日本香粧品学会誌

Vol. 44, No. 1, pp. 1–5（2020）〈Regular Article〉

Plasmin Derived from Senescent Fibroblasts Is Induced by Prostaglandin E2 andIncreases the Degradation of Collagen
Aska SONOKI1, *, Yuri OKANO2, Yuichiro YOSHITAKE1(Accepted: November 5, 2019)

Abstract
Photoaging and intrinsic aging of the skin results from collagen degradation in the dermis by matrix metalloproteinases(MMPs), but photoaging differs from intrinsic aging due to the obvious emergence of skin wrinkles. It could be thought thatphotoaging is increased by intrinsic aging because its signs are expressed suddenly in the dermis of advanced intrinsicallyaged skin. In this study, we constructed a 3D photoaged model of the dermis using collagen-embedded senescent ﬁbroblasts
and analyzed collagen degradation and plasmin activity, because we had found that plasmin derived from ﬁbroblasts activates MMP-1. Senescent ﬁbroblasts had increased levels of plasmin activity in a non-irradiated 3D model and had increased
degradation of collagen following exposure of the 3D model to ultraviolet (UV)-A radiation. Moreover, it was found thatprostaglandin E2 (PGE2) increased plasmin levels in normal ﬁbroblasts and the increase of plasmin in senescent ﬁbroblasts
was reduced by treatment with the PGE2 inhibitor NS398. Treatment with tranexamic acid, plasmin or NS398 reduced collagen degradation in the 3D photoaged model. These results suggest that the increased level of plasmin in the 3D senescentﬁbroblast model depends on the expression of PGE2. Our study suggests that intrinsic aging increases photoaging in a plasmin- and PGE2-dependent manner and that tranexamic acid prevents photoaging especially in aged dermis.
Key words: plasmin, prostaglandin E2, MMP-1, 3D collagen model, senescent ﬁbroblast.
1.

Introduction

Ultraviolet (UV)-A radiation reaches deep into the dermis
and causes collagen degradation that leads to photoagingof the skin, which is distinct from intrinsic aging. Photoaging is marked by the emergence of obvious wrinkles in theskin and mainly involves the degradation of the extracellularmatrix (ECM) in the dermis. Both photoaging and intrinsic
aging result from collagen degradation by matrix metalloproteinases (MMPs), but there are some histological differences
between them, for example ﬂattened dermal-epidermal junctions in photoaged skin1, 2). We consider that photoaging may
be increased by intrinsic aging since the sun-exposed skinof young people does not usually have obvious wrinkles andsigns of photoaging are expressed suddenly in advanced aged
dermis.
MMP-1 is one of the most important collagen-degrading
enzymes produced by ﬁbroblasts in the dermis. It has beenreported that the expression of MMP-1 is induced by UV-Airradiation3), that its activity is increased in aged dermis4)
and that the expression of MMP-1 is increased in senescentﬁbroblasts5). On the other hand, MMPs cannot act on collagen
without being activated by proteinases and the behavior of1

OPPEN COSMETICS CO., LTD. (61–1Yamedera-cho, Kusatsu-shi,
Shiga 525–0042, Japan)
2
School of Bioscience and Biotechnology, Tokyo University of Technology* Corresponding author: OPPEN COSMETICS CO., LTD., 61–1

Yamedera-cho, Kusatsu-shi, Shiga 525–0042, Japan (E-mail: aska.
sonoki@gmail.com)

activator(s) of MMP-1 in aged dermis and in ﬁbroblasts has
not been characterized. We previously reported that plasmin
produced by ﬁbroblasts is an activator of MMP-1 in the dermis using a 3D collagen model6). In intrinsically aged dermis,
the level of prostaglandin E2 (PGE2) is increased and stimulates the expression of several collagen degradation factors,
including MMP-15, 7), but the behavior of activators of MMP-1
during the aging process has not been reported.
In this study, we focused on plasmin as a factor that increases the collagen degradation involved in skin aging because it has been suggested that plasmin is induced by PGE2in osteoblasts8), and it was reported that plasmin activity is increased in the serum during the aging process9). The factor(s)involved in collagen degradation that increases not only
in young photoaged skin but also in intrinsically aged skinmight cause the difference between photoaging and intrinsic
aging. We constructed a 3D photoaged dermal model using
collagen-embedded ﬁbroblasts to investigate the conditions of
the lattices and plasmin in order to reveal differences between
young or aged photoaging and intrinsic aging in the dermis.