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Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves' Orbitopathy
Bo Yi Kim1, Soo Hyun Choi1, Ji-Young Kim1
1Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea.
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.
Insights
Bone morphogenic protein 7 (BMP7) levels are lower in Graves
Area of Science:
- Endocrinology and immunology
- Ophthalmology
Background:
- Graves' orbitopathy (GO) is an autoimmune condition affecting the eye muscles and tissues.
- The role of bone morphogenic protein 7 (BMP7) in GO pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of BMP7 in the pathogenic mechanisms of Graves' orbitopathy (GO).
- To evaluate the therapeutic effects of BMP7 on inflammation and fibrosis in cultured Graves' orbital fibroblasts.
Main Methods:
- Real-time PCR was used to compare BMP7 mRNA expression in orbital tissues from GO patients and controls.
- Orbital fibroblasts from GO and control patients were cultured and treated with recombinant human BMP7 (rhBMP7).
- The effects of rhBMP7 on fibrosis-related proteins and inflammatory cytokines were analyzed using Western blotting and signaling pathway analysis.
Main Results:
- BMP7 mRNA expression was lower in GO orbital tissues compared to controls.
- rhBMP7 suppressed TGF-β-induced fibrosis markers (fibronectin, collagen 1α, α-SMA) and modulated SMAD signaling.
- rhBMP7 inhibited IL-1β or TNF-α-induced pro-inflammatory molecules (IL-6, IL-8, ICAM-1) by suppressing NFκB and Akt activation.
Conclusions:
- BMP7 transcript levels are downregulated in Graves' orbital tissues.
- Exogenous BMP7 demonstrated inhibitory effects on profibrotic and proinflammatory factors in orbital fibroblasts.
- BMP7 may represent a potential therapeutic agent for GO by counteracting TGF-β/SMAD signaling and inflammation.
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