CCN2/CTGF promotor activity in the developing and adult mouse eye

Dillinger, Andrea E.; Kuespert, Sabrina; Froemel, Franziska; Tamm, Ernst R.; Fuchshofer, Rudolf

doi:10.1007/s00441-020-03332-4

Cited by 5 publications

(7 citation statements)

References 86 publications

(110 reference statements)

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“…In situ results of this study show that there is a direct connection between biomechanical load and the expression of CCN2/CTGF in astrocytes of the ONH region. The astrocytes of the prelaminar region of the glial lamina site showed a strong signal for the CCN2/CTGF promoter activity, whereas the astrocytes of the postlaminar region and the retinal astrocytes exhibit only a faint staining ( Dillinger et al, 2021 ). Our findings clearly support that astrocytes can sense mechanical cues in their ambient substratum and react on biomechanical alterations of the surrounding environment with changes in GFAP, vimentin and CCN2/CTGF synthesis.…”

Section: Discussionmentioning

confidence: 99%

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CCN2/CTGF—A Modulator of the Optic Nerve Head Astrocyte

Dillinger

Weber

Mayer

et al. 2022

Front. Cell Dev. Biol.

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In primary open-angle glaucoma (POAG), a neurodegenerative disease of the optic nerve (ON) and leading cause of blindness, the optic nerve head (ONH) undergoes marked structural extracellular matrix (ECM) changes, which contribute to its permanent deformation and to degeneration of ON axons. The remodeling process of the ECM causes changes in the biomechanical properties of the ONH and the peripapillary sclera, which is accompanied by an increased reactivity of the resident astrocytes. The molecular factors involved in the remodeling process belong to the Transforming growth factor (TGF)-β superfamily, especially TGF-β2. In previous publications we showed that TGF-β2 induced ECM alterations are mediated by Cellular Communication Network Factor (CCN)2/Connective Tissue Growth Factor (CTGF) and recently we showed that CCN2/CTGF is expressed by astrocytes of the ON under normal conditions. In this study we wanted to get a better understanding of the function of CCN2/CTGF under normal and pathologic conditions. To this end, we analyzed the glial lamina and peripapillary sclera of CCN2/CTGF overexpressing mice and studied the effect of CCN2/CTGF and increasing substratum stiffness on murine ON astrocytes in vitro. We observed enhanced astrocyte reactivity in the ONH, increased ECM protein synthesis in the peripapillary sclera and increased Ccn2/Ctgf expression in the ONH during the pathologic development in situ. CCN2/CTGF treatment of primary murine ON astrocytes induced a higher migration rate, and increase of ECM proteins including fibronectin, elastin and collagen type III. Furthermore, the astrocytes responded to stiffer substratum with increased glial fibrillary acidic protein, vimentin, actin and CCN2/CTGF synthesis. Finally, we observed the reinforced appearance of CCN2/CTGF in the lamina cribrosa of glaucomatous patients. We conclude that reactive changes in ONH astrocytes, induced by the altered biomechanical characteristics of the region, give rise to a self-amplifying process that includes increased TGF-β2/CCN2/CTGF signaling and leads to the synthesis of ECM molecules and cytoskeleton proteins, a process that in turn augments the stiffness at the ONH. Such a scenario may finally result in a vicious circle in the pathogenesis of POAG. The transgenic CTGF-overexpressing mouse model might be an optimal model to study the chronic pathological POAG changes in the ONH.

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Section: Discussionmentioning

confidence: 99%

“…Both effects continue to increase with increasing age ( Junglas et al, 2012 ). Recently we could show that astrocytes are the cellular source of CCN2/CTGF in the murine ON and ONH ( Dillinger et al, 2021 ). A detailed analysis of the CCN2/CTGF distribution in the ONH of glaucomatous eyes is missing.…”

Section: Introductionmentioning

confidence: 99%

CCN2/CTGF—A Modulator of the Optic Nerve Head Astrocyte

Dillinger

Weber

Mayer

et al. 2022

Front. Cell Dev. Biol.

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“…Weiss et al demonstrated that the glutamatergic synapse controlled apoptosis and the degeneration of different retinal cells induced by CTGF [ 172 ]. Furthermore, glutaminolysis promotes the apoptosis resistance of IPF fibroblasts through the epigenetic regulation of XIAP and survival [ 173 ].…”

Section: Ctgf Drives Senescence In Ipfmentioning

confidence: 99%

Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge

Effendi

Nagano

2022

IJMS

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CTGF is upregulated in patients with idiopathic pulmonary fibrosis (IPF), characterized by the deposition of a pathological extracellular matrix (ECM). Additionally, many omics studies confirmed that aberrant cellular senescence-associated mitochondria dysfunction and metabolic reprogramming had been identified in different IPF lung cells (alveolar epithelial cells, alveolar endothelial cells, fibroblasts, and macrophages). Here, we reviewed the role of the CTGF in IPF lung cells to mediate anomalous senescence-related metabolic mechanisms that support the fibrotic environment in IPF.

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“…Further evidence in mice shows that the astrocytic levels of CTGF in the ONH increases in glaucomatous animals as a result of elevated IOP and stiffness, which agrees with the observation that there are elevated levels of CTGF in glaucomatous ONHs of humans as well [ 68 ]. At least in mice, CTGF seems to be predominantly expressed by astrocytes in the ONH [ 69 ], but there is reason to suggest that CTGF may affect other cell types such as LC cells [ 37 ].…”

Section: Glial Cellsmentioning

confidence: 99%

Remodeling of the Lamina Cribrosa: Mechanisms and Potential Therapeutic Approaches for Glaucoma

Strickland

Garner

Gross

et al. 2022

IJMS

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Glaucomatous optic neuropathy is the leading cause of irreversible blindness in the world. The chronic disease is characterized by optic nerve degeneration and vision field loss. The reduction of intraocular pressure remains the only proven glaucoma treatment, but it does not prevent further neurodegeneration. There are three major classes of cells in the human optic nerve head (ONH): lamina cribrosa (LC) cells, glial cells, and scleral fibroblasts. These cells provide support for the LC which is essential to maintain healthy retinal ganglion cell (RGC) axons. All these cells demonstrate responses to glaucomatous conditions through extracellular matrix remodeling. Therefore, investigations into alternative therapies that alter the characteristic remodeling response of the ONH to enhance the survival of RGC axons are prevalent. Understanding major remodeling pathways in the ONH may be key to developing targeted therapies that reduce deleterious remodeling.

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CCN2/CTGF promotor activity in the developing and adult mouse eye

Cited by 5 publications

References 86 publications

CCN2/CTGF—A Modulator of the Optic Nerve Head Astrocyte

CCN2/CTGF—A Modulator of the Optic Nerve Head Astrocyte

Connective Tissue Growth Factor in Idiopathic Pulmonary Fibrosis: Breaking the Bridge

Remodeling of the Lamina Cribrosa: Mechanisms and Potential Therapeutic Approaches for Glaucoma

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