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Aesthetic Dermatology
Figure 1: Effects of Ultraviolet on Epidermal Growth the transforming growth factor-beta (TGF-β) pathway. In human skin,
Factor Receptor Pathway
TGF-β induces synthesis and secretion of both collagen and elastin.
19
It
also inhibits enzymes that break down collagen, including MMP-1 and
MMP-3. TGF-β exerts its action by binding to its cell surface receptor
complex, which is typically composed of TGF-β receptor proteins type I
(TβRI) and II (TβRII).
20
When TGF-β binds to TβRII within this complex, it
ROS
activates the intrinsic serine–threonine kinase activity of TβRI and
(H2o2 OH) phosphorylates transcription factors Smad2 and Smad3, which can
then combine with Smad4, translocate into the nucleus and regulate
EGF-R tyrosine phosphatase genes, including type I collagen.
21
UV irradiation results in
downregulation of TβRII within eight hours (see Figure 2). This prevents
downstream phosphorylation of Smad2 and Smad3, as well as
EGF-R- P EGF-R
subsequent expression of type I procollagen.
20
UV irradiation also
(constitutively active) (physiological) induces expression of Smad7, which acts as a negative regulator of
Smad2 and Smad3.
22
Activation of Smad7 by UV is actually mediated by
MAP kinase
(ERK, JNK, p38)
AP-1; therefore, AP-1 has the direct effect of inducing MMPs that can
break down collagen, and also has the indirect effect of downregulating
AP-1
collagen production through Smad7 (see Figure 3).
23
To sum up, AP-1
effects a ‘double hit’ on collagen levels in the dermis: it increases
MMPs
collagen breakdown and decreases the production of new collagen.
Collagen breakdown
UV exposure is typically episodic. After each exposure to UV radiation,
Ultraviolet (UV) irradiation results in the upregulation of reactive oxygen species (ROS), which
the skin repairs itself and its collagen with a micro-scar. Initially, these
oxidise epidermal growth factor receptor (EGFR) tyrosine phosphatase, rendering it inactive.
As tyrosine phosphatase is not actively removing phosphate from the EGFR, the receptor is
micro-scars are clinically undectectable. However, with repeated UV
rendered constitutively active, with subsequent upregulation of mitogen-activated protein
insults, these micro-scars accumulate and are thought to eventually
(MAP) kinases, activator protein 1 (AP-1), matrix metalloproteinases (MMPs) and, eventually,
increased collagen breakdown.
result in wrinkles and other clinical features of photoageing. Photoaged
skin is also characterised by an approximately 50% reduction in mature
Figure 2: Effects of Ultraviolet on Transforming Growth
intact collagen.
24
However, fragmented collagen is elevated by about
Factor-beta Pathway
four-fold compared with sun-protected skin.
25
In cell culture, this
reduction in intact collagen can be corrected, indicating that
the deficiency is not due to defective fibroblasts. Rather, in vivo the
fibroblast does not make adequate collagen.
25
In addition, fibroblasts in
photodamaged skin are under less mechanical tension than fibroblasts
TβRII in healthy sun-protected skin. In healthy skin, an interstitial fibroblast is
surrounded by and in contact with substantial amounts of intact
Smad2/Smad3- P
collagen. It is attached to the surrounding collagen at many contact
sites; these points of contact generate isometric tension in all directions,
resulting in a flattened shape. This increase in mechanical tension on the
Procollagen I
fibroblast leads to increased collagen production and decreased
Ultraviolet (UV) irradiation results in downregulation of transforming growth factor-beta
collagenase production.
26
When the surrounding collagen matrix is
(TGF-β) receptor protein type II (TβRII). In turn, this prevents downstream phosphorylation of
Smad2 and Smad3, with subsequent decreased production of procollagen I.
damaged and fragmented, there are fewer contact points; the
fragmented collagen surrounding the fibroblast cannot support much
composed of the proteins c-Jun and c-Fos, and it regulates transcription tension, and the fibroblast develops a collapsed and elongated shape.
24
of several matrix metalloproteinases (MMPs). MMPs are able to degrade In a state of mechanical relaxation, when cells lose contact with the
many extracellular matrix proteins. Several MMPs are upregulated by matrix, the fibroblast is unable to function appropriately so that
AP-1. These include: MMP-1 (collagenase 1), which breaks down types I procollagen synthesis is downregulated and MMP production
and III collagen; MMP-9 (gelatinase B), which further breaks down the increases.
25
In photoageing, characterised by decreases in mature, intact
collagen fragments produced by collagenase; and MMP-3 (stromelysin collagen and increases in fragmented collagen, fibroblasts exist in a
1), which also degrades collagen. In human skin in vivo, expression loose, fragmented framework and are collapsed. Once initiated, this
of these three MMPs is induced by UV irradiation.
15,16
This activation of cycle of degradation of collagen and failure to produce sufficient new
MMPs is accompanied by increased collagen breakdown, which has collagen continues and is self-perpetuating, leading to the thin, fragile
been demonstrated within 24 hours of UV irradiation in human skin in skin characteristic of photoageing.
26
vivo.
16
AP-1 also inhibits collagen synthesis by negatively regulating
transcription of genes that encode type I procollagen.
17
Messenger RNA Molecular Changes Associated with
(mRNA) and protein expression of type I procollagen are decreased Intrinsic Skin Ageing
within eight hours of UV irradiation of human skin in vivo, and become In sun-protected aged skin, AP-1 activity is also increased,
27
as are levels
almost absent in the upper dermis within 24 hours of UV irradiation.
18
of MMP-1 and MMP-9.
5
Levels of degraded collagen are four-fold higher
in aged versus young subjects.
28
Type I procollagen synthesis is also
Whereas UV irradiation destroys collagen via the EGF receptor pathway reduced.
29
This combination of increased collagen degradation and
and AP-1 as described above, collagen formation normally proceeds via decreased synthesis of new collagen results in an overall decrease in
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