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Enhancement of collagen 1 expression by prostaglandin F2α agonists is pivotally involved in the pathogenesis of deepening of the upper eyelid sulcus
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  • Kaku Itoh,
  • Yosuke Ida,
  • Hiroshi Ohguro,
  • Fumihito Hikage
Kaku Itoh
Sapporo Medical University
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Yosuke Ida
Sapporo Medical University
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Hiroshi Ohguro
Sapporo Medical University
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Fumihito Hikage
Sapporo Medical University
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Abstract

Background and Purpose:Deepening of the upper eyelid sulcus (DUES) is recognized as an unfavorable and causeless side effect observed among long-term users of prostaglandin analogues (PGs). To elucidate the molecular pathology of DUES, we characterized thee-dimension (3D) cultures of human orbital fibroblasts (HOFs). Experimental Approach: HOF organoids were cultured without or with their adipogenic differentiation and at several concentrations (1, 100, 10000 nM) of PGs (bimatoprost acid; BIM-A, PGF2α, latanoprost acid; LAT-A). Their sizes, the mRNA expression of adipogenic related genes, extracellular matrix (ECM) and tissue inhibitors of metalloproteinases (TIMPs) were measured by electron microscope (EM) and the physical properties were measured by a micro-squeezer. Key Results: Adipogenesis caused significant downsizing of the organoids, and these were markedly inhibited in the presence of PGs in a concentration dependent manner. BIM-A was the most effective. The downsizing induced by PGs was also observed in conditions without adipogenesis. The size of each organoid under several conditions was inversely correlated with the mRNA expression profile of collagen 1 (COL1), which was also confirmed by immunolabeling. An mRNA expression profile similar to that for COL1 was also observed in Lysyl oxidase (LOX) and TIMP2. Analyses by EM and the micro squeezer clearly indicated that PGs induced an increase in ECM deposits and the physical solidity of the organoids. Conclusions and Implications: The findings reported herein indicate that PGs affects the expression of LOX, COL1 and TIMP2 which, in turn, modulate the 3D ECM network within the organoids, thus resulting in their downsizing.