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Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves’ Orbitopathy

PURPOSE: We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-β superfamily on pathogenic mechanism of Graves’ orbitopathy (GO). The therapeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves’ orbital fibroblasts. METHODS: Expression of BMP...

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Autores principales: Kim, Bo Yi, Choi, Soo Hyun, Kim, Ji-Young, Ko, JaeSang, Yook, Jong In, Kim, Hyun Sil, Lee, Eun Jig, Kikkawa, Don O., Yoon, Jin Sook
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187939/
https://www.ncbi.nlm.nih.gov/pubmed/35671049
http://dx.doi.org/10.1167/iovs.63.6.7
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author Kim, Bo Yi
Choi, Soo Hyun
Kim, Ji-Young
Ko, JaeSang
Yook, Jong In
Kim, Hyun Sil
Lee, Eun Jig
Kikkawa, Don O.
Yoon, Jin Sook
author_facet Kim, Bo Yi
Choi, Soo Hyun
Kim, Ji-Young
Ko, JaeSang
Yook, Jong In
Kim, Hyun Sil
Lee, Eun Jig
Kikkawa, Don O.
Yoon, Jin Sook
author_sort Kim, Bo Yi
collection PubMed
description PURPOSE: We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-β superfamily on pathogenic mechanism of Graves’ orbitopathy (GO). The therapeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves’ orbital fibroblasts. METHODS: Expression of BMP7 was compared in cultured orbital tissue explants from GO (n = 12) and normal control (n = 12) subjects using real-time PCR. Orbital fibroblasts were cultured from orbital connective tissues obtained from GO (n = 3) and normal control patients (n = 3). Cells were pretreated with recombinant human BMP7 (rhBMP7) before stimulation with TGF-β, IL-1β, and TNF-α. Fibrosis-related proteins and inflammatory cytokines were analyzed by Western blotting. The activation of signaling molecules in inflammation and fibrosis was also analyzed. RESULTS: The expressions of BMP7 mRNA were lower in GO orbital tissues than control. Fibrosis-related proteins, fibronectin, collagen 1α, and α-SMA induced by TGF-β were suppressed by treating rhBMP7, and rhBMP7 upregulated TGF-β induced SMAD1/5/8 protein expression, whereas downregulated SMAD2/3. Increased pro-inflammatory molecules, IL-6, IL-8, and intercellular adhesion molecule-1 (ICAM-1) by IL-1β or TNF-α were blocked by rhBMP7 treatment, and the expression of phosphorylated NFκB and Akt was suppressed by rhBMP7 treatment. CONCLUSIONS: BMP7 transcript levels were downregulated in Graves’ orbital tissues. Exogenous BMP7 treatment showed inhibitory effects on the production of profibrotic proteins and proinflammatory cytokines in orbital fibroblasts. Our results provide a molecular basis of BMP7 as a new potential therapeutic agent through the opposing mechanism of profibrotic TGF-β/SMAD signaling and proinflammatory cytokine production.
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spelling pubmed-91879392022-06-12 Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves’ Orbitopathy Kim, Bo Yi Choi, Soo Hyun Kim, Ji-Young Ko, JaeSang Yook, Jong In Kim, Hyun Sil Lee, Eun Jig Kikkawa, Don O. Yoon, Jin Sook Invest Ophthalmol Vis Sci Biochemistry and Molecular Biology PURPOSE: We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-β superfamily on pathogenic mechanism of Graves’ orbitopathy (GO). The therapeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves’ orbital fibroblasts. METHODS: Expression of BMP7 was compared in cultured orbital tissue explants from GO (n = 12) and normal control (n = 12) subjects using real-time PCR. Orbital fibroblasts were cultured from orbital connective tissues obtained from GO (n = 3) and normal control patients (n = 3). Cells were pretreated with recombinant human BMP7 (rhBMP7) before stimulation with TGF-β, IL-1β, and TNF-α. Fibrosis-related proteins and inflammatory cytokines were analyzed by Western blotting. The activation of signaling molecules in inflammation and fibrosis was also analyzed. RESULTS: The expressions of BMP7 mRNA were lower in GO orbital tissues than control. Fibrosis-related proteins, fibronectin, collagen 1α, and α-SMA induced by TGF-β were suppressed by treating rhBMP7, and rhBMP7 upregulated TGF-β induced SMAD1/5/8 protein expression, whereas downregulated SMAD2/3. Increased pro-inflammatory molecules, IL-6, IL-8, and intercellular adhesion molecule-1 (ICAM-1) by IL-1β or TNF-α were blocked by rhBMP7 treatment, and the expression of phosphorylated NFκB and Akt was suppressed by rhBMP7 treatment. CONCLUSIONS: BMP7 transcript levels were downregulated in Graves’ orbital tissues. Exogenous BMP7 treatment showed inhibitory effects on the production of profibrotic proteins and proinflammatory cytokines in orbital fibroblasts. Our results provide a molecular basis of BMP7 as a new potential therapeutic agent through the opposing mechanism of profibrotic TGF-β/SMAD signaling and proinflammatory cytokine production. The Association for Research in Vision and Ophthalmology 2022-06-07 /pmc/articles/PMC9187939/ /pubmed/35671049 http://dx.doi.org/10.1167/iovs.63.6.7 Text en Copyright 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Biochemistry and Molecular Biology
Kim, Bo Yi
Choi, Soo Hyun
Kim, Ji-Young
Ko, JaeSang
Yook, Jong In
Kim, Hyun Sil
Lee, Eun Jig
Kikkawa, Don O.
Yoon, Jin Sook
Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves’ Orbitopathy
title Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves’ Orbitopathy
title_full Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves’ Orbitopathy
title_fullStr Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves’ Orbitopathy
title_full_unstemmed Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves’ Orbitopathy
title_short Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves’ Orbitopathy
title_sort potential therapeutic role of bone morphogenic protein 7 (bmp7) in the pathogenesis of graves’ orbitopathy
topic Biochemistry and Molecular Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187939/
https://www.ncbi.nlm.nih.gov/pubmed/35671049
http://dx.doi.org/10.1167/iovs.63.6.7
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