TY - JOUR
T1 - A novel ocular function for decorin in the aqueous humor outflow
AU - Schneider, Magdalena
AU - Pawlak, Ramona
AU - Weber, Gregor R.
AU - Dillinger, Andrea E.
AU - Kuespert, Sabrina
AU - Iozzo, Renato V.
AU - Quigley, Harry A.
AU - Ohlmann, Andreas
AU - Tamm, Ernst R.
AU - Fuchshofer, Rudolf
N1 - Funding Information:
This work has been supported by the Deutsche Forschungsgemeinschaft (FU734/6–1). The original work on the decorin null mice was supported in part by NIH grant CA39481 (RVI). We thank Dr. L. Schaefer for providing the breeding pair of Dcn −/− mice to start our animal colony
Funding Information:
This work has been supported by the Deutsche Forschungsgemeinschaft (FU734/6?1). The original work on the decorin null mice was supported in part by NIH grant CA39481 (RVI). We thank Dr. L. Schaefer for providing the breeding pair of Dcn?/? mice to start our animal colony, All experiments conformed to the tenets of the National Institutes of Health Guidelines on the Care and Use of Animals in Research, the EU Directive 2010/63/E and the Association for Research in Vision and Ophthalmology Statement for the Use of Animals in Ophthalmic in Vision Research, and were approved by local authorities (54?2532.1?44/12; Regierung Oberpfalz, Bavaria, Germany)
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/3
Y1 - 2021/3
N2 - Primary open-angle glaucoma, a neurodegenerative disorder characterized by degeneration of optic nerve axons, is a frequent cause of vision loss and blindness worldwide. Several randomized multicenter studies have identified intraocular pressure as the major risk factor for its development, caused by an increased outflow resistance to the aqueous humor within the trabecular meshwork. However, the molecular mechanism for increased outflow resistance in POAG has not been fully established. One of the proposed players is the pro-fibrotic transforming growth factor (TGF)-β2, which is found in higher amounts in the aqueous humor of patients with POAG. In this study we elucidated the role of decorin, a small leucine-rich proteoglycan and known antagonist of TGF-β, in the region of aqueous humor outflow tissue. Utilizing decorin deficient mice, we discovered that decorin modulated TGF-β signaling in the canonical outflow pathways and the lack of decorin in vivo caused an increase in intraocular pressure. Additionally, the Dcn−/− mice showed significant loss of optic nerve axons and morphological changes in the glial lamina, typical features of glaucoma. Moreover, using human trabecular meshwork cells we discovered that soluble decorin attenuated TGF-β2 mediated synthesis and expression of typical downstream target genes including CCN2/CTGF, FN and COL IV. Finally, we found a negative reciprocal regulation of decorin and TGF-β, with a dramatic downregulation of decorin in the canonical outflow pathways of patients with primary open-angle glaucoma. Collectively, our results indicate that decorin plays an important role in the pathogenesis of primary open-angle glaucoma and offers novel perspectives in the treatment of this serious disease.
AB - Primary open-angle glaucoma, a neurodegenerative disorder characterized by degeneration of optic nerve axons, is a frequent cause of vision loss and blindness worldwide. Several randomized multicenter studies have identified intraocular pressure as the major risk factor for its development, caused by an increased outflow resistance to the aqueous humor within the trabecular meshwork. However, the molecular mechanism for increased outflow resistance in POAG has not been fully established. One of the proposed players is the pro-fibrotic transforming growth factor (TGF)-β2, which is found in higher amounts in the aqueous humor of patients with POAG. In this study we elucidated the role of decorin, a small leucine-rich proteoglycan and known antagonist of TGF-β, in the region of aqueous humor outflow tissue. Utilizing decorin deficient mice, we discovered that decorin modulated TGF-β signaling in the canonical outflow pathways and the lack of decorin in vivo caused an increase in intraocular pressure. Additionally, the Dcn−/− mice showed significant loss of optic nerve axons and morphological changes in the glial lamina, typical features of glaucoma. Moreover, using human trabecular meshwork cells we discovered that soluble decorin attenuated TGF-β2 mediated synthesis and expression of typical downstream target genes including CCN2/CTGF, FN and COL IV. Finally, we found a negative reciprocal regulation of decorin and TGF-β, with a dramatic downregulation of decorin in the canonical outflow pathways of patients with primary open-angle glaucoma. Collectively, our results indicate that decorin plays an important role in the pathogenesis of primary open-angle glaucoma and offers novel perspectives in the treatment of this serious disease.
KW - Decorin
KW - Extracellular matrix
KW - Glaucoma
KW - Intraocular pressure
KW - TGF-β
KW - Trabecular meshwork
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U2 - 10.1016/j.matbio.2021.02.002
DO - 10.1016/j.matbio.2021.02.002
M3 - Article
C2 - 33582236
AN - SCOPUS:85101841394
SN - 0945-053X
VL - 97
SP - 1
EP - 19
JO - Matrix Biology
JF - Matrix Biology
ER -