ANTI-AGING SKINCARE FOR CUTANEOUS PHOTO-AGING
Satoshi Amano, Ph.D.
Shiseido Research Center,
2-2-1 Hayabuchi, Tsuzuki-ku,
Yokohama
Kanagawa 224-8558
Japan
TEL +81-45-590-6000
FAX +81-45-590-6087
satoshi.amano@to.shiseido.co.jp
Abstract
This paper briefly reviews the characteristics of photoaged skin, and the
mechanisms involved in skin photoaging and repair. Sun-exposed skin shows superficial
changes, such as wrinkles, sagging, telangiectasis and pigmentary changes, pathological
changes such as neoplasia, and also many internal changes in the structure and function
of epidermis, basement membrane and dermis. These changes (so-called photoaging)
are predominantly due to the ultraviolet (UV) component of sunlight.
Enzymes such as matrix metalloproteinases (MMPs), urinary plasminogen
activator (uPA)/plasmin and heparanase are increased in epidermis of UV-irradiated skin.
These enzymes degrade epidermal basement membrane (BM) components, dermal
collagen fibers and elastic fibers. The BM, which is located at the dermal-epidermal
junction, controls dermal-epidermal signaling and is essential for maintaining a healthy
epidermis and dermis. Repeated BM damage occurs in sun-exposed skin compared to
unexposed skin, leading to epidermal and dermal deterioration and accelerated skin
aging. Elastic fibers, such as oxytalan fibers in papillary dermis, are associated with not
only skin resilience, but also skin surface texture, and elastic fiber formation by
fibroblasts is facilitated by increased expression of fibulin-5. Thus, induction of
fibulin-5 expression is a damage-repair mechanism, and fibulin-5 is an early marker of
photoaged skin.
UV-induced skin damage is cumulative, and leads to premature aging of skin.
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However, appropriate daily skincare may ameliorate photoaging by inhibiting processes
causing damage and enhancing repair processes.
Keywords: basement membrane, laminin 332, angiogenesis, thrombospondin-1,
heparanase, uPA/plasmin, oxytalan fiber, fibulin-5
Photoaging and intrinsic aging of skin
Skin aging can be classified into two types, intrinsic aging and photoaging (1).
Intrinsic aging is a basic biological process common to all living things and is
characterized as an age-dependent deterioration of functions and structures, such as
epidermal atrophy and flattening of the epidermal-dermal junction (DEJ) in the case of
skin (2). On the other hand, photoaging is well known to be a consequence of chronic
exposure of the skin to sunlight, particularly to the ultraviolet (UV) component of
sunlight; UVA (400 – 315 nm) penetrates deeply into skin and is more damaging, while
UVB (315 – 280 nm) penetrates only to the papillary dermis. Sun-exposed skin, such as
facial or neck skin, clearly shows a “prematurely aged” appearance in comparison with
the relatively sun-protected skin of the trunk or thigh, and is characterized by various
clinical features, including wrinkles, laxity, roughness, sallowness, pigmentary changes,
telangiectasis and neoplasia (3, 4). The histological features of sun-exposed skin include
cellular atypia, loss of polarity, flattening of the DEJ, decrease of collagen (5), and
dermal elastosis (2, 6).
Ultrastructural alteration of epidermal basement membrane in sun-exposed skin.
The basement membrane (BM) at the DEJ has many functions, of which the
most obvious is to tightly link the epidermis to the dermis (7). It also determines the
polarity of the epidermis and provides a barrier against epidermal migration. Once the
BM has been assembled, the epidermal cells recognize the surface adjacent to the BM
as the basal surface. Stratification of the epidermis proceeds with proliferating cells
remaining attached to the BM and daughter cells migrating into the upper layers (8). It
is thought that the BM influences epidermal differentiation and maintains the
proliferative state of the basal layer. Under normal circumstances, the BM prevents
direct contact of epidermal cells with the dermis. Another important function of the BM
derives from the positioning of the structure between epidermal and dermal cells. The
epidermis and the dermis do not function independently (9); instead, normal skin
homeostasis requires the constant passage of signals back and forth between the two cell
types. In general, these signals are small molecules, synthesized in one compartment,
2
that diffuse to the opposite compartment. In other words, these signals must cross the
BM. Components of the BM can selectively facilitate or prevent the passage of these
signals. In some cases, the signaling molecules are stored by the BM and only released
if the BM is damaged or destroyed. Thus, epidermal-dermal communication through the
BM is extremely important.
Duplication of lamina densa at the DEJ of sun-exposed skin occurs in aged
adults (2) and mice (10), and may result in a more fragile epidermal-dermal interface
and decreased resistance of the epidermis to shearing forces in aged skin. Even in
30-year-old females, severe disruption and reduplication of lamina densa are frequently
observed beneath keratinocytes and anchoring fibrils are also associated with detached
lamina densa, mainly on the dermis side, in sun-exposed cheek skin (11). On the other
hand, in sun-protected skin of both young and old subjects, scarcely any alteration of
the epidermal BM structure is apparent at the DEJ. In sun-exposed skin of old subjects,
the number of layers of reduplicated lamina densa is increased and laminae densae
branch in various directions (11). These findings suggest that repair of damaged BM is
important, since the damage may accelerate skin aging by affecting both epidermis and
dermis.
Effect of laminin 332 on BM repair
Laminin 332 is a glycoprotein (MW: 410 kDa) composed of 165 kDa (3), 140
kDa (3), and 105 kDa (2) chains (12). It is essential for epidermal attachment, as
mutations in the genes encoding the laminin 332 chains are associated with the severe
blistering phenotype of Herlitz' junctional epidermolysis bullosa (13). Since laminin 332
was thought to be a good candidate for promoting BM repair, it was purified from
keratinocyte-conditioned medium and added to culture medium of a skin-equivalent
(SE) model (12). The purified laminin 332 enhanced the formation of
hemidesmosome-like structures and improved the BM at the DEJ in the SE as compared
with the control without laminin 332 (14). Increasing the production of BM components
such as laminin 332, collagen IV and collagen VII also is an effective approach to
enhance BM repair or formation of BM at the DEJ (11, 15).
Roles of matrix metalloproteinases and plasminogen activator/plasmin in BM
damage
Matrix metalloproteinases (MMPs) are considered to be involved in photoaging,
since MMPs-1, 2, 3, and 9 were found to be increased by UV irradiation in experiments
using human fibroblasts (16-18) and human skin (19, 20). Fisher et al. demonstrated an
3
increase of MMPs in human skin following exposure even to an extremely low level of
UVB (20), and suggested that MMPs are UV-induced aging factors. Indeed, gelatinase
activities have been detected in the epidermis of forehead skin by in situ
gelatin-zymography (21). Further studies have employed SEs as a model for BM
damage; SEs partially mimic the photoaging process because of missing BM structure
at the DEJ and the presence of large amounts of MMPs, including gelatinases (MMP-2
and MMP-9), in the culture medium (15, 22). An MMP inhibitor, CGS27023A,
enhanced assembly of BM at the DEJ in SE (Figs. 1a and 1b) (15, 22), suggesting that
MMPs play an important role in the degradation of BM components and induction of
BM structural damage, such as detachment of BM from basal keratinocytes and
disruption of lamina densa, which are observed in sun-exposed skin (11).
UVB exposure increases the synthesis of urokinase-type plasminogen activator
(uPA) (23, 24), as well as MMPs (20, 25). uPA is present in conditioned medium of SE,
and the addition of plasminogen enhances degradation of BM components and impairs
assembly of BM structure at the DEJ, even in the presence of an MMP inhibitor (26).
Aprotinin, a plasmin inhibitor, restores the assembly of BM structure at the DEJ
damaged by the addition of plasminogen (Figs. 1c and 1d) (26).
Role of heparanase in BM functional damage
Heparan sulfate (HS) proteoglycans are essential for biological processes
mediated by HS-binding growth factors (27). Perlecan, with its large multivalent protein
core, is a structural constituent of BM and is a key regulator of these growth factor
signaling pathways (28). HS chains of perlecan at the BM act as a reservoir of
heparin-binding growth factors, such as fibroblast growth factors (FGFs) (29),
granulocyte-macrophage colony-stimulating factor (GM-CSF) (30) and vascular
endothelial growth factor-A (VEGF-A) (31), and serve to prevent uncontrolled diffusion
of these factors from the epidermis to the dermis and vice versa (32). KGF, SCF and
HGF are produced by dermal fibroblasts and act on epidermal keratinocytes and
melanocytes (33, 34). Heparanase is an endo--D-glucuronidase and is capable of
cleaving HS fragments of quite appreciable size (5-7 kDa) (35). In normal tissue,
heparanase is expressed in placenta, keratinocytes and platelets, but not in connective
tissue cells (36). In normal skin, heparanase is expressed in stratum corneum and hair
inner root sheath, and may be involved in differentiation, desquamation and hair growth
(37). Recently we found that it is increased in inflammatory conditions, such as in
UVB-irradiated skin, and degradation of HS at the DEJ impairs the function of the BM
in photo-aged skin, altering transfer of several growth factors between epidermis and
4
dermis (38) (39). Heparanase was activated in human keratinocytes by UVB exposure
and heparan sulfate (HS) of perlecan was markedly degraded at the DEJ in
UVB-irradiated human skin (38). Degradation of HS leads to a remarkable reduction in
the binding activity of VEGF, FGF-2 and FGF-7 to the BM at the DEJ (39).
Degradation of heparan sulfate was observed not only in acute UVB-irradiated skin but
also in daily sun-exposed skin (39). Interestingly, heparan sulfate was degraded in
sun-exposed skin but not in sun-protected skin (39). These findings suggest that daily
UVB exposure activates heparanase, leads to degradation of heparan sulfate in the BM
and increases growth factor interaction between epidermis and dermis. These changes
would facilitate photo-aging.
To repair BM damage in sun-exposed skin, it is necessary to control heparanase
(40) in addition to MMPs such as gelatinases (15) and/or uPA/plasmin (26). In the SE
model, BP180 and β4 integrin were polarized to the basal side, while deposition of
collagen VII was polarized to the basal side and increased by combined treatment with
MMP inhibitor and heparanase inhibitor (Fig. 2a-2c), which enhanced the formation of
anchoring fibrils and hemidesmosomes as observed by transmission electron
microscopy (Fig. 2d) (41). These inhibitors may protect perlecan, thereby stabilizing
BM structure at the DEJ, since perlecan is reported to serve as a connector between
laminin- and collagen IV-containing networks at the DEJ (42).
Dermal structure: collagen fibrils and elastic fibers
Dermal collagen fibers contribute to the morphology and mechanical properties
of the skin. Aging-related structural changes in dermal collagen have been extensively
investigated by histological study of skin biopsy specimens. Recently aging-related
structural changes of collagen fibers in the reticular dermis were clearly visualized in a
non-invasive manner by using collagen-sensitive second harmonic generation (SHG)
microscopy (43). SHG images of human facial skin clearly show aging-related
structural changes in dermal collagen fibers (5). In addition to collagen fibers, elastic
fibers play an important role in skin resilience and are composed of filaments called
microfibrils, and an amorphous component (44). Fibrillin is one of the major
components of microfibrils (45, 46). Tropoelastins, a precursor of elastin, are
cross-linked by lysyl oxidase and converted to elastin (44). Fibulin-5 plays an important
role in the association of tropoelastin with microfibrils (47, 48). Fibulin-5 is colocalized
with other elastic fiber components. In the reticular dermis, fibulin-5 decreases and
disappears with increasing age even in sun-protected skin. But, fibulin-5 was greatly
decreased in the dermis of sun-exposed cheek skin even from a 20-year-old man. UVB
5
irradiation reduced fibulin-5 and elastin markedly and weakly, respectively, compared
with the levels in control nontreated skin. Interestingly, the deposition of fibulin-5 was
increased in solar elastosis, like that of other elastic fiber components. These results
suggest that fibulin-5 is a good marker of skin aging, and early loss of fibulin-5 may
lead to changes in other elastic fiber components (49). Moreover, elastic fibers in the
upper dermis influence skin surface texture, based on an analysis of the association of
recovery of skin texture with restructuring of elastic fibers after grafting of cultured
epidermal autografts to treat tattoo excision wounds or burn scar excision wounds (50)
(51); normalization of keratinocyte differentiation in the epidermis occurred
concomitantly (50, 52).
Role of fibulin-5 in restructuring of elastic fibers
Elastogenesis is initiated by deposition of microfibrils, which form a template
for tropoelastin deposition (44). Fibrillin is one of the major components of microfibrils
(45). Tropoelastin, a precursor of elastin, is cross-linked by lysyl oxidase and converted
to elastin (44). Fibulin-5 plays an important role in the association of tropoelastin with
microfibrils (47, 53). We found that dermal fibroblasts overexpressing human fibulin-5
cDNA facilitated deposition of elastic fibers, suggesting that fibulin-5 is a critical
component in the control of elastic fiber assembly by dermal fibroblasts.
Conclusion
We have focused on MMPs, uPA/plasmin, heparanase, and laminin 332 in the
epidermis, structural damage of the BM, and fibulin-5 in elastic fibers in the dermis as
key factors associated with photoaging of skin. The epidermal changes directly or
indirectly induce BM damage and dermal deterioration, and accelerate the aging process.
Therefore, an effective approach to ameliorate photoaging might be to modulate the
production or activity of the above factors. The BM at the DEJ plays important roles in
maintaining a healthy epidermis and dermis. Therefore, photoaging might be reduced by
repairing BM damage through increased synthesis of BM components such as laminin
332, or inhibition of enzymes that damage the BM. We also showed that dermal elastic
fibers function to maintain skin surface texture, and therefore reconstruction of dermal
elastic fibers could reduce the appearance of skin aging. Thus, an understanding of the
mechanisms of photoaging offers many opportunities for intervention by means of
appropriate daily skincare.
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Figure Legends
Figure 1 Roles of MMP and uPA/plasmin in BM damage in SE
An MMP inhibitor, CGS27023A, enhances assembly of BM at the DEJ in SE (b)
as compared to the control without inhibitor (a). Addition of plasminogen damaged BM
structure (c). Aprotinin, a plasmin inhibitor, restores the assembly of BM structure at the
DEJ (d).
11
Figure 2 Role of heparan sulfate chains in assembly of BM structure.
β4 Integrin (a) and BP180 (b) were polarized to the basal surface, while
deposition of collagen VII (c) was polarized to the basal side and increased by
combined treatment with MMP inhibitor and heparanase inhibitor. The inhibitors
facilitated assembly of anchoring complex, especially hemidesmosomes and anchoring
fibrils (arrows), as observed by transmission electron microscopy (d).
Figure 3 Schematic illustration of skin-damaging mechanisms associated with
photoaging due to repeated UV exposure
12