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Cited by 41Glaucoma and retinal disordersTGF-β signaling in diseasesBone and Dental Protein Studies

Regulation of SPARC by Transforming Growth Factor β2 in Human Trabecular Meshwork

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Kang, Min Hyung, Oh, Dong-Jin, Kang, Ja-heon, Rhee, Douglas J.·2013·Investigative Opthalmology & Visual Science
DOI 10.1167/iovs.12-11474PMC PMC3626313
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Abstract

PURPOSE: An increased aqueous level of TGF-β2 has been found in many primary open-angle glaucoma patients. Secreted Protein, Acidic, and Rich in Cysteine (SPARC)-null mice have a lower intraocular pressure. The mechanistic relationship between SPARC and TGF-β2 in trabecular meshwork (TM) is unknown. We hypothesized that TGF-β2 upregulates SPARC expression in TM. METHODS: Cultured TM cells were incubated with selective inhibitors for p38 MAP kinase (p38), Smad3, p42, JNK, RhoA, PI3K, or TGF-β2 receptor for 2 hours, and then TGF-β2 was added for 24 hours in serum-free media. Quantitative polymerase chain reaction (qPCR) and immunoblot analysis were performed. Immunofluorescent microscopy was used to determine nuclear translocation of signaling proteins. Ad5.hSPARC and Lentiviral shRNA for p38 and Smad3 were constructed, and infected human TM cells. RESULTS: SPARC was upregulated by TGF-β2 in the human TM cells (3.8 ± 1.7-fold, n = 6, P = 0.01 for protein and 7.1 ± 3.7-fold, n = 6, P = 0.01 for mRNA), while upregulation of SPARC had no effect on TGF-β2. TGF-β2-induced SPARC expression was suppressed by inhibitors against p38 (-40.3 ± 20.9%, n = 10, P = 0.0001), Smad3 (-56.2 ± 18.9%, n = 10, P = 0.0001), JNK (-49.1 ± 24.6%, n = 10, P = 0.0001), and TGF-β2 receptor (-83.6 ± 14.4%, n = 6, P = 0.003). Phosphorylation and translocation of Smad3, p38, and MAPKAPK2 were detected at 30 minutes and 1 hour, respectively, following TGF-β2 treatment. Phosphorylation of JNK and c-jun was detected before TGF-β2 treatment. SPARC was suppressed 31 ± 13% (n = 5, P < 0.0001) by shRNA-p38 and 41 ± 3% (n = 5, P < 0.0001) by shRNA-Smad3. CONCLUSIONS: TGF-β2 upregulates SPARC expression in human TM through Smad-dependent (Smad2/3) or -independent (p38) signaling pathways. SPARC may be a downstream regulatory node of TGF-β2-mediated IOP elevation.

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  • SPARC is upregulated upon TGF-β stimulation in a p38- and JNK-dependent manner, with inhibition of either pathway sufficient to suppress SPARC upregulation.

    “has been shown to be upregulated upon TGF-β stimulation, in a p38- and JNK-dependent manner, with an inhibition of either pathway being sufficient to suppress SPARC upregulation [ 121 ]”

    From MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges (2023) · cites this paper as [121]

    The Results report that TGF-β2 upregulated SPARC in cultured human trabecular meshwork cells and that separate p38 and JNK inhibitors each reduced the induced expression. The Discussion cautions that JNK may not be involved: its inhibitor’s effect could have been nonspecific and could not be confirmed with silencing RNA. Thus, the claim overstates JNK dependence; neither inhibitor was shown to eliminate upregulation completely. (LLM, conf=0.88)

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  1. Bollinger KE, Crabb JS, Yuan X, Putliwala T, Clark AF, Crabb JW. Quantitative proteomics: TGFbeta(2) signaling in trabec- ular meshwork cells. Invest Ophthalmol Vis Sci. 2011;52: 8287-8294.

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Authors
Kang, M. H., Oh, D.-J., Kang, J.-H., & Rhee, D. J.
Affiliations
  • Massachusetts Eye and Ear Infirmary (US)
  • Department of Ophthalmology, Kyung Hee University Hospital at Gangdong, Seoul, Korea
Corresponding author
Rhee, Douglas J.
ORCID
Rhee, Douglas J.
Venue
Investigative Opthalmology & Visual Science
Publisher
Association for Research in Vision and Ophthalmology (ARVO)
Published
2013-04-05
Volume
54
Issue
4
Pages
2523
ISSN
  • 0146-0404 (ISSN-L)
  • 1552-5783
DOI
10.1167/iovs.12-11474
PMC
PMC3626313
OpenAlex
W1993655784
Cited by
41
References
39
Citations by year
2026: 2 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 3 · 2017: 3 · 2016: 1 · 2015: 4 · 2014: 8 · 2013: 1
FWCI
4.60
Type
journal article
Language
en
Open access
Licence
public-domain
Locations
  • Investigative Ophthalmology & Visual Science (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Massachusetts Lions Eye Research Fund
  • American Glaucoma Society
  • National Eye Institute (EY019654-01, R01EY019654, EY-14104, P30EY014104)
Topics
  • Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
Keywords
SPARC, transforming growth factor-beta2, trabecular meshwork, primary open-angle glaucoma, p38 MAPK, Smad3, JNK, MAPKAPK2, c-Jun, intraocular pressure, gene expression regulation, MAPK signaling, aqueous humor outflow, SPARC-null mice, shRNA
MeSH terms
Adenoviridae, Adult, Aged, Cells, Cultured, Child, Enzyme Inhibitors, Humans, Middle Aged, Phosphorylation, RNA, Messenger, Trabecular Meshwork, Transfection, Immunoblotting, Osteonectin, Up-Regulation, Fluorescent Antibody Technique, Indirect, MAP Kinase Signaling System, Tumor Suppressor Proteins, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta2, Real-Time Polymerase Chain Reaction

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