1‐(2‐Hydroxyethyl)‐2‐imidazolidinone, a heparanase and matrix metalloproteinase inhibitor, improves epidermal basement membrane structure and epidermal barrier function

Abstract

Daily exposure to sunlight is known to affect the structure and function of the epidermal basement membrane (BM), as well as epidermal differentiation and epidermal barrier function. The aim of this study is to clarify whether the inhibition of BM‐degrading enzymes such as heparanase and matrix metalloproteinase 9 (MMP‐9) can improve the epidermal barrier function of facial skin, which is exposed to the sun on a daily basis. 1‐(2‐hydroxyethyl)‐2‐imidazolidinone (HEI) was synthesized as an inhibitor of both heparanase and MMP‐9. HEI inhibited not only the BM damage at the DEJ but also epidermal proliferation, differentiation, water contents and transepidermal water loss abnormalities resulting from ultraviolet B (UVB). This was determined in this study by the use of UVB‐induced human cultured skins as compared with the control without HEI. Moreover, topical application of HEI improved epidermal barrier function by increasing water content and decreasing transepidermal water loss in daily sun‐exposed facial skin as compared with non‐treated skins. These results suggest that the inhibition of both heparanase and MMP‐9 is an effective way to care for regularly sun‐exposed facial skin by protecting the BM from damage.

Decrease of laminin-511 in the basement membrane due to photoaging reduces epidermal stem/progenitor cells

“…Laminin-511 is known to be associated with perlecan networks in basement membrane 49 by binding to heparan sulfate proteoglycan 50,51 . We previously reported that heparanase was activated in the epidermis of UVB-exposed skin, leading to degradation of heparan sulfate of perlecan in the basement membrane at the DEJ 29,40,52 . Furthermore, treatment with inhibitors of MMPs and heparinase not only protected the heparan sulfate staining but also blocked the loss of laminin-511 at the DEJ in organotypic human skin 29,30 .…”

“…We previously reported that heparanase was activated in the epidermis of UVB-exposed skin, leading to degradation of heparan sulfate of perlecan in the basement membrane at the DEJ 29,40,52 . Furthermore, treatment with inhibitors of MMPs and heparinase not only protected the heparan sulfate staining but also blocked the loss of laminin-511 at the DEJ in organotypic human skin 29,30 . In addition, we found that UVB irradiation did not change the gene expression levels of LAMA5 and LAMB1 in cultured keratinocytes (Supplementary Fig.…”

“…Some sun-exposed facial skin samples were obtained with the approval of the ethics committees at Gunma University and Shiseido. The experimental protocols were also , and bifunctional inhibitor hydroxyethyl-imidazoridinone (HEI) were synthesized at Shiseido Co. Ltd. (Yokohama, Japan) according to the literature 52,55,56 . organotypic human skin model.…”

“…Blocking loss of laminin-511 in UVB-exposed and UVB-unexposed organotypic human skin maintained McSp-positive cell levels. We previously reported that UVB exposure induced and activated MMP-9 and heparanase in the epidermis, and damaged the structure of the basement membrane at the DEJ, leading to a reduction of proliferative keratinocytes and barrier disruption 18,19,30 . We also showed that MMP and heparanase inhibitors suppressed the degradation of the basement membrane and maintained proliferative keratinocytes and epidermal barrier function in UVB-exposed organotypic human skin 29,30 .…”

“…We previously reported that UVB exposure induced and activated MMP-9 and heparanase in the epidermis, and damaged the structure of the basement membrane at the DEJ, leading to a reduction of proliferative keratinocytes and barrier disruption 18,19,30 . We also showed that MMP and heparanase inhibitors suppressed the degradation of the basement membrane and maintained proliferative keratinocytes and epidermal barrier function in UVB-exposed organotypic human skin 29,30 . Thus, we next performed ex vivo human skin cultures in the presence of MMP inhibitor CGS27027A, heparanase inhibitor BIPBIPU, and bifunctional inhibitor HEI after UVB exposure, in order to investigate the mechanisms underlying the effect of laminin-511 on epidermal stem/progenitor cells.…”