Yeger H, Perbal B.. The CCN family of genes: a perspective on CCN biology and therapeutic potential. J Cell Commun Signal 1: 159-164

Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Canada, .
Journal of Cell Communication and Signaling 12/2008; 1(3-4):159-64. DOI: 10.1007/s12079-008-0022-6
Source: PubMed


The CCN family of genes currently comprises six secreted proteins (designated CCN1-6 after Cyr61/CCN1; ctgf/CCN2; Nov/CCN3; WISP1/CCN4; WISP2/CCN5, WISP3/CCN6) with a similar mosaic primary structure. It is now well accepted that CCN proteins are not growth factors but matricellular proteins that modify signaling of other molecules, in particular those associated with the extracellular matrix. CCN proteins are involved in mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration of multiple cell types. Since their first identification as matricellular factors, the CCN proteins now figure prominently in a variety of major diseases and are now considered valid candidates for therapeutic targeting. Dissection of the molecular mechanisms governing the biological properties of these proteins is being actively pursued by an expanding network of scientists around the globe who will meet this year at the 5th International Workshop on the CCN family of Genes, organized by the International CCN Society ( ), home for an international cadre of collaborators working in the CCN field.

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    • "Three additional Wnt-inducible secreted proteins were later identified (CCN4, CCN5, CCN6). Early studies suggested that these proteins were bona-fide growth factors; however data now supports the role of CCN proteins as matricellular proteins that can bind to matrix and modulate cellular functions (Leask and Abraham, 2006; Yeger and Perbal, 2007; Chen and Lau, 2009) via the modification of signals from other molecules such as transforming growth factor beta (TGFβ). Evidence proposes that CTGF is strongly associated with fibrosis (Brigstock, 2009), that CTGF is a TGFβ inducible gene, and CTGF is significantly up-regulated in experimental models of fibrosis associated with aberrant ECM deposition (Ito et al., 1998; Lasky et al., 1998; Gupta et al., 2000; Sato et al., 2000; Lang et al., 2008). "
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    ABSTRACT: Glaucoma is an optic neuropathy affecting approximately 60 million people worldwide and is the second most common cause of irreversible blindness. Elevated intraocular pressure (IOP) is the main risk factor for developing glaucoma and is caused by impaired aqueous humor drainage through the trabecular meshwork (TM) and Schlemm's canal (SC). In primary open angle glaucoma (POAG), this elevation in IOP in turn leads to deformation at the optic nerve head (ONH) specifically at the lamina cribrosa (LC) region where there is also a deposition of extracellular matrix (ECM) molecules such as collagen and fibronectin. Matricellular proteins are non-structural secreted glycoproteins that help cells communicate with their surrounding ECM. This family of proteins includes connective tissue growth factor (CTGF), also known as CCN2, thrombospondins (TSPs), secreted protein acidic and rich in cysteine (SPARC), periostin, osteonectin, and Tenascin-C and -X and other ECM proteins. All members appear to play a role in fibrosis and increased ECM deposition. Most are widely expressed in tissues particularly in the TM and ONH and deficiency of TSP1 and SPARC have been shown to lower IOP in mouse models of glaucoma through enhanced outflow facility. The role of these proteins in glaucoma is emerging as some have an association with the pathophysiology of the TM and LC regions and might therefore be potential targets for therapeutic intervention in glaucoma.
    Full-text · Article · Jul 2014 · Matrix Biology
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    • "Synaptic functions are highly dependent on functional cytoskeleton that regulates intracellular transport and protein turnover in the synapses. Cstb−/− granule neurons revealed also significant overexpression of several genes encoding kinesins, CCN family of proteins and annexins, that have been associated in axonal transport, nuclear division, mitosis, extracellular matrix production, apoptosis and GABAergic signaling [40]–[44]. Taken together, the data from Cstb−/− granule cells propose neuron specific alterations in processes central to neuronal function and architecture and emphasizes nuclear functions of CSTB. "
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    ABSTRACT: Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited neurodegenerative disease, manifesting with myoclonus, seizures and ataxia, caused by mutations in the cystatin B (CSTB) gene. With the aim of understanding the molecular basis of pathogenetic events in EPM1 we characterized gene expression changes in the cerebella of pre-symptomatic postnatal day 7 (P7) and symptomatic P30 cystatin B -deficient (Cstb(-/-) ) mice, a model for the disease, and in cultured Cstb(-/-) cerebellar granule cells using a pathway-based approach. Differentially expressed genes in P7 cerebella were connected to synaptic function and plasticity, and in cultured cerebellar granule cells, to cell cycle, cytoskeleton, and intracellular transport. In particular, the gene expression data pinpointed alterations in GABAergic pathway. Electrophysiological recordings from Cstb(-/-) cerebellar Purkinje cells revealed a shift of the balance towards decreased inhibition, yet the amount of inhibitory interneurons was not declined in young animals. Instead, we found diminished number of GABAergic terminals and reduced ligand binding to GABAA receptors in Cstb(-/-) cerebellum. These results suggest that alterations in GABAergic signaling could result in reduced inhibition in Cstb(-/-) cerebellum leading to the hyperexcitable phenotype of Cstb(-/-) mice. At P30, the microarray data revealed a marked upregulation of immune and defense response genes, compatible with the previously reported early glial activation that precedes neuronal degeneration. This further implies the role of early-onset neuroinflammation in the pathogenesis of EPM1.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "The CCN family proteins were initially classified as growth factors. However, later studies showed that CCN proteins are matricellular proteins that modify cellular responses to extracellular factors via direct binding to cell surface receptors [5, 10–14]. Importantly, in vivo studies have indicated that aberrant expression of CCN proteins is involved in many diseases, including arthritis, atherosclerosis, fibrosis, diabetic nephropathy, retinopathy, and cancer [15]. "
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    ABSTRACT: The CCN family of proteins is composed of six extracellular matrix-associated proteins that play crucial roles in skeletal development, wound healing, fibrosis, and cancer. Members of the CCN family share four conserved cysteine-rich modular domains that trigger signal transduction in cell adhesion, migration, proliferation, differentiation, and survival through direct binding to specific integrin receptors and heparan sulfate proteoglycans. In the present review, we discuss the roles of the CCN family proteins in regulating resident cells of the bone microenvironment. In vertebrate development, the CCN family plays a critical role in osteo/chondrogenesis and vasculo/angiogenesis. These effects are regulated through signaling via integrins, bone morphogenetic protein, vascular endothelial growth factor, Wnt, and Notch via direct binding to CCN family proteins. Due to the important roles of CCN family proteins in skeletal development, abnormal expression of CCN proteins is related to the tumorigenesis of primary bone tumors such as osteosarcoma, Ewing sarcoma, and chondrosarcoma. Additionally, emerging studies have suggested that CCN proteins may affect progression of secondary metastatic bone tumors by moderating the bone microenvironment. CCN proteins could therefore serve as potential therapeutic targets for drug development against primary and metastatic bone tumors.
    Full-text · Article · Jan 2014
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