Emollients are the cornerstone of the treatment of dry skin conditions6 and are typically delivered in over-thecounter (OTC) moisturizers. Today, consumers and dermatologists can choose from a plethora of moisturizers. Each contains a combination of ingredients designed to treat or ameliorate the symptoms of dry skin. The so-called active ingredients in basic OTC moisturizers can be categorized into three classes: (1) emollients, which soften and smooth the skin; (2) occlusives, which provide a barrier that sits on the surface of the skin and prevents transepidermal water loss; and (3) humectants, which bind and hold water in the stratum corneum.2 Urea is a well-known humectant that for decades has been included in moisturizers to improve skin hydration.7 Lactate is another humectant used in a number of moisturizers. More recently, some moisturizing formulations have included various amino acids, pyrrolidone carboxylic acid (PCA; a potent humectant), and salts. The ingredients urea, lactate, amino acids, and PCA are part of a group of components collectively called natural moisturizing factor (NMF), which exist in normal skin.
NATURAL MOISTURIZING FACTOR
The term “natural moisturizing factor” first appeared in English-language publications in 1959, coined by Jacobi and colleagues.8 The term was not universally adopted at first, with many early articles referring to “naturally occurring humectants”9 or “hygroscopic water soluble substances.”10Studies reporting the discovery of the NMF in the epidermis refer to “water-soluble compounds” or ingredients11-13 whose removal decreased water-binding capacity,10 indicating that while its exact composition and origin were unknown, it was apparent that it was involved in water binding in the stratum corneum.
The role of the NMF is to maintain adequate skin hydration. Adequate hydration of the stratum corneum serves three major functions: (1) it maintains plasticity of the skin, protecting it from damage3; (2) it allows hydrolytic enzymes to function in the process of desquamation14,15; and (3) it contributes to optimum stratum corneum barrier function.
The NMF is composed principally of free amino acids, and various derivatives of these amino acids such as PCA, urocanic acid (a natural absorber of ultraviolet [UV] light), and inorganic salts, sugars, as well as lactic acid and urea (Table 2).15,16 Inorganic salts identified include the chlorides, phosphates, and citrates of sodium, potassium, calcium, and magnesium.17 The NMF is packaged within the corneocytes, making up approximately 10 percent of the corneocyte mass18 and 20 percent to 30 percent of the dry weight of the stratum corneum.19
NMF components are highly efficient humectants that attract and bind water from the atmosphere, drawing it into the corneocytes.14 This process can occur even at a relative humidity as low as 50 percent, allowing the corneocytes to maintain an adequate level of water in low-humidity environments. 14 The water absorption is so efficient that the NMF essentially dissolves within the water it has absorbed.14 Hydrated NMF (particularly the neutral and basic amino acids) forms ionic interactions with keratin fibers, reducing the intermolecular forces between the fibers and thus increasing the elasticity of the stratum corneum.20 This elasticity serves to make the skin appear healthy and supple and to help prevent cracking or flaking due to mechanical stress.14 In addition, the NMF allows the corneocyte cells to balance the osmotic pressure exerted by the intracellular “cement” surrounding them.21 Keeping the solute concentrations balanced is important for preventing excessive water influx, as seen in the wrinkled skin of someone who has been in the bath too long, or water efflux, which would cause the corneocytes to shrink.
Traditionally, the stratum corneum is thought of as nonviable
tissue. While this is true, the stratum corneum is a
dynamic structure in which numerous enzymes still function,
and these enzymes require a certain amount of liquid
water to perform. NMF water binding provides much of this
necessary water. Many of these enzymes are involved in the
process of desquamation, breaking the various bonds and
forces holding the corneocytes together in the most superficial
layers of the skin. Research shows the activity of these desquamatory enzymes is affected by water levels within the
tissue.15 Reductions or the lack of NMF have been correlated
with various stratum corneum abnormalities that manifest
clinically as areas of dry skin with scaling, flaking, or even fissuring
and cracking. These conditions include AD, psoriasis,
ichthyosis vulgaris, and xerosis.22-24 In AD, it has been shown
that the reduction in NMF levels is a global feature,25,26
while in psoriatic skin and ichthyosis, the NMF is essentially
absent.15,27 Reduced NMF levels are also seen in more common skin conditions such as xerosis.28 Routine soap washing of the skin has been shown to remove the NMF from
the superficial layers of the stratum corneum.17 In fact, the outermost layers typically show reduced NMF levels, largely
due to bathing or exposure to UV light.17 In addition, aging appears to dramatically reduce the amino acid content in
the stratum corneum.28 Studies have shown a significant
correlation between the hydration of the skin and its amino
acid content.23 All of these conditions show characteristics
of abnormal desquamation, with the accumulation of corneocytes
resulting in the visible dryness, roughness, scaling,
and flaking properties of dry skin.15,29 The source of NMF was a topic of intense research for a
considerable time. Numerous studies on urocanic acid and
PCA had determined that these compounds were derived
from amino acids in the stratum corneum—an area containing
only dead cells and therefore presumed to contain
no active enzymes.9,30-32 Today,
the stratum corneum is recognized
as biologically dead but
biochemically very active.33
An analysis of the amino acid
composition of the stratum
corneum eventually led to
the realization that the NMF
components were breakdown
products from the proteolysis
of the filaggrin protein.34 Filaggrin is a large, histidinerich
protein localized in the
newly formed corneocyte layer
above the granular layer.35 Its
function, as the name suggests,
is to aggregate filaments.
Specifically, filaggrins align epidermal
and inner root sheath
keratin filaments into highly
ordered linear arrays, or macrofibrils
(Figure 1).36,37 Filaggrin starts out as a high-molecular-weight precursor
called profilaggrin, located in the keratohyalin granules
of the granular layer.35,38 As the granular cells differentiate into cornified cells, the profilaggrin is dephosphorylated and degraded into the highly basic, lower molecular weight filaggrin.35 It is at this stage that filaggrin works to aggregate filaments, catalyzing the formation of disulfide bonds between the keratin fibers.36 These aggregated fibers are part of the envelope that surrounds cells entering the stratum corneum, allowing them to maintain the extremely
flattened shape characteristic of corneocytes.34 However, the formation of filaggrin is not the end of the
process, nor is keratin aggregation filaggrin's only function.
Filaggrin continues to be degraded almost immediately
after the keratin fibers are formed.35 One of the first steps in this degradation process is the conversion of arginine
residues in the filaggrin molecule to citrulline. This process
increases the acidity of the filaggrin molecule, resulting in
the loosening of the filaggrin/keratin complex and increasing
the access of proteolytic enzymes.35 At this point, the
filaggrin molecules are completely degraded into their
respective amino acids and derivatives, making up 70
percent to 100 percent of the free amino acids and their
derivatives present in the stratum corneum.34 The conversion of filaggrin to NMF occurs as the corneocytes
are moving to the more superficial layers of the
stratum corneum. The timing and exact depth in the
stratum corneum of filaggrin processing is dependent on
the water activity within the corneocyte and the external relative humidity. In a humid environment where there are
no drying effects, the hydrolysis of filaggrin occurs almost
at the outermost surface. In low humidity, the proteolysis
occurs at deeper layers where the NMF works to prevent
desiccation of the skin.15,39 It has been demonstrated that occlusive patches applied to the skin can prevent filaggrin
degradation altogether.39 Conversion of filaggrin to
NMF is also controlled by the water activity within the
corneocyte, and only occurs within a narrow range—if the
water activity is too high, the filaggrin is stable, while if it
is too low, the hydrolytic enzymes will be unable to function
and degrade the filaggrin.15 Thus, the skin's hydration
status influences the degradation process of filaggrin. It
should also be noted that the creation of NMF creates
tremendous osmotic pressure from within the corneocyte.
Therefore, the degradation process does not occur until
the corneocytes have matured and strengthened and
migrated toward the more superficial layers of the stratum
corneum, where the surrounding lipids and other extracellular
components balance this osmotic pressure.15 While the importance of the NMF in skin hydration has
been understood by some skin researchers since the 1960s
and its relationship to filaggrin processing determined in
the 1980s, the full significance of this association has only
been appreciated with the recent identification of filaggrin
loss-of-function mutations. Inherited loss-of-function
mutations in the filaggrin gene (FLG) have been shown
to cause moderate-to-severe ichthyosis vulgaris,40 and to
predispose patients to AD,25 including early-onset atopic
eczema that recurs or persists into adulthood.41 In AD,
the levels of PCA, urocanic acid, and histidine have been
shown to be correlated with the FLG genotype, being
reduced in patients carrying various FLG mutations.26
Multiple mutations in the FLG gene have been identified;
just two of these variants are carried by approximately
nine percent of people of European origin, suggesting a
noteworthy prevalence of filaggrin mutations in certain
populations.25 Patients carrying loss-of-function filaggrin mutations have significantly reduced levels of the NMF in
the stratum corneum at all depths.42 In addition, carriers of filaggrin mutations exhibit increased transepidermal water
loss compared with non-carriers.42 Filaggrin proteolysis abnormalities can occur in response
to environmental factors. As already mentioned, low
humidity impairs the ability of hydrolytic enzymes to break
down filaggrin into NMF, thus generating skin surface dryness.
In addition, UV radiation has been shown to impair
the natural breakdown of filaggrin to its NMF components.
19 NMF levels in the skin decline with age. This decline
in NMF has been attributed to the decreased synthesis of
profilaggrin and a decline in barrier function in the elderly.17 Approximately one-third of water contained within the
stratum corneum is bound, with the remainder being
free water. Increasing the level of free water has no effect
on the elasticity of the stratum corneum.20 Thus, it is the NMF-bound water that provides the skin with its elastic
qualities. Replacing or replenishing the supply of the NMF
in the skin through the external application of moisturizers
containing NMF appears to be a successful approach for
the treatment of xerotic skin. Several NMF components have been used for decades in
moisturizing vehicles without a true understanding as to
why they are effective. For example, urea has been included
in moisturizing creams as far back as 1943.15 However, skin urea levels, which are now known to be reduced in patients
with AD and in elderly skin43,44 were not measured in normal and atopic patients until 1966.45 Topical application of urea or its precursor arginine has been shown to correct these urea deficits.6,43 Lactate was first reported to be used in a moisturizer as a treatment for ichthyosis in 1946. It has been shown to improve and prevent the reappearance of
symptoms of dry skin compared with lactate-free moisturizers.
15 L-lactic acid and D,L-lactic acid appear to work by
stimulating the synthesis of ceramides in the stratum corneum.
46 PCA is the most prevalent single component of the NMF and has been shown to be reduced in the outermost
layers of the skin as a consequence of soap washing and/or
age. Topical application of PCA has been widely reported to
alleviate the symptoms of dry skin.15 NMF components are of key importance in the maintenance
of adequate skin hydration. The water they bind
provides healthy skin with appropriate elasticity and allows
hydrolytic enzymes of desquamation to function correctly.
Reduced levels of the NMF have been found in many disorders
such as AD, psoriatic skin, ichthyosis, and general
xerosis, a consequence, in some cases, of filaggrin loss-offunction
mutations. Many of these disorders show abnormal
desquamation. Environmental changes and advanced
age can also result in lowered NMF levels. The NMF may
be reduced by decreased production or processing of
filaggrin, or by excessive bathing or exposure to UV light.
Several NMF components have long been used in moisturizers
to successfully treat xerosis. Thus, there is evidence to
support the incorporation of additional NMF components
into treatments for xerosis and other skin conditions that
can result in dry, flaky skin. Over the past 50 years, research
has provided us with a greater understanding of the degradation
and processing of filaggrin, and the genetic and
environmental factors that influence both the presence
and function of filaggrin and the NMF. We can now more
fully recognize the importance of the NMF in healthy and
diseased skin, and the beneficial clinical role that these
humectant substances can have as therapeutic agents.SOURCE OF NMF: FILAGGRIN
ROLE OF NMF IN TREATING XEROSIS
CONCLUSION
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