the embryonic central nervous system. In contrast, since Ccn2-null mice usually die upon delivery, probably due to the respiratory failure caused by skeletal defects, analysis of the role of CCN2 in the postnatal development of the nervous system has been left undone for a long time [51]. However, restricted expression of CCN2 in the olfactory bulb in the postnatal brain of normal mice was already known in 2005, indicating a possible physiological role therein [61].

The olfactory bulb is the first central station to process and filter the signal from the olfactory epithelium for output to the brain cortex. Consistent with this expression pattern of Ccn2 in the mouse brain, the critical function of CCN2 in postnatal neuron development was finally uncovered by recent research [61]. Detailed immunohistochemical analysis confirmed CCN2 protein in the glomerular layer of the olfactory bulb, which layer accepts olfactory input from the olfactory epithelium. Of note, except for that of the main two excitatory neuronal cells, development of olfactory bulb interneurons mostly occurs after birth and continues during adulthood, enabling olfactory memory and learning. CCN2 is indeed involved in this process. Namely, CCN2 production is enhanced by odour stimuli, and CCN2 controls the survival of postnatally generated neurons, especially inhibitory interneurons in the glomerular layer via TGF-β-mediated apoptotic signalling, resulting in the regulation of the olfactory sensitivity. Although the olfactory system has relatively regressed in humans, and the biological significance of olfaction may not be so critical in our species, CCN2 may still play an important role in furnishing human life with detection of aromas through this postnatal neuron developmental process.

Pancreatic development

The pancreas is a multifunctional secretory organ. One of its major functions is to produce and store the proforms of digestive enzymes that are eventually activated and excreted into the duodenum. The central component of the pancreatic excretory system is the acinar cells, which form clusters. Around the acini and ducts, pancreatic stellate cells are also present, which cells play principal roles in the development of fibrotic disorders, as described later on [62]. The other major mission of this organ, its endocrine function, is exerted in a small district called the islet of Langerhans, where α-cells produce and secrete glucagon and β-cells, insulin and amylin, as is widely known. Additionally, somatostatin and ghrelin are also secreted by pancreatic δ- and ε-cells, respectively; whereas PP cells produce pancreatic polypeptide [62].

CCN2 plays a physiological role in the development of the islets among the pancreatic components. In the course of the development of this endocrine component, particular transcription factors, such as neurogenin 3, function for the expression of the relevant genes required for specification of the fate of the cellular components towards islet construction. During this process, Ccn2 expression is found transiently in the mouse pancreas; and this expression is restricted to β-cells, suggesting its positive function in their development. Interestingly, binding motifs for neurogenin 3 and a few other factors can be found in the CCN2 proximal promoter [62]. These findings are in line with the phenotype observed in the pancreas of Ccn2-deficient mice. In the Ccn2-null mouse embryo, decreased β-cell proliferation results in hypoplasia of the islets. Moreover, even Ccn2 heterozygous-null mice that survive after birth display pancreatic defects resulting in dysregulated glucose homoeostasis [62]. Finally, overexpression of CCN2 in embryonic β-cells increases the number of both α- and β-cells in the pancreas at birth. CCN2 required for these physiological processes has been shown to be supplied either by β-cells, endothelial cells or epithelial cells, depending on the stage of development [62].

Skin and hair development

In spite of the clear involvement of CCN2 in skin fibrosis, skin epidermis develops normally without CCN2, and the expression of CCN2 therein is extremely low. Nevertheless, a recent report pointed to a physiological role of CCN2 in hair follicle cycling in mice [63]. Indeed, by a close look, highly restricted expression of CCN2 was found only in the dermal papillae and outer root sheath of hair follicles. Functional analyses in vitro and in vivo revealed that CCN2 physiologically suppresses hair follicle formation by hair follicle stem cells by acting through a canonical Wnt signalling pathway. In fact, deletion of Ccn2 induces an increase in the number of hair follicles [63]. From a molecular point of view, this effect of CCN2 is possibly exerted through interaction between CCN2 and low-density lipoprotein receptor-related 6 (LRP6) and/or Wnt-inhibitory factor 1 (WIF1), both of which are CCN2 partners and Wnt repressors [11].

Tooth development

The tooth is a unique organ covered with enamel, which is the hardest tissue in the body. Teeth are formed as implants in the alveolar bone through initial invagination of the oral epithelium into the underlying mesenchymal tissue, followed by multiple-staged developmental processes under mutual molecular interactions [59]. The invaginated epithelium forms a tooth bud, together with the surrounding odontogenic mesenchyme, which afterwards leaves the surface of oral epithelium towards the inside at a certain developmental stage (crown stage) when enamel formation is initiated. As such, the resultant enamel and other tooth components are constructed by epithelial ameloblasts and other cells of mesenchymal origin, respectively. During this developmental pathway, expression of CCN2 is observed in the dental mesenchyme juxtaposing the dental epithelium, preferentially around signal centres under strict spatiotemporal regulation. These observations indicate that CCN2 is one of the molecular messengers or conductors of information transmitted from the dental mesenchyme to the epithelium. In fact, CCN2 was shown to promote both proliferation and differentiation of dental epithelial cells as well as mesenchymal cells [59]. Nevertheless, tooth germs develop normally even in the absence of CCN2, at least during embryogenesis, so far as has been examined histologically [64]. Again, since Ccn2-null mice do not survive after birth, it is not clear whether CCN2 is required for the development of physically intact and functional teeth, or not. It should also be noted that another CCN family member may compensate the signalling role of CCN2 in its absence during tissue development, considering that CCN1 and CCN4 occasionally exert cell biological effects comparable with those of CCN2.

Other tissues and organs

In spite of its strong expression in embryonic podocytes, CCN2 is not critically required for the development of the kidneys [65], since Ccn2-null mice display no abnormality in the glomerular tissue or even in the podocytes themselves [65]. This negative finding does not necessarily mean that CCN2 has no effect on kidney development, as is found in other organs including the teeth. Dynamic expression of CCN2 is detected along the course of eye development with a peak at embryonic day 14 [24]. Concomitant with this expression, formation and development of the capillary plexus is observed in the developing retina. After the establishment of the retinal vasculature, CCN2 expression therein persists at a reduced level. Interestingly, this expression pattern is similar to that of CCN1, in spite of their antithetic effects on retinal neovascularization [24]. Thus, it is anticipated that CCN1 and CCN2 collaboratively support adequate development of the retinal vasculature around the optic nerve, which collects visional information. In cardiovascular development, the CCN family member most critically involved is CCN1, a defect in which causes physical defects in atrial and ventricular septa in the heart, as well as inefficient chorioallantoic fusion and placental vascular system [66]. In contrast, although the pathological contributions of CCN2 are frequently noted, mice develop at least with a functional cardiovascular system in the absence of CCN2, as evidenced by the fact that Ccn-2 null mice survive until birth.

In normal cells of the haematopoietic lineage, CCN2 expression is generally quite low; nevertheless, CCN2 is found in abundance in platelets [11,67]. Strange to say, the platelet producers, i.e., the megakaryocytes, do not produce CCN2 [11]. Therefore, it is suspected that nascent platelets may incorporate CCN2 that is produced by other cells in the same microenvironment. Interestingly, an unknown soluble factor secreted by megakaryocytes induces CCN2 production by mesenchymal cells [67]. Since CCN2 is a critical component of platelets for the promotion of wound healing, the supply of CCN2 through mesenchymal–haematopoietic interaction can be regarded as the final step of thrombopoiesis.

ROLES UNDER PATHOLOGICAL CONDITIONS

Inflammation, wound healing and fibrosis

CCN2 is probably best known as a molecule that mediates the development of fibrotic disorders in a variety of tissues and organs [3,5,11,13]. Although the precise mechanism causing fibrosis in each organ is remarkably different, the principle of CCN2-mediated fibrosis can be briefly summarized as follows.

Inflammation, wound healing and fibrosis are mutually related biological events involved in bio-defence. Inflammation occurs upon tissue injury and/or invasion of pathogenic factors, which usually causes extra damage to the tissues. The involvement of CCN2 in this phase is well represented by the fact that CCN2 regulates the behaviour of the mediators of inflammation and vice versa. For example, CCN2 is induced by TGF-β and is repressed by tumour necrosis factor (TNF)-α; whereas this gene product induces inflammatory interleukin (IL)-6, MCP1 and ECM-remodelling MMPs [13,6870]. In fact, elevated CCN2 expression is observed in inflamed joints of patients with rheumatoid arthritis and osteoarthritis [59,71]. According to a recent study, the CT module seems to be a key domain for CCN2 to exert its pro-inflammatory effects [72]. Integrin αvβ5, TrkA and epidermal growth factor receptor (EGFR) on the cell surface were shown to mediate inflammatory response and tissue damage induced by CCN2 [11,68,73,74]. After tissue injury and inflammation, wound healing/tissue repair takes place, which may be defined as the last phase of inflammation. Expression and positive roles of CCN2 in wound healing are already generally recognized [75]. If wound healing is carried out in an improper manner, the damaged tissue becomes disorganized due to massive collagen deposition, which is called fibrosis. This condition is usually accompanied by chronic inflammation, during which incomplete wound healing continues in parallel with extended inflammatory tissue damage. Therefore, the fibrogenic property of CCN2 can be regarded as the other side of its regenerative potential.

Generally, fibrosis is initiated by the constitutive induction of CCN2 by particular upstream factors that are specific to the organs and pathogenic conditions. Thereafter, overproduced CCN2 collaborates with TGF-β and provokes the production of ECM remodelling molecules including a vast amount of collagen. This serial process may happen virtually almost anywhere where fibroblastic cells are found in the human body. In this process, ECM remodelling is conducted by α-smooth muscle cell actin (SMA)-positive myofibroblasts that produce CCN2 acting in an autocrine manner. For example, in the case of diabetes mellitus, elevated levels of glucose and fatty acids act as inducers of CCN2, which induction results in fibrotic damage in the kidneys and heart [25,65]. Currently known cases of CCN2-related fibrosis in various organs and tissues are summarized in Table 1.

Table 1
CCN2 in fibrosis and related disorders
Organ/tissueAetiological factorInvolvement of CCN2Reference
Heart Chronic heart failure Correlation between severity and CCN2 level in blood [117
Lung Scleroderma Correlation between severity and CCN2 level in blood [118
 Bleomycin CCN2-mediated induction of collagens [119
Liver Ethanol CCN2-mediated induction of collagens [120
 Biliary atresia Correlation between severity and CCN2 level in blood [118
 Chronic viral hepatitis Correlation between severity and CCN2 level in blood [118
Kidney Diabetes melitus Correlation between severity and CCN2 level in urine [118
 Allograft fibrosis Correlation between severity and CCN2 level in blood and urine [118
Pancreas Chronic pancreatitis Correlation between severity and CCN2 level in pancreas [62
Skin Scleroderma Correlation between severity and CCN2 level in blood/dermal interstitial fluid [118
 Bleomycin CCN2-mediated induction of collagens [121
Gingiva Phenytoin, nifedipine and cyclosporine A CCN2-mediated induction of collagens [122
 Nicotine CCN2-mediated induction of collagens [16
Artery LRP1 deficiency Correlation between severity and CCN2 level in aorta [123
Muscle Dystrophin deficiency Correlation between severity and systemic CCN2 level [100
Eye Proliferative diabetic retinopathy Correlation between severity and CCN2 level in vitreous [124
Organ/tissueAetiological factorInvolvement of CCN2Reference
Heart Chronic heart failure Correlation between severity and CCN2 level in blood [117
Lung Scleroderma Correlation between severity and CCN2 level in blood [118
 Bleomycin CCN2-mediated induction of collagens [119
Liver Ethanol CCN2-mediated induction of collagens [120
 Biliary atresia Correlation between severity and CCN2 level in blood [118
 Chronic viral hepatitis Correlation between severity and CCN2 level in blood [118
Kidney Diabetes melitus Correlation between severity and CCN2 level in urine [118
 Allograft fibrosis Correlation between severity and CCN2 level in blood and urine [118
Pancreas Chronic pancreatitis Correlation between severity and CCN2 level in pancreas [62
Skin Scleroderma Correlation between severity and CCN2 level in blood/dermal interstitial fluid [118
 Bleomycin CCN2-mediated induction of collagens [121
Gingiva Phenytoin, nifedipine and cyclosporine A CCN2-mediated induction of collagens [122
 Nicotine CCN2-mediated induction of collagens [16
Artery LRP1 deficiency Correlation between severity and CCN2 level in aorta [123
Muscle Dystrophin deficiency Correlation between severity and systemic CCN2 level [100
Eye Proliferative diabetic retinopathy Correlation between severity and CCN2 level in vitreous [124

Additionally, in considering the role of CCN2 in fibrosis as well, one should be aware of the contribution of other CCN family members in this process. It has been reported that, in synoviocytes, not only CCN2, but also CCN1 and CCN4, can stimulate the production of the same inflammatory agent, IL-6, through the same cell-surface receptor (Figure 5) [11,70,76,77]. According to other reports from different research groups, CCN3 counteracts CCN2 during the conversion of fibroblastic cells into myofibroblasts [48,78]. The involvement of CCN4 as well as CCN2 has also been suggested in the development of pulmonary and cardiac fibrosis [47,79]. CCN1 is also expressed during wound healing and development of fibrosis; however, this molecule appears to terminate these processes by inducing senescence in myofibroblasts through a DNA damage response pathway and ROS formation [5,80,81]. Collectively, significant types of fibrosis found in several tissues, such as kidney, skin and eye, seem to be induced as a result of an imbalance among CCN1, CCN2 and CCN3 (Figure 5). In this context, one may not overlook the possible involvement of CCN4 and CCN6 as well [11,82].

Molecular action of CCN2 in pathological fibrosis

Figure 5
Molecular action of CCN2 in pathological fibrosis

Collaborative molecular network of CCN2 together with other CCN family members during inflammatory and fibrotic response are briefly summarized. Objects represent molecules in specific categories as explained in the legend of Figure 4. Abbreviations: FGF, fibroblast growth factor; LRP6, low-density lipoprotein receptor-like protein 6 [130,131]. Here again, the red arrow between CCN2 and CCN3 indicates both direct interaction and functional counteraction between them.

Figure 5
Molecular action of CCN2 in pathological fibrosis

Collaborative molecular network of CCN2 together with other CCN family members during inflammatory and fibrotic response are briefly summarized. Objects represent molecules in specific categories as explained in the legend of Figure 4. Abbreviations: FGF, fibroblast growth factor; LRP6, low-density lipoprotein receptor-like protein 6 [130,131]. Here again, the red arrow between CCN2 and CCN3 indicates both direct interaction and functional counteraction between them.

Carcinogenesis and tumour development

In contrast with the distinct contribution of CCN2 to fibrosis and associated diseases, the role of CCN2 in a variety of malignancies is highly variable among different types of tumours and thus is controversial. Namely, in many cases, CCN2 is observed to promote the development of tumours, whereas in other cases the same molecule is found to repress it. These apparently contradictory findings are, of course, based on the unique mode of molecular action commonly shared by CCN family proteins (Figure 3). Nevertheless, such complex biological effects of CCN2 on tumour development come to be more understandable, when the autocrine and paracrine effects of CCN2 produced by tumour cells are differentially considered.

In most cases, with the exception being ovarian and lung cancers, CCN2 expression is found to be elevated in various types of tumours. These malignancies include breast cancer, prostate cancer, glioma, pancreatic cancer, colon cancer, thyroid carcinoma, chondrosarcoma, gallbladder carcinoma, melanoma and leukaemia [5,11,39,8387]. In those tumours with enhanced CCN2 expression, the most prominent characteristics that are commonly observed are enhanced tumour angiogenesis and metastasis. Contrarily, in the exceptional lung and ovarian cancer findings, a tumour-suppressing function of CCN2 has been clearly described [86,87]. In these findings, CCN2 silencing in the tumour samples was shown to be strongly related to tumour growth, tumour stage and patient survival. Interestingly, however, the relationship between CCN2 expression and tumour angiogenesis or metastatic potential is not distinctly indicated in these cancers. These findings may represent the dual functional aspects of CCN2, i.e. repression of oncogenesis in an autocrine or intracrine manner and activation of the normal cells surrounding these producers, such as vascular endothelial cells and osteoclasts, to accelerate invasion and metastasis. This idea is actually supported by several reports, in which the effects of CCN2 on tumour cells and normal cells around them were analysed in in vitro and animal models. In these reports, overexpression of CCN2 in oral squamous cell carcinoma cells and ovarian cancer cells conferred benign conversion of these malignant tumour cells [86,88]. In line with these findings, a correlation between reduced CCN2 expression and enhanced cell proliferation and invasion was observed in nasopharyngeal carcinoma [89]. In this context, cell-cycle arrest caused by CCN2 overexpression in a monkey kidney cell line is worthy of note [90]. Interestingly, no CCN2 secretion was detected from the overexpressing cells, suggesting an intracrine as well as autocrine action of CCN2 [90]. On the other hand, CCN2 is known to be an angiogenic molecule and to enhance osteoclastogenesis [4,57,58], as stated in a previous section. Tumour cells may utilize these physiological effects of CCN2 in a paracrine manner in order to recruit blood vessels to nourish themselves and to prepare the space for invasion. Using these two action modes, CCN2 can modify the growth and invasion/metastasis in an independent fashion. However, exceptionally again, a recent report showed that silencing of endogenous CCN2 in gallbladder carcinoma cells causes repression of cell growth, viability and migration of those cells [85]. Also, CCN2 was once reported to promote pancreatic tumour growth [62]. To account for all such complex findings, one should probably go back to the molecular network described in Figure 3(B). Typically, the involvement of all six CCN family members is soundly indicated in the pathogenesis of breast cancers [5,11].

Neural and ocular disorders

In vertebrates, the eye originally develops from the same neural tube as the brain, being formed in close proximity to it. CCN2 is also known to be involved in the pathological changes that occur in this integrated central nervous system. In the brain, increased CCN2 expression triggered by dietary-induced insulin resistance was found to mediate the progression of Alzheimer's disease, a well-known neurodegenerative disorder [91]; and a number of ocular diseases were shown to be associated with CCN2 [24].

Apart from fibrotic changes, aberrant neovascularization is a major etiological factor of several ocular diseases, including retinopathy of prematurity and diabetic retinopathy, in which hypoxia and hyperglycaemia with AGEs are thought to induce CCN2 therein [24]. By the use of an animal model called oxygen-induced retinopathy (OIR), the role of CCN2 in the aetiology of such a retinopathy is being unveiled [24]. OIR mice display drastically increased CCN2 expression, which accelerates neovascularization in the retina, which effect is consistent with its angiogenic property. However, in this case, the CCN2-induced neovascularization is partly mediated by the induction and activation of MMP-2, which catabolically drives vascular remodelling. According to a relevant report, the induction of MMP-2 by CCN2 is performed at the transcriptional level via p53 [92]. Also, basal lamina thickening of retinal capillaries is reduced in diabetic heterozygous Ccn2-knockout mice in comparison with the degree of thickening in diabetic wild-type mice [24]. These findings suggest the solid contribution of CCN2 to this type of retinopathy. Additionally, modulation of vascular endothelial growth factor (VEGF) function by CCN2 via direct molecular interaction and subsequent proteolytic cleavage of CCN2 [11] can contribute to the CCN2-associated neovascularization in the retina, since VEGF is a key molecule involved in vascular development in the eye. In this function, the formation of proteolytic fragments of CCN2 in the vitreous of patients with diabetic nephropathy is of particular note [93].

Myopia is one of the most common ocular disorders in advanced countries. By the use of a guinea pig model, in which the animals are exposed to a flashing red light, CCN2 was recently found to be induced upon the provocation of experimental myopia. Since the induction of TGF-β accompanied these changes, myofibroblast-like cellular changes triggered by this combination may be responsible for the decrease in the refraction upon myopia development [94]. The fact that myopia is associated with age-related macular degeneration (AMD), which eventually causes blindness in adults and is characterized by choroidal neovascularization, suggests the possible involvement of CCN2 in the onset and/or progression of AMD [24].

Glaucoma is another major cause of blindness found throughout the world. In this ocular disease, elevated production of CCN2 and TGF-β is also indicated [95]. Since CCN2 is induced in a variety of cells by mechanical stimuli, increased intraocular pressure in glaucoma is assumed to play a role in certain pathological changes via the induction of CCN2 in collaboration with TGF-β, probably through ECM remodelling.

POSSIBLE CCN2-ASSOCIATED MOLECULAR THERAPEUTICS

Utility of CCN2 in regenerative medicine

Since CCN2 was found to enhance the development of mesenchymal tissues by promoting both the proliferation and differentiation of those cells, the utility of CCN2 itself as a tissue regenerator is being explored. By the use of full-length recombinant CCN2 in combination with gelatin hydrogel for sustained release into the tissue, efficient regeneration of damaged articular cartilage and bone tissues was actually confirmed in vivo [1,49,96]. As such, the effectiveness of CCN2 on mesenchymal hard tissues regeneration is already recognized. However, before forwarding CCN2 to clinical trials, we need to address a few technical issues. For a clinical application, a stable production system of active and safe CCN2 has to be established. Generally, recombinant CCN2 produced by Escherichia coli is less active than the one produced by eukaryotic cells [97] and is always accompanied by the risk of endotoxin contamination. In sharp contrast, despite higher bioactivity, massive production of CCN2 with animal cells can be difficult. In our hands, secretory production of full-length CCN2 by Gram-positive bacteria was also attempted, but was not successful [98]. These difficulties are probably due to the fragility of full-length CCN2 in molecular nature [44] at least in part. Nevertheless, more recent research revealed that a single TSP1 module of CCN2 was more effective than the intact CCN2 in regenerating articular cartilage damaged in pre-clinical experimental osteoarthritis models with rats [60]. Since this molecule can be prepared in a large scale from Gram-positive bacteria and can be stably stored, clinical application of such modular fragments may be of closer reality than the full-length CCN2. Alternatively, several findings discovered small molecules, including harmine [17], that can induce endogenous CCN2 in chondrocytes to enhance tissue regeneration, as described in a previous section. In this context, cartilage-protective effects of overexpressed CCN2 in transgenic mice are of particular note [99]. Harmine is a natural compound found in botanical extracts traditionally used in humans, and thus can be readily forwarded to clinical evaluation. Induction of endogenous CCN2 with harmine, or another CCN2 inducer, in human cartilage may yield protective effects comparable to those observed in the model mice. Additionally, as CCN2 was also shown to promote reparative dentinogenesis [34], this protein may be helpful in renovating a pulp-capping dental material to promote the formation of secondary dentin, for which calcium hydroxide-based simple materials have been used for over half of a century.

Developing CCN2-targeted therapeutics to combat intractable diseases

From the major clinical standpoint, CCN2 is not considered as a therapeutic agent, but as a therapeutic target, in combating tumour metastasis, fibrosis and related disorders in a variety of organs and tissues. Currently, a number of molecules that repress CCN2 expression or counteract CCN2 function are indicated. Considering the target specificity, anti-CCN2-neutralizing antibodies can be the best candidates for accomplishing this clinical aim. Duchenne muscular dystrophy, which is an intractable muscular disease with CCN2-mediated fibrotic changes in the skeletal muscles, is improved by the administration of one such antibody in a mouse model [100]. Metastasis of aggressive CCN2-producing breast cancer and melanoma cells was also suppressed by the injection of anti-CCN2 monoclonal antibodies in vivo [101,102]. Antibody or short hairpin RNA (shRNA)-mediated down-regulation of CCN2 results in an enhanced chemotherapy response in murine pancreatic cancer, leukaemia xenograft model in mice, and osteosarcoma cells [103105]. The utility of such an antibody in the treatment of rheumatoid arthritis is also indicated by the fact that the anti-CCN2 antibody ameliorates the symptom in collagen-induced arthritic mice [71]. Additionally, immunosuppression of CCN2 function led to the attenuation of fibrotic phenotype in human trabecular meshwork and lamina cribrosa cells, suggesting its possible use in glaucoma treatment [106]. As CCN2 gene silencers, in addition to losartan (an angiotensin II inhibitor), curcumin and statins, and even coffee, have been suggested [18,21,22,107114], all of which are quite easy to administer in vivo in sharp contrast with the antibodies. Especially, since the renin–angiotensin–aldosterone system (RAAS) is widely known to play a critical role in the development of fibrosis through the induction of CCN2 [109], therapeutic agents that block the renin–angiotensin system (RAS) has been extensively evaluated [110112]. Indeed, the effect of losartan on CCN2 production in relation to nephropathy was already clinically evaluated with Type 1 diabetic patients with diabetic nephropathy in 2005 [108]. Another interesting CCN2 silencer is BMP9, which inhibits bone metastasis of breast cancer cells by acting through CCN2 [115]. Concerning chronic cardiac disorders, one should be careful in targeting CCN2, since a cardioprotective effect of this protein itself is also indicated [116].

CCN2 as a possible biomarker in fibrotic disorders

Upon the development of fibrosis, CCN2 overproduced in local microenvironments occasionally released into blood stream or other body fluids, which can be utilized as biomarkers of relevant diseases. In fact, as summarized in Table 1, elevated amount of CCN2 in blood stream is observed in the cases with fibrosis in heart, lung, liver, kidney and skin tissues. These findings firmly indicate that CCN2 in blood can be a biomarker of fibrosis in certain organs, whereas it may not specifically represent a particular disease in a particular organ. Therefore, plasma CCN2 level is a quite useful marker for the screening of fibrotic tissue remodelling occurring somewhere in the living body, and for monitoring the state of particular fibrotic disorder in combination with other organ-specific biomarkers. However, one should carefully note that CCN2 is strongly induced by certain medications, such as systemic administration of glucocorticoids, whenever interpreting the data from those patients. In contrast, urinary CCN2 level may be of higher diagnostic value, since its elevation is specific in renal fibrosis.

SUMMARY

Representing the molecular property of the CCN family of proteins, CCN2 interacts with a number of different molecular counterparts via four conserved modular hands that are all highly interactive. Therefore, CCN2 exerts pleiotropic functions, highly depending upon the microenvironmental context where CCN2 is produced. Thus, the spatiotemporal regulation of CCN2 expression mediated by the transcriptional and post-transcriptional protein and RNA regulators determines its role in the relevant microenvironment. During physical processes, CCN2 plays major roles in the formation and growth of the skeletal system, in postnatal olfactory development, in proper formation of islets in the pancreas, and in hair follicle development in the skin. The involvement of CCN2 in the development of other tissues including tooth, eye and platelet is also suggested. In spite of its profound contribution to these physiological processes, CCN2 is most widely recognized as a profibrotic mediator. In most fibrotic disorders, CCN2 induced by biochemical or mechanical stimuli collaborates with TGF-β to promote the phenotypic conversion of fibroblastic cells to the myofibroblasts that conduct fibrosis. CCN1 and CCN3 counteract these events in distinct manners, whereas CCN4 shows a similar behaviour. Another major CCN2-associated disorder is malignancy in a variety of organs and tissues. CCN2 is produced by tumour cells and acts on themselves, principally suppressing their aggressive phenotype, whereas it promotes the invasion and metastasis by enhancing angiogenesis and bone resorption through the activation of vascular endothelial cells and osteoclast progenitors in a paracrine manner. In addition, CCN2 is involved in the pathogenesis of Alzheimer's disease and eye disorders including myopia and glaucoma as well as in neovascularization-associated infant and adult retinopathies. Considering such physiological and pathological aspects of CCN2 functions, CCN2 can be either a promising therapeutic tool to enhance tissue regeneration or a critical target in combating fibrosis, its related disorders and tumour metastasis.

Abbreviations

     
  • AGE

    advanced glycation end-product

  •  
  • AMD

    age-related macular degeneration

  •  
  • BMP

    bone morphogenetic protein

  •  
  • CAESAR

    cis-acting element of structure-anchored repression

  •  
  • CCN2

    CCN family protein 2

  •  
  • CT

    cystine-knot

  •  
  • CTGF

    connective tissue growth factor

  •  
  • CYR61

    cysteine-rich protein 61

  •  
  • ECM

    extracellular matrix

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • EMT

    epithelial–mesenchymal transition

  •  
  • ET

    endothelin

  •  
  • GAPDH

    glyceraldehyde-3-dehydrogenase

  •  
  • HIF

    hypoxia-inducible factor

  •  
  • IFN

    interferon

  •  
  • IGFBP

    insulin-like growth factor binding protein-like

  •  
  • IL

    interleukin

  •  
  • LIPUS

    low-intensity pulsed ultrasound

  •  
  • MCP

    monocyte chemotactic protein

  •  
  • miRNA

    microRNA

  •  
  • MMP

    matrix metalloproteinase

  •  
  • NPM

    nucleophosmin

  •  
  • NOV

    nephroblastoma-overexpressed

  •  
  • OIR

    oxygen-induced retinopathy

  •  
  • PKC

    protein kinase C

  •  
  • RANK

    receptor-activator of NF-κB

  •  
  • RAS/RAAS

    renin–angiotensin–aldosterone system

  •  
  • ROS

    reactive oxygen species

  •  
  • sFRP

    secreted frizzled-like protein

  •  
  • shRNA

    short hairpin RNA

  •  
  • SMA

    smooth muscle cell actin

  •  
  • TGF

    transforming growth factor

  •  
  • TSP1

    thrombospondin type 1 repeat

  •  
  • VEGF

    vascular endothelial growth factor

  •  
  • VWC

    von Willebrand factor type C repeat

  •  
  • WISP

    Wnt-inducible secretory protein

FUNDING

Our own work was supported the programme grants-in-aid for Scientific Research (B) [grant number 24390415 (to M.T.)] and (C) [grant number 25462886 (to S.K.)] sponsored by the Japan Society for the Promotion of Science; and Wesco Scientific Promotion Foundation.

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