Selective Inhibition of Skin Fibroblast Elastase Elicits a Concentration-Dependent Prevention of Ultraviolet B-Induced Wrinkle Formation

Abstract

We previously reported that wrinkle formation in the skin following long-term ultraviolet B irradiation is accompanied by decreases in skin elasticity and the curling of elastic fibers in the dermis. We further showed that wrinkles could be repaired by treatment with retinoic acid and that this was concomitant with the recovery of skin elasticity ascribed to the repair of damaged elastic fibers. Those studies suggested that decreasing the tortuosity of dermal elastic fibers is an important factor involved in inhibiting or repairing wrinkle formation. Therefore, it is of particular interest to determine whether the inhibition of elastase activity in vivo would prevent the damage of dermal elastic fibers and might abolish wrinkle formation associated with the loss of skin elasticity. Because the major elastase in the skin under noninflammatory conditions is skin fibroblast elastase, we used a specific inhibitor of that enzyme to assess its biologic role in wrinkle formation. The hind limb skins of Sprague-Dawley rats were irradiated with ultraviolet B at a suberythemal dose three times a week for 6 wk. During that period, 0.1-10.0 mM N-phenetylphosphonyl-leucyl-tryptophane, an inhibitor of skin fibroblast elastase, was applied topically five times a week. N-phenetylphosphonyl-leucyl-tryptophane application at concentrations of 0.1-1.0 mM abolished wrinkle formation in a concentration-dependent manner, with a peak for inhibition at 1.0 mM. This inhibition was accompanied by a continued low tortuosity of dermal elastic fibers and a maintenance of skin elasticity. Measurement of elastase activity after 6 wk of ultraviolet B irradiation demonstrated that whereas phosphoramidon-sensitive elastase activity was significantly enhanced in the ultraviolet B-exposed skin, there was no significant increase in that activity in the ultraviolet B-exposed, N-phenetylphosphonyl-leucyl-tryptophane-treated skin. These findings suggest that skin fibroblast elastase plays an essential part in the degeneration and/or tortuosity of elastic fibers induced by cumulative ultraviolet B irradiation.

Mechanistic Effects of Long-Term Ultraviolet B Irradiation Induce Epidermal and Dermal Changes in Human Skin Xenografts

“…4,6,7,9,11,21,22,24,29 Moreover, gene chip analysis indicated a lot of similarities in the comparisons between young versus old skins and our control versus UVB-exposed skins, corroborating the validity of our photodamage or premature photoaging model. Taken together, the present study discloses a novel photodamage model with human skin xenograft that recapitulates mechanisms underlying morphological changes such as wrinkling reported to date, and can be used for the further study of photoaging.…”

“…5,8,10,11,20 On the other hand, it has been reported that the degeneration of these fibers in chronologically and/or photoaged skin stems from an increase in matrix metalloproteinase-12 (MMP-12) and/or elastase, an elastin-degrading enzyme that is produced and secreted by dermal fibroblasts. [21][22][23][24] To date, the mechanisms underlying the alteration of elastin fibers in photoaged skin including their production, accumulation, and degradation are not fully understood.…”

The Effect of Sunscreen on Skin Elastase Activity Induced by Ultraviolet-A Irradiation

“…1,6,7) Inhibition of the UVB-induced increase in skin elastase activity prevented by the agent maintained the linearity of dermal elastic fibers and inhibited the decrease in skin elasticity, resulting in the inhibition of wrinkle formation. 1,6,7) This finding suggested that application of an elastase inhibitor immediately after UVB exposure would inhibit photoaging of the skin, mainly wrinkles.It has been shown that chronic UVB irradiation of the dorsal skin forms wrinkles in hairless mice 8,9) and that chronic ultraviolet-A (UVA) irradiation forms mainly sags. 8,9) In animal models, chronic UVA irradiation increased skin elastase activity and destroyed the 3-dimensional structure of dermal elastic fibers, decreasing skin elasticity, similarly to UVB irradiation.…”

“…1,6,7) Inhibition of the UVB-induced increase in skin elastase activity prevented by the agent maintained the linearity of dermal elastic fibers and inhibited the decrease in skin elasticity, resulting in the inhibition of wrinkle formation. 1,6,7) This finding suggested that application of an elastase inhibitor immediately after UVB exposure would inhibit photoaging of the skin, mainly wrinkles.…”

Potential prevention effects of Rubus occidentalis seed on UVB-induced MMP-1 production and procollagen degradation in CCD-986sk cells

“…MMPs are a family of extracellular matrix (ECM)-degenerating enzymes and are generated from different types of cells including fibroblasts and endothelial cells, as well as immune cells. MMPs play a key role in the dynamic remodeling of the ECM and are comprised of functional subclassified groups including membrane-type MMPs, and other nonclassified MMPs (Visse and Nagase 2003); in particular, collagenase-1 (MMP-1) production is significantly enhanced in late passage skin fibroblasts Tsukahara et al 2001;Varani et al 2002;Brennan et al 2003). Collagenase can cleave the interstitial collagenases that are found in the skin such as type I collagen (Lee et al 2008).…”