Regulation of pancreatic function by connective tissue growth factor (CTGF, CCN2)

Charrier, Alyssa; Brigstock, David R.

doi:10.1016/j.cytogfr.2012.07.001

Cited by 57 publications

(57 citation statements)

References 71 publications

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“…The expression and functionality of CCN2 during the development of islet morphogenesis and the proliferation of β-cells during embryonic development have been unveiled by recent studies (115). Concerning the eyes, vascular network formation is a critical step in both physiological development and establishment of major eye disorders.…”

Section: Other Organsmentioning

confidence: 98%

“…Although elevated expression of particular CCN family members is observed in the tumors, there is significant controversy regarding their pathological roles. For example, CCN2 promotes pancreatic tumor growth (115), whereas the same molecule suppresses the growth of oral squamous cell cancer by promoting epithelial differentiation (135). Considering the molecular nature of the CCN family, such context-dependent effects in view of tumor development is understandable.…”

Section: Malignanciesmentioning

confidence: 99%

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The CCN family acting throughout the body: recent research developments

Kubota

Takigawa

2013

BioMolecular Concepts

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The animal body is composed of a variety of cells and extracellular matrices that are organized and orchestrated in a harmonized manner to support life. Therefore, the critical importance of a comprehensive understanding of the molecular network surrounding and integrating the cells is now emphasized. The CCN family is a novel group of matricellular proteins that interact with and orchestrate a number of extracellular signaling and matrix molecules to construct and maintain living tissues. This family comprises six distinct members in mammals, which are characterized by a unique and conserved modular structure. These proteins are not targeted to limited and specific receptors to execute specific missions, but manipulate a vast number of biomolecules in the network by serving as a molecular hub at the center. The unified nomenclature, CCN, originates from a simple acronym of the three classical members, which helps us to avoid having any preconception about their pleiotropic and anonymous functional nature. In this review, after a brief summary of the general molecular concepts regarding the CCN family, new aspects of each member uncovered by recent research are introduced, which represent, nevertheless, only the tip of the iceberg of the profound functionality of these molecules.

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Section: Other Organsmentioning

confidence: 98%

Section: Malignanciesmentioning

confidence: 99%

The CCN family acting throughout the body: recent research developments

Kubota

Takigawa

2013

BioMolecular Concepts

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“…About 80,000 people in the USA are diagnosed each year with chronic pancreatitis (CP), a disorder characterized by progressive destruction of pancreatic tissue, deposition of fibrous scar material, and increased risk of developing pancreatic cancer (Charrier and Brigstock 2013). CCN2 mRNA is enhanced in pancreata of human CP patients (di Mola et al 1999) and in mouse experimental CP (Charrier and Brigstock 2010).…”

Section: Introductionmentioning

confidence: 99%

Connective tissue growth factor (CCN2) and microRNA-21 are components of a positive feedback loop in pancreatic stellate cells (PSC) during chronic pancreatitis and are exported in PSC-derived exosomes

Charrier

Chen

et al. 2014

J. Cell Commun. Signal.

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Pancreatitis is an inflammatory condition of the pancreas which, in its chronic form, involves tissue destruction, exocrine and endocrine insufficiency, increased risk of pancreatic cancer, and an extensive fibrotic pathology which is due to unrelenting collagen deposition by pancreatic stellate cells (PSC). In response to noxious agents such as alcohol-excessive consumption of which is a major cause of pancreatitis in the West-normally quiescent PSC undergo a phenotypic and functional transition to activated myofibroblasts which produce and deposit collagen at high levels. This process is regulated by connective tissue growth factor (CCN2), expression of which is highly up-regulated in activated PSC. We show that CCN2 production by activated PSC is associated with enhanced expression of microRNA-21 (miR-21) which was detected at high levels in activated PSC in a murine model of alcoholic chronic pancreatitis. A positive feedback loop between CCN2 and miR-21 was identified that resulted in enhancement of their respective expression as well as that of collagen α1(I). Both miR-21 and CCN2 mRNA were present in PSC-derived exosomes, which were characterized as 50-150 nm CD9-positive nanovesicles. Exosomes from CCN2-GFP-or miR-21-GFPtransfected PSC were taken up by other PSC cultures, as shown by direct fluorescence or qRT-PCR for GFP. Collectively these studies establish miR-21 and CCN2 as participants in a positive feedback loop during PSC activation and as components of the molecular payload in PSC-derived exosomes that can be delivered to other PSC. Thus interactions between cellular or exosomal miR-21 and CCN2 represent novel aspects of fibrogenic regulation in PSC. Summary Chronic injury in the pancreas is associated with fibrotic pathology which is driven in large part by CCN2-dependent collagen production in pancreatic stellate cells. This study shows that CCN2 up-regulation in PSC is associated with increased expression of miR-21 which, in turn, is able to stimulate CCN2 expression further via a positive feedback loop. Additionally miR-21 and CCN2 were identified in PSC-derived exosomes which effected their delivery to other PSC. The cellular and exosomal miR-21-CCN2 axis is a novel component in PSC fibrogenic signaling.

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“…This particular CCN family member plays significant roles in physiological development [7][8][9][10][11][12][13][14][15], wound healing [16], and in the pathological fibrotic remodeling of multiple tissues, organs [17][18][19][20][21][22][23][24][25][26][27][28], and malignancies throughout the body [3,5]. CCN2 is required for the proper development of the olfactory central nervous system [29], pancreas [30], hair follicles [31], and skeletal system [11]; hence, Ccn2-null mice die upon delivery [32,33]. CCN2 is also known to be involved in multiple steps of orofacial development [34,35].…”

mentioning

confidence: 99%