Decorin—An Antagonist of TGF-β in Astrocytes of the Optic Nerve

Schneider, Magdalena; Dillinger, Andrea E.; Ohlmann, Andreas; Iozzo, Renato V.; Fuchshofer, Rudolf

doi:10.3390/ijms22147660

Cited by 13 publications

(8 citation statements)

References 72 publications

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“…The increase of CCN2/CTGF in the glial lamina of the transgenic animals was associated with a reactive phenotype in the resident astrocytes, indicated by the increase of their GFAP immunoreactivity and a thickening of their processes. Similar findings were described in the ONH of decorin knockout mice, where morphological changes of astrocytes in the glial lamina caused by an increased IOP were accompanied by increased GFAP and CTGF/CCN2 synthesis in the ONH ( Schneider et al, 2021a ; Schneider et al, 2021b ). An upregulation of CCN2/CTGF was observed in reactive astrocytes during other neurodegenerative diseases like multiple sclerosis ( Holley et al, 2003 ), amyotrophic lateral sclerosis ( Spliet et al, 2003 ) and Alzheimer’s disease ( Ueberham et al, 2003 ).…”

Section: Discussionsupporting

confidence: 83%

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: Discussionsupporting

confidence: 83%

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

Dillinger

Weber

Mayer

et al. 2022

Front. Cell Dev. Biol.

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“…The typical structural function of decorin is to adjust the diameter and space between collagen fibers in fibrous tissues, which are primarily composed of type I collagen ( Han et al, 2019 ). Moreover, decorin is an endogenous substance in the ECM and a natural inhibitor of TGF-β1 ( Border et al, 1992 ; Hocking et al, 1998 ; Zhu et al, 2007 ; Schneider et al, 2021 ). Furthermore, the levels of decorin are downregulated in fibrotic conditions such as a postburn hypertrophic scar, whereas TGF-β1 is increased compared with normal conditions ( Zhang et al, 2007 ; Honardoust et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

The Preventive Effect of Decorin on Epidural Fibrosis and Epidural Adhesions After Laminectomy

Ding

Sheng

et al. 2021

Front. Pharmacol.

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Laminectomy is commonly performed to treat degenerative spinal diseases by reducing compression on the spinal cord and nerve roots. The postoperative epidural fibrosis and epidural adhesions may result in failed back surgery syndrome, which is characterized by the symptoms of lower back pain or leg pain. There is currently no satisfactory treatment for this complication. The pathological processes of epidural fibrosis and epidural adhesions are relevant to the proliferation of fibroblasts, transdifferentiation of fibroblasts into myofibroblasts, and the excessive deposition of extracellular matrix (ECM) protein. According to reports, transforming growth factor-β1 (TGF-β1) played a vital role in the development of fibrosis by promoting aforementioned processes. Decorin, an endogenous proteoglycan and natural inhibitor of TGF-β1, has exhibited prominent anti-fibrosis activity in various scar formation and fibrosis models of many organs. However, the preventive effect of decorin on epidural fibrosis and epidural adhesions requires further investigation. Here, we investigated the therapeutic effects and potential mechanisms of decorin on epidural fibrosis and epidural adhesions. Our results indicated that decorin could significantly suppress the TGF-β1-induced proliferation, transdifferentiation, and extracellular matrix production in primary fibroblasts. Furthermore, Smad2/3 signaling pathway had been demonstrated to be involved in the preventive effect of decorin. Moreover, administration of decorin in vivo could notably inhibit epidural fibrosis and epidural adhesions after laminectomy. To date, there is no approved therapy to target TGF-β1 for the treatment of epidural fibrosis and epidural adhesions after laminectomy. Our research proved the anti-fibrosis effect of decorin, which may provide an effective and promising treatment for epidural fibrosis and epidural adhesions.

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“…Decorin is a well-studied small leucine-rich proteoglycan (SLRP) with a complex genomic structure and complex promoter region regulated by various growth factors 158 , 159 , 160 , 161 Decorin has been implicated for a long time in the regulation of collagen fibrillogenesis, 162 , 163 , 164 , 165 , 166 cartilage and tendon homeostasis, 165 , 166 , 167 , 168 regulation of TGFβ activity, wound healing and fibrosis, 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 angiogenesis, 154 , 171 , 178 , 179 , 180 Lyme disease, 181 and ocular pathophysiology. 166 , 175 , 182 , 183 , 184 Soluble decorin inhibits cancer growth primarily by acting as a pan-RTK inhibitor 185 , 186 ; it binds to EGFR and downregulates its biological activity 187 , 188 , 189 , 190 while elevating cytosolic Ca 2+ in A431 carcinoma cells. 191 Decorin suppresses the growth of various tumors with different histopathological backgrounds, 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , …”

Section: Proteoglycans and Heparanase As Proautophagic Secreted Factorsmentioning

confidence: 99%

Global impact of proteoglycan science on human diseases

Xie,

Schaefer,

Iozzo

2023

iScience

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Decorin—An Antagonist of TGF-β in Astrocytes of the Optic Nerve

Cited by 13 publications

References 72 publications

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

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

The Preventive Effect of Decorin on Epidural Fibrosis and Epidural Adhesions After Laminectomy

Global impact of proteoglycan science on human diseases

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