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Cutaneous effects of topical tretinoin on cellular level

Tretinoin from the time when it was developed (in sixties) is the most studied retinoid. It plays a role in the treatment of photoaging, acne as well as in some types of hair loss managements. Photoaging of the skin is one of the most important factors in premature skin aging. Topical retinoids offer a powerful class of medications which efficacy is scientifically proven. Aging of the skin can be a result of many factors but to simplify the issue the causes can be divided into two groups:
- Genetic predisposition (intrinsic ageing)
- Environmental causes (extrinsic ageing)
Intrinsic ageing, chronologic ageing, it is the rate at which people age, which is largely determined by their genetics, but also gravity and hormonal variations. All the changes of the skin due to chronologic ageing are physiological and include: increased skin laxity, redistribution of the fat, appearance of wrinkles, expression and sleep lines, as well as benign neoplasms like seborrheic keratoses and cherry angiomata.
Extrinsic ageing means influence of environmental factors on the aging of the skin. It is often called photoaging as out of all environmental causes of aging ultraviolet radiation is the most important element. Other factors of the extrinsic ageing include smoking, exposure to the wind or chemicals. Sun exposure is the most important of UV radiation but other sources like tanning beds, phototherapy and even fluorescent light must not be forgotten. Many of the characteristic typical for intrinsically aged skin are much aggravated by photoaging.
The signs of photoaging of the skin include: increased appearance of wrinkles (fine and coarse), increased laxity, irregular pigmentation, hyperplasia and later atrophy, telangiectasia, fat redistribution, solar lentigines, a sallow colour and leather like appearance. The damage of keratinocytes results in development of actinic keratoses. There is an enlargement of pores filled with horny material observed which can lead to Favre-Racouchot’s syndrome (nodular elastoidosis with cysts and comedones). Many of neoplasms are observed, some of them include:
- Benign: seborrheic keratosis, fibromas, cherry spots
- “Premalignant”: lentigo maligna, actinic keratosis
- Malignant: melanomas, squamous and basal cell carcinomas
On histological and cellular level aged skin shows so called epidermal polarity; keratinocytes, mostly in the lower epidermal layers, show atypia. At early stage the viable epidermal layers are hypertrophic but at later stage become atrophic.
The dermis undergoes even more dramatic changes: degeneration of collagen and elastic fibers, decreased number of collagen fibers, deposits of elastotic material, so called solar elastosis and decreased amount of GAG (glycosaminoglycan) needed for hydration, changes in microcirculation leading to telangiectasia. Due to UV radiation there is decreased number of antioxidant enzymes and due to solar elastosis the elasticity of the skin is markedly decreased.
The end result of photoaged skin presents with loss of volume of water and increased amount of damaged elastic fibers creating solar elastosis (heliosis). The zone between epidermis and deposits of elastotic material is called border zone (grenz) and consists of normal appearing collagen fibers. Most of the methods to improve photoaged skin target this area of the dermis.
Retinoids are a large family of retinol (vitamin A) and its natural and synthetic derivatives. They are classified as
- First generation – retinol, retinal, tretinoin, isotretinoin, alitretinoin
- Second generation- etretinate, acitretin
- Third generation- tazarotene, bexarotene, adapalene
There are many studies proving the effectiveness of topical tretinoin on photoaged skin. There are evident positive antiaging results at macroscopic, histological and cellular levels.
It is well documented that on the molecular level tretinoin
- Enters the eukarotic cell though endocytosis
- CRABP (cellular retinoic acid-binding protein) transfers the tretinoin molecule to the nucleus ( in human skin the CRABP type II plays predominating role)
- At the nucleus tretinoin binds to retinoid receptors: RAR (retinoic acid receptors) and RXR (retinoid X receptors) and stimulates formation of homo- or heterodimer receptor complexes. The discovery of the receptors indicates that tretinoin works as a hormone.
- Homo/heterodimer receptor complexes bind to specific DNA sequences in gene region known as retinoid response elements (RRE) which stimulates transcription of “retinoid-sensitive” gene. The transcription can be regulated by activation or inhibiting transcription factors like activator protein-1.


The below summary illustrates the mechanism of action of retinoid (R) at the cellular level (3)

Retinoid ( R)  endocytosis in cytoplasm (R) binds with CRABP  in nucleus (R) binds with RXR and RAR  formation of homodimer and heterodimer receptor complexes homo and heterodimer complexes bind with DNA in RRE ( retinoid response elements) Transcription of retinoid “sensitive gene” modification of cellular functions
The cutaneous effects of tretinoin on photoaged skin can be described in below points:
1. Topical tretinoin blocks activator protein-1 (AP-1) therefore inhibits degradation of collagen in the dermis. This is achieved by inhibition of AP-1 (activator protein-1) which activates the collagen-degrading MMPs.
2. Retinoids are able to stimulate the synthesis of new collagen (type I procollagen and collagen type III and VII) and replace elastotic material with the newly synthetized collagen. This process is accomplished by blocking UV-induced c-Jun and alteration in the TGF-beta expression.
3. Through improved vascularity (angiogenesis) and blood flow tretinoin improves repair processes.
4. Through deposition of glycosaminoglycans in the epidermis as well as alteration of proliferation and thickening of epidermis tretinoin can improve wrinkles and skin smoothness.
5. Inhibition of tyrosinase activity as well as blocking of melanosome transfer causes decreased content of melanin with increased keratinocytes shedding what macroscopically is observed as improvement in irregular pigmentation.

Studies on tretinoin found that after
- 1 month of treatment there was noticeable compaction of stratum corneum with fading of dysplasia and atypia. At this stage there were no significant changes in the dermis
- 3 months of treatment, wrinkles were improved and epidermis became thicker
- 4 months of treatment compaction of stratum corneum was clearly documented as well as increased amount of GAGs (glycosaminoglycans) therefore improvement of wrinkles and roughness of the skin.
- 6 months of treatment mottled pigmentation, sallowness, skin texture and laxity were improved as well as significant improvement in wrinkles was observed.
- 12 months of treatment new collagen fibers were formed and nodularity of degraded microfibrillar material was reduced.
Studies clearly indicated that long term treatment with tretinoin is required in order to achieve desirable effects.
In chronological (intrinsic) aging tretinoin also plays a role. After applying tretinoin for 9 months on the skin of an inner thigh, the below histological changes were observed:
- Decreased vacuolization of melanocytes
- Increased epidermal and granular thickness
- Presence of anchoring fibrils at the level of dermo-epidermal junction
- Angiogenesis
- Synthesis of elastic material and GAGs.
Clinically the above changes were manifested as modest improvement of the skin in form of less scaly and less wrinkled skin with mild improvement in firmness.
Role of tretinoin in acne
In mild to moderate acne tretinoin is beneficial in treatment for its comedolytic benefits as well as promoting the normal flow of sebum and stimulating the new cells growth, but mostly tretinoin is used for its anti-inflammatory properties.
Acne vulgaris belongs to inflammatory dermatoses. It all starts at the pilosebaceous unit which consists of follicle (pore), sebaceous gland and vellus hair. At first an inflammatory response anticipate the hyperkeratinization of the follicle, then sebaceous gland hyperplasia leading to excess of sebum production is observed. Next altered epithelial growth and differentiation in the follicle is seen as well as overgrowth of Propionibacterium.
Keratinocytes synthetize chemokines and cytokines; they induce movements of lymphocytes to the infected area. In the presence of P. acnes many other inflammatory responses take place and they include activity of lipase, hyaluronidase, protease, neuraminidase, CD 4 cells, monocytes, neutrophils, leukotrienes, compliment etc. Sebum becomes rich of pro-inflammatory lipids.
The inflammatory processes damage the wall of the follicle and further lead to formation of papules, pustules and inflamed nodules.
Tretinoin is able to enhance as many as 17 immunomodulatory effects classified as anti- inflammatory
The comedolytic properties of Tretinoin include:
- Normalization of exfoliation of the epithelium in the follicle
- Inhibition of activity of transglutaminase resulting in cellular adhesion
- Prevention of follicular plugging
- Assisting in drainage of the excess of sebum
- Assisting in establishing an aerobic environment which is unfavorable for growth of P.acne.
In hair loss treatments retinoids (tretinoin) can play an important role by controlling the cycle of the hair growth as well as by regulation of differentiation as well as maintenance of hair follicles. Well known properties of Tretinoin in regulation of cell proliferation and differentiation in the epidermis as well as angiogenesis are important factors in treatment of alopecia.
Synergistic effect is observed when applied with minoxidil. Tretinoin augments absorption of minoxidil by enhancing permeability of the stratum corneum.
In summary, the cutaneous effects of tretinoin on cellular level can be quoted:
“tretinoin is a potent biochemical modulator capable of eliciting changes in the gene expression pattern by regulating the activity of transcription factors as well as influencing epithelial cell proliferation and differentiation”. (1)
“Epidermal and dermal thickening, stimulation of keratinocytes as well as increased production of GAGs and collagen in the dermal layer leads to smoothing of the skin and improves wrinkles. “ (1) In acne “tretinoin’s immunomodulating properties suggest that it possesses five important comedolytic-related properties that can be considered anti-inflammatory in natures, as well as 17 other potential activities that may beneficially temper the inflammatory cascade of acne and the production of inflammatory vectors associated with it.” (5)
In alopecia- “retinoids increase the rate of hair growth, prolong the anagen phase of the hair cycle, play a role in converting vellus to terminal hairs, and act synergistically with minoxidil to produce more dense hair regrowth”. (7)
Finally in more simple words it can be said that tretinoin:
- Activates DNA and by normalizing gene expression affects cell differentiation and keratinization in the pilosebaceous units, prevents comedone formation and initiates lysis of present comedones.
- Inhibits activated by P. acnes toll-like receptors therefore has anti-inflammatory properties
- Affects cell differentiation and growth, improves vascularity, helps to improve irregular pigmentation, increases collagen productions as well as inhibits collagen degradation, therefore has a positive effect in reversal of signs of photoaging
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References
1. Ahluwadia G., “Cosmeceuticals” in Kim J., Lask G., Nelson A., 2012 Comprehensive Aesthetic Rejuvenation: A Regional Approach. Informa Healthcare

2. Mukherjee S., Date A., Patravale V., Korting H.C., Roeder A., Weindl G., 2006 Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety Clinical Intervention in Aging 1(4):327-348

3. Darlenski R., Surber C., Fluhr J.W. 2010 Topical Retinoids in the Management of Photodamaged Skin: From Theory to Evidence-based Practical Approach The British Journal of Dermatology 163(6):1157-1165 www.medscape.com Retrieved 17.09.2015

4. Abrishami M., Batra S., Rohrer T.E., “Aging and photoaging” in Kaminer M.S. Arndt K.A., Dover J.S., Rohrer T.,E., Zachary C.B., 2009 Atlas of Cosmetic Surgery, Saunders Elsevier

5. Schmidt N., Gans E., 2011 Tretinoin: A Review of its Anti-inflammatory Properties in the Treatment of Acne. The Journal of Clinical and Aesthetic Dermatology 4(11);22-29

6. Kwon O.S., Pyo H.K., Oh Y.J., Lee S.R., Chung J.H., 2007 Promotive Effect of Minoxidil Combined with all-trans Retinoic Acid (tretinoin) on human Hair Growth in Vitro Journal of Korean Medical Science 22(2):283-289

7. Terezakis N.K., Bazzano G.S., 1988 Retinoids: compounds important to hair growth. Clinical Dermatology 6(4):129-31