DERMATOLOGIC THERAPY - Endogenous growth factors as cosmeceuticals.

DERMATOLOGIC THERAPY  

Endogenous growth factors as cosmeceuticals

RAHUL  C. MEHTA * & RICHARD  E. F ITZPATRICK †
* Research and Development, SkinMedica, Inc., Carlsbad, California and  † La Jolla Cosmetic Surgery Center, La Jolla, California.

ABSTRACT:

Growth factors play an important role in reversing the effects of skin aging mediated by chronological and environmental factors. Excessive oxidation of intra- and extracellular components result in breakdown of collagen and elastin network in the dermis and produce the effect of facial aging. Topical application of human growth factors in multiple clinical studies has been shown to reduce the signs and symptoms of skin aging, including statically significant reduction in fine lines and wrinkles and increase in dermal collagen synthesis. More double-blind and controlled studies are needed to confirm the preliminary clinical effects of growth factor products, and more controls on product quality and stability need to be established.

Introduction:

Aging of the skin is mediated by a combination of the effects of time (intrinsic aging) and environmental factors (extrinsic aging) on cellular and extracellular infrastructure. These are two independent, clinically and biologically distinct, processes that affect the skin structure and function simultaneously (1,2). Growing evidence now suggests that the two aging processes have converging biochemical and molecular pathways that lead to photoaging of skin (3,4). The common mechanisms of the two aging processes may provide several unique opportunities to develop new antiaging therapies. Recent advances in understanding the role of endogenous growth factors in the aging process provide one such opportunity to develop novel antiaging cosmeceutic products. 


Intrinsic and extrinsic aging of skin:
 
Intrinsic or sun-protected aging of skin is mediated by the “biologic clock” that affects the skin in the same manner as it affects the internal organs, i.e., by slow, irreversible tissue degeneration. Telomere shortening combined with metabolic oxidative damage is believed to play a major role in the intrinsic aging process (5). Intrinsic aging affects everyone at different rates based on genetic factors (6). Intrinsically aged skin is thinner, more evenly pigmented, shows higher laxity, and less fold accentuation as compared to photoaged skin. Extrinsic aging is mediated by environmental factors including exposure of skin to solar UV radiation and environmental pollutants. Photoaged skin usually shows coarseness, wrinkling, sallow discoloration, telangiectasia, elastosis, irregular pigmentation, and a variety of benign, premalignant and malignant neoplasm (3). Intrinsic and extrinsic aging are cumulative processes that occur simultaneously, and over time result in photoaging. Histologic evaluations show that sun-protected skin contains a lower number of fibroblasts, flat epidermal–dermal interface with loss of the dermal papillae, elevated levels of partially degraded collagen, and irregularly thickened, fragmented, and disorganized elastic tissue network (7,8). It also shows a reduction in total elastin content and ability to synthesize type I procollagen as compared to young skin (8,9). Photoaged skin shows a statistically significant decrease (20%) in total collagen as compared to sun-protected skin 

FIG. 1. Biochemical pathways of intrinsic and extrinsic aging leading to the symptoms of photoaging.

(10–12). Photoaged skin also shows marked elastosis with thickened, tangled, and amorphous elastic structures containing fragments of elastin and collagen that replace degenerating collagenous meshwork (8,13–17). The mean epidermal thickness appears to decrease with age in either sunprotected or photoaged skin (18,19).

Biochemical pathways of skin aging:
 
Extensive research in the area of photoaging over the past decade has resulted in an improved understanding of the molecular mechanism of the aging process. FIGURE 1 shows a summary of major pathways involved in the aging process. Absorption of UV radiation by chromophores in the skin results in formation of reactive oxygen species (ROS) including superoxide anion and hydrogen peroxide. Normal oxidative metabolism (mitochondrial oxidative energy generation) also results in formation of excess ROS (20,21). ROS play a central role in intrinsic and extrinsic aging by increasing oxidative phosphorylation of cell surface receptors causing activation of one or more components of MAP kinase signaling pathways resulting in activation of transcription factors activator protein 1 (AP-1) and nuclear factor-kappa B (NF κ B) (22–25).
AP-1 stimulates transcription of matrix metalloproteinase (MMP) growth factor genes in fibroblast and keratinocytes, and inhibits type I procollagen gene expression in fibroblasts (10). Multiple studies have shown that activation of the MMP secretion as a result of intrinsic and extrinsic aging produces breakdown of dermal matrix (14,26,27). Different subtypes of MMP have different substrate proteins on which they act to produce a break in their primary sequence. MMP-1 (collagenase) produces cleavage at a single site in central triple helix of fibrillar type I and type III collagen. The cleaved subunits are further degraded by MMP-3 (stromelysine 1) and MMP-9 (gelatinase). Activity of MMP is decreased by binding with tissue inhibitors of metalloproteinase (TIMP). ROS inactivates TIMP thereby increasing MMP activity. AP-1 mediated reduction in synthesis of procollagen appears to result from two mechanisms, interference of AP-1 with type I and type III procollagen gene transcription and blocking the profibrotic effects of TGF β  by impairment of TGF β  type II receptor/ smad pathway (28). Activation of NF κ B stimulates transcriptions of proinflammatory cytokine genes including IL-1, TNF α , IL-6, and IL-8 (29). Inflammation resulting from these cytokines increases secretion of ROS and more cytokines further enhancing the effect of UV exposure. Inflammation causes protease

FIG. 2. Healing and remodeling of skin damaged by the effect of intrinsic aging, extrinsic aging, wound, or laser procedures.

mediated degradation of elastin and UV exposure causes formation of abnormal elastin by fibroblasts (19). UV light is also an inhibitor of leukocyte elastase thereby increasing accumulation of elastotic materials (30). The accumulation of elastotic materials is accompanied by degeneration of surrounding collagenous network (14). The overall effects of these interlinked biochemical activities is reduction of procollagen synthesis, increase of collagen degradation in the dermal extracellular matrix, and increase in irregular elastin deposition.


Growth factors as adjuncts to procedure:

Laser resurfacing rejuvenates skin primarily by producing controlled wounds to localized area,

FIG. 3. Visible reduction is periorbital wrinkles in 3 months with continued improvements for 6 months in a patient using TNS Recovery Complex twice daily for 60 days.

FIG. 4. Mean of facial wrinkle and texture scores as a function of time as assessed by investigators. The scores are baseline, after 30 days, and after 60 days of twice daily use of NeoCutis Bio-Restorative Skin Cream. (n = 18). (39)

which is followed by inflammation and healing resulting in stimulation of cytokine-mediated dermal collagen formation and structural remodeling of superficial dermis (45,46). Histologic studies have shown degrees of grenz zone collagen with laser rejuvenation similar to those with treatment
using topical retinoids, vitamin C and growth factors. For noninvasive, nonablative laser resurfacing, the post-treatment application of growth factors in a topical formulation may provide benefit in accelerated or improved wound healing. Laser resurfacing also alters the barrier properties

of skin and may allow greater penetration of growth factors immediately postprocedure. Therefore, combining growth factors with laser resurfacing should not only improve postprocedure recovery time but also provide a synergistic effect on skin rejuvenation. Growth factors are also useful in the preprocedure period to condition the skin and allow for a more robust rejuvenating response to laser resurfacing. 

Conclusion:

Aging of skin mediated by the effect of time and environmental factors shows a common molecular pathway involving reactive oxygen species. Aging results in loss of dermal collagen and accumulation of unorganized collagen and elastin in the dermis, resulting in formation of wrinkles, elastosis, and loss of skin tone. The process of reversing some of the effects of aging can be accelerated by use of topically applied growth factors that accelerate wound healing. Although it is unclear how large proteins such as growth factors actually penetrate the site of action, results of multiple clinical studies and continued marketplace success of products containing growth factors show the beneficial effects of these cosmeceutic products on reducing the signs and symptoms of facial skin aging. More double-blind and controlled studies are needed to confirm the preliminary clinical effects of growth factor products and more controls on product quality and stability need to be established. Synergistic effects of growth factors with other noninvasive procedures and other cosmeceutic products should also be evaluated further.