June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Activation of the aryl hydrocarbon receptor induces matrix metalloproteinase-1 in thyroid eye disease orbital fibroblasts: implications for anti-scarring therapies
Author Affiliations & Notes
  • Collynn Woeller
    Ophthalmology, University of Rochester, Rochester, New York, United States
  • Elisa Roztocil
    Ophthalmology, University of Rochester, Rochester, New York, United States
  • Christine Hammond
    Ophthalmology, University of Rochester, Rochester, New York, United States
  • Steven E Feldon
    Ophthalmology, University of Rochester, Rochester, New York, United States
  • Footnotes
    Commercial Relationships   Collynn Woeller, None; Elisa Roztocil, None; Christine Hammond, None; Steven Feldon, None
  • Footnotes
    Support  National Institutes of Health Grants EY027308 and an unrestricted grant from Research to Prevent Blindness.
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2935. doi:
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      Collynn Woeller, Elisa Roztocil, Christine Hammond, Steven E Feldon; Activation of the aryl hydrocarbon receptor induces matrix metalloproteinase-1 in thyroid eye disease orbital fibroblasts: implications for anti-scarring therapies. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2935.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Thyroid eye disease (TED), sometimes called Graves’ orbitopathy or Graves’ ophthalmopathy, affects 25-50% of patients with Graves’ Disease. In TED, collagen accumulation leads to an expansion of the extracellular matrix (ECM) which causes tissue reorganization, inflammatory cell retention and ultimately, tissue damage. The purpose of this study was to investigate the therapeutic potential of activating the aryl hydrocarbon receptor (AHR) to induce matrix metalloproteinase-1 (MMP1). MMP1 is an extracellular proteinase that degrades fibrous collagen to limit excessive ECM.

Methods : Primary human orbital fibroblasts from TED patients and Non-TED patients were isolated and cultured under standard conditions. Fibroblasts were treated with the pro-scarring cytokine, transforming growth factor beta (TGFβ) with or without activation of the AHR by its ligand, FICZ. MMP1 production was measured by Luminex assay, Western blotting and quantitative PCR. MMP1 activity was measured by collagen zymography. AHR and its transcriptional binding partner, ARNT1 were depleted using specific siRNA to determine their role in activating expression of MMP1 in orbital fibroblasts.

Results : TGFβ treatment reduced MMP1 expression and increased collagen 1A1 levels in primary human orbital fibroblasts. In contrast, FICZ induced MMP1 mRNA, protein expression and MMP1 activity. AHR induced MMP1 expression led to a reduction in collagen 1 levels. Furthermore, MMP1 expression requires both the AHR and ARNT1, suggesting that the AHR-ARNT1 transcriptional complex is necessary for production of MMP1.

Conclusions : These data show that activation of the AHR by FICZ increases MMP1 expression while reducing collagen levels. A reduction in collagen limits excessive ECM deposition in TED orbital fibroblasts. Taken together, these studies reveal that AHR activation is a promising target to block detrimental ECM production and tissue remodeling that occurs in TED.

This is a 2020 ARVO Annual Meeting abstract.

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