Enhancement of collagen 1 expression by prostaglandin F2α agonists is
pivotally involved in the pathogenesis of deepening of the upper eyelid
sulcus
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.