Connective-Tissue Alterations in Photoaging: The Role of Matrix Metalloproteinases

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Photoaged skin is characterized by alterations of the dermal connective
tissue. The extracellular matrix in the dermis mainly consists of type I and
type III collagen, elastin, proteoglycans, and fibronectin. In particular,
collagen fibrils are important for the strength and resiliency of skin, and
alterations in their number and structure are thought to be responsible for
wrinkle formation. In photoaged skin, collagen fibrils are disorganized
and abnormal elastin-containing material accumulates [21]. Biochemical
studies have revealed that in photoaged skin levels of types I and III collagen
precursors and cross-links are reduced, whereas elastin levels are
increased [22,23].
How does UV radiation cause these alterations? In principle it is conceivable
to assume that UV radiation leads to an enhanced and accelerated
degradation and/or a decreased synthesis of collagen fibers and our current
knowledge indicates that both mechanisms may be involved.
A large number of studies unambiguously demonstrate that the induction
of matrix metalloproteinases (MMPs) plays a major role in the pathogenesis
of photoaging. As indicated by their name, these zinc-dependent
endopeptidases show proteolytic activity to degrade matrix proteins such
as collagen and elastin. Each MMP degrades different dermal matrix
proteins, for example MMP-l cleaves collagen type I, II, and III, whereas
MMP-9, which is also called gelatinase, degrades collagen types IV and V,
and gelatin. Under basal conditions, MMPs are part of a coordinate network
and are precisely regulated by their endogenous inhibitors, i.e., tissue-specific

inhibitors of MMPs (TIMPs), which specifically inactivate certain MMPs.
An inbalance between activation of MMPs and their respective TIMPs
could lead to excessive proteolysis.
It is now very well established that UV radiation induces MMPs without
affecting the expression or activity ofTIMPs [24,25]. These MMPs can be
induced by both UVB and UVA radiation, but the underlying photobiological
and molecular mechanisms differ depending on the type of irradiation.
In a very simplified scheme, UVA radiation would mostly act indirectly
through the generation of reactive oxygen species, in particular singlet
oxygen, which subsequently can exert a multitude of effects such as lipid
peroxidation, activation of transcription factors, and generation of DNAstrand
breaks [24]. While UVB radiation-induced MMP induction has
been shown to involve the generation of ROS as well [26], the main mechanism
of action of UVB is the direct interaction with DNA via the induction
of DNA damage. Recent studies have indeed provided evidence that
enhanced repair of UVB-induced cyclobutane pyrimidine dimers in the
DNA of epidermal keratinocytes through topical application of liposomally
encapsulated DNA repair enzymes on UVB-irradiated human skin prevents
UVB radiation-induced epidermal MMP expression [10].
The activity of MMPs is tightly regulated by transcriptional regulation,
and elegant in vivo studies by Fisher et aI. have demonstrated that exposure
of human skin to UVB radiation leads to the activation of the respective
transcription factors [27]. Accordingly, UV exposure of human skin not
only leads to the induction of MMPs within hours after irradiation. but
already within minutes, transcription factors AP-l and NFkB, which are
known stimulatory factors of MMP genes, are induced. These effects can
be observed at low UVB dose levels, because transcription factor activation
and MMP-l induction could be achieved by exposing human skin to onetenth
of the dose necessary for skin reddening (0.1 minimal erythema
dose). Subsequent work by the same group clarified the major components
of the molecular pathway by which UVB exposure leads to the
degradation of matrix proteins in human skin. Low-dose UVB irradiation
induced a signaling cascade that involves upregulation of epidermal growth
factor receptors, the GTP-binding regulatory protein p2l Ras, extracellular
signal-regulated kinase, c-jun amino terminal kinase, and p38. Elevated
c-jun together with constitutively expressed c-fos increased activation
of AP-l. Identification of this UVB-induced signaling pathway does
not only unravel the complexity of the molecular basis that underlies
UVB radiation-induced gene expression in human skin, but also provides

a rationale for the efficacy of tretinoin (all-trans-retinoic acid) in the treatment
of photo aged skin. Accordingly, topical pretreatment with tretinoin
inhibited the induction and activity of MMPs in UVB-irradiated skin
through prevention of AP-I activation.
Inaddition to destruction of existing collagen through activation of MMPs,
failure to replace damaged collagen is thought to contribute to photoaging
as well. Accordingly, in chronically photodamaged skin, collagen synthesis
is downregulated as compared to sun-protected skin [28]. The mechanism
by which UV radiation interferes with collagen synthesis is not yet known,
but in a recent study evidence has been provided that fibroblasts in severely
(photo )damaged skin have less interaction with intact collagen and are
thus exposed to less mechanical tension, and it has been proposed that this
situation might lead to decreased collagen synthesis [29].

Author : kaabinet

kaabinet

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