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Page 2 of 24 Reilly et al. Plast Aesthet Res 2021;8:2 I http://dx.doi.org/10.20517/2347-9264.2020.153

INTRODUCTION
Synthesis and structure of collagen in skin
Collagen Synthesis by fibroblasts
Collagen provides the support matrix/mattress underpinning healthy skin and is a key determinant to the
[1,2]
preservation of skin firmness and elasticity . Type I is the main collagen found in skin, representing 80%-
90% of skin collagen. It is produced by cells called fibroblasts, which are a mesenchymal cell type, found
[3]
predominantly in the dermis . Fibroblasts also produce elastin protein which gives skin the flexibility to
stretch by facilitating a long-range deformability, followed by a recoil to allow tissues to return to their
[4,5]
original conformation . This is a critical functionality to maintain the skin elasticity and resilience
[Figure 1]. Another product of fibroblast metabolic function is the production of glycosaminoglycans
(GAGs) which are long unbranched heteropolysaccharides such as hyaluronates and dermatan sulphate
(the most abundant GAG in skin). The unique combination of high viscosity, high hygroscopicity and low
compressibility are key to their many functions, including maintenance of the skin’s essential moisture
[6]
content .
Fibroblasts are sensitive to the physical tension of the extracellular matrix (ECM) in which they are
embedded, and to biochemical stimuli and signalling pathways, both of which can induce fibroblast
[7]
activation and proliferation . Small molecular weight, diffusible ligands can bind to receptors located on
the fibroblast extracellular membrane inducing their activation. Physical tension in the ECM can directly
cause activation of mechanoreceptors and anchoring fibrils of the inherent cytoskeletal framework and
[8]
initiate signalling pathways involved in cell-to-ECM communication . The activation of fibroblasts results
[9]
in an increase in the production of collagen, elastin and associated GAGs .
Many anti-ageing strategies are targeted at influencing production of ECM components by fibroblasts. A
wide range of ligands can influence fibroblast proliferation and activation, including bioactive peptides,
antioxidants, retinoids, vitamins, ω6- and ω3-fatty acids, growth factors, hydroxy acids and a bewildering
array of botanical extracts [10-12] . A common theme for the majority of these ingredients is that they can
influence, either directly or indirectly, the production of collagen and ECM components.

From early adulthood, fibroblasts become less active and collagen production declines by about 1.0%-
1.5% a year [13,14] . This can also be aggravated by certain lifestyle choices like smoking and external factors
[15]
like sun exposure . Ongoing sunlight and pollution exposure and reduced efficiency in eliminating
free radical chemicals add to the damage. Many studies have shown that if collagen peptides (and other
active compounds) are ingested they will travel throughout the body, including to sites where fibroblasts
are present. This stimulates fibroblasts to produce more collagen, elastin and hyaluronic acid, thereby
rejuvenating skin and other tissues. This mechanism is key to the successful production of collagen
reported in clinical studies following long term supplement use and the consequent reported improvement
in skin elasticity and hydration.

[16]
A recent in vitro study from Edgar et al. has shown that hydrolysed collagen peptides significantly
increase collagen and elastin synthesis by fibroblasts while significantly inhibiting the release of two
collagenases, namely metalloproteinase-1 (MMP-1) and MMP-3. The research primarily investigated the
interactions between collagen peptides and other constituents (including GAGs and antioxidants) present

in the hydrolysed collagen-based nutraceutical, Gold Collagen®Forte, on normal primary dermal fibroblast
function. The effects of the addition of collagen peptides, alone or in combination with other bioactive and
antioxidant constituents, were tested and compared to the effect of media alone. The increase in collagen
and elastin synthesis was accompanied by a decrease in the activity of MMP enzymes. MMP enzymes are
responsible for matrix breakdown and elastin degradation and an increase in MMP activity is associated
with UV-irradiation and reactive oxygen based free radical damage to the ECM components [17,18] . The