Fibroblast Growth Factors: A Controlling Mechanism Of Skin Aging Part 2

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Growth Factors and Skin Aging

The search for new compounds to prevent or mitigate the aging process has become a priority in the development of new cosmetic assets, which already have a range of options in use, such as antioxidants, retinoids, and alpha-hydroxy acids,anti-metalloproteinases of silicon, and an-ti-glycans [26,27].

Rozman and Bolta [28] and Fitzpatrick and Rostan [29] found that topical application of growth factors resulted in improved photoaging related to the formation of new collagen, epidermal thickening, and improved clinical appearance of the skin with a visible reduction of wrinkles. Thus, the class of growth factors has aroused the interest of cosmeceuticals manufacturers as a promising anti-aging agent, due to studies that evaluated their repair role in cutaneous wounds through action on tissue regeneration, which demonstrated positive cosmetic results against skin photoaging [30], becoming a class widely investigated in the last decade as a skin anti-aging agent.

Growth factors are regulatory proteins that mediate important signaling pathways and act on cell regeneration and repair processes[30]. cistanche stem They act at the cell membrane level, activating a biochemical cascade that pro-motes the transcription of cyclin-dependent kinases in the cell nucleus, the major intracellular molecules that control the process of cell division.

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Growth factors act mainly through binding to tyrosine kinase receptors(Fig.1), which leads to autophosphorylation of the receptor and posterior phosphorylation of serine, threonine, and tyrosine residues of specific target proteins such as Raf-1, MAPK/Erk kinase(MEK) and-intracellular signal-regulated kinase-1(ERK)[13]. These enzymes initiate signaling cascades where each kinase activates the following one by phosphorylation, inducing mitosis and cell division and causing alterations in cellular functions [31].

The Raf-1, MEK, and ERK proteins belong to three families with different nomenclatures. ERK is a member of the MAPK(mitogen-activated protein kinase) family; MEK(extracellular signal-regulated kinase) is part of the MAPKK(mitogen-activated protein kinase) family that phosphorylates and activates ERK-MAPK. Raf-1 is from the family of MAPKKK(mitogen-activated protein kinase kinase kinase) phosphorylase and activates MEK-MAPKK [32].

Thus, by stimulating the proliferation of cells such as fibroblasts and keratinocytes, growth factors play a major role in the skin repair process, inducing reepithelialization through the replacement of disorganized collagen and elastin structures and the reposition of the extracellular matrix in aged skin.

The use of growth factors is a new anti-aging strategy to rejuvenate and reverse the signs of photoaged skin. cistanche tubulosa benefits and side effects Understanding the role of growth factors in wound healing may predict their role in skin infrastructure remodeling and skin rejuvenation [33].

Fig.1.FGFs bind to FGFRs, inducing receptor dimerization, kinase activation, and transference of tyrosine residues from FGFR. This, in turn, leads to the fitting of adapter proteins and the consequent activation of downstream signaling pathways. The activated FGFR2 substrate(FRS2)recruits and activates the RAS-RAF-MAPK and PI3K-AKT pathways involved in cell proliferation and antiapoptotic activity, respectively. cistanche tubulosa extract Activation of PKC and intracellular release of Ca2* are induced by recruitment and phosphorylation of PLCy, events that regulate cell motility.

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FGF in the Control of Skin Aging

The FGF family members increase the proliferation and activation of fibroblasts by stimulating the accumulation of collagen as well as stimulating endothelial cell division. Thus, FGFs stimulate angiogenesis, having an important function in the cell repair process [6,13].

FGFs comprise a growing group of structurally related polypeptide mitogens, which includes 23 different mem-bers.In addition to the previously discovered acid FGF (aFGF,FGF-1)and basic FGF(bFGF, FGF-2),the family also includes int-2(FGF-3).proto-oncogene products (FGF-4),FGF-5,and FGF-6, as well as keratinocyte growth factor(KGF, FGF-7), androgen-induced growth factor(AIGF,FGF-8),GAF(FGF-9),andFGF-10,among others [34].

With the aging process, fibroblasts have their activity diminished and consequently, the synthesis and activity of proteins that guarantee elasticity and resistance such as elastin and collagen are also affected. Thus, in aged skin, there is a lower production of collagen by the fibroblasts and a greater action of the enzymes that degrade it. cistanche tubulosa reviews This lack of balance speeds up the aging process [12,25].

FGF is a family that presents several forms, two of which stand out in the cell signaling process that correlates with aging: fibroblastic acid growth factor(FGF)and basic fibroblastic growth factor(FGF), which affect recruitment, activation, mitogenesis, migration, and differentiation of various cell types. FGF and FGFb are secreted by multiple cell types, such as mast cells, endothelial cells, macrophages, and fibroblasts [35,36].

Most FGFs have a very broad mitogenic spectrum and perform various activities such as stimulating the proliferation of a variety of mesodermal, ectodermal, and en-dodder mal cells and acting as neurotrophic and angiogenic factors in vivo[37]. A study by Werner[34] has shown that FGFa and FGFb stimulate the meso-, endo-, and ectodermal origin of fibroblasts as well as cell proliferation and differentiation through their mitogenic action.

FGF receptors are transmembrane tyrosine kinases with two or three immunoglobulin-like domains and a highly acidic region in the extracellular portion. FGFs bind to tyrosine kinase receptors causing its dimerization and initiating the intracellular signal transduction cascade [38]. cistanche UK Different members of the FGF family can bind to the four different known FGF receptors(FGFR1-FGFR4)with different affinities, and can act in a complementary way, resulting in several biological phenomena such as development [39], differentiation, migration, survival, cell division and proliferation [40], and wound healing [41].

Although the functions of FGFs are well characterized, their mechanisms of action are still not completely clear. It is known that it involves inter-and extracellular signaling pathways that may be related to the RAS-MAP kinases pathways, PI3K-AKT, PLC-y, or STAT. Therefore, FGF cell signaling involves interactions with multiple cell signaling pathways and complex feedback mechanisms[42].

Phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K-AKT)are enzymes that act at different stages of intracellular signal transduction. PI3K/Akt-mediated signal transduction may be initiated by interacting with receptor tyrosine kinases or by binding with the small G protein, Ras[43].In this way, they present a function in regulating the proliferation, migration, survival, and cellular metabolism, as well as in gene expression, calcium flux, inflammatory response, and cytoskeletal rearrangements [44].

Phospholipase C-γ（PLC-y）is an isoform of the PLC family and its activation results in the formation of two products: inositol 1,4,5-triphosphate and diacylglycerol (DAG). The first one induces changes in cytosolic free Ca2+ concentration (Ca2+).is important for the response of agents such as the growth factor, since it is responsible for activating protein kinase C isoforms; the formation of inositol in turn is related to the transient increase in intracellular free Ca2+[45]. The former causes a transient increase in intracellular free Ca2+, while the latter serves as a direct activator of several protein kinase C isoforms and thus is important for the response of agents such as growth factors.

The transcription factor family of signal transducers and transcription activators (STAT)is related to various cytokine signaling pathways, especially those that activate the gp130 membrane receptor. Through the JAK-STAT (Janus-family tyrosine kinase/signal transducer and activator of transcription)signaling pathway, many cytokines and growth factors exert their biological effects. STATs form homo-and heterodimers when phosphorylated, which allows their passage into the nucleus, where they can regulate gene transcription [46].

The pharmaceutical formulations containing growth factors such as FGF have therefore become a dermo-cos-metic option for anti-aging products, as levels of growth factors decrease with the advancement of age, and these, in turn, have functions that are important in the repair of the extracellular matrix [4,13,20].

FGFs Related to the Aging Process

Acid Fibroblastic Growth Factor (FGF-1, FGFa)The activation of FGFs promotes effects that help in the process of aging delay. Activation of FGF-1 improves skin elasticity and induces the synthesis of collagen and elastin[4,13,47].Xie et al.[48]applied FGFatorat ulcers and observed the proliferation and migration of epithelial cells and fibroblast augmentation.

FGF-1 belongs to a large family of growth factors that bind to transmembrane receptors with a cytoplasmic tyrosine kinase domain. FGF-1 is a powerful mitogen involved in the stimulation of the synthesis and proliferation of DNA from a wide variety of cell types, including mast cells, endothelial cells, macrophages, and fibroblasts. It plays important roles in various stages of development and morphogenesis, as well as in angiogenesis and wound healing processes [24]. Therefore, due to its mitogenic functions, FGF-1 has become a potential active ingredient with a wide range of uses in cosmetology directed to various processes of skin regeneration, stimulating meso-, endo-, and ectodermal cells, including fibroblasts, keratinocytes, macrophages, and endothelial cells.

One study investigated the impact of FGF-1 on skin cells and assessed the anti-aging properties of a genetically modified FGF-1 to improve its stability and resistance to protease degradation(Q40P/S47I/H93Grecom-Dinant FGF-1 [rFGF) as an active agent in cosmetics [33]. Results showed that FGF-1 has a strong effect on cellular proliferation of keratinocytes and fibroblasts, which was confirmed by all the tests(in vitro, ex vivo, and in vivo)with the Q40P/S47I/H93GrFGF-1, suggesting a high potential for the use of this protein in anti-aging skin products and in wound healing.

Positive effects were also obtained in the study by Ha and colleagues [49], who established a scalable expression system for recombinant human aFGF(RH-FGF1)us-ing transient and a DNA replicon vector expression in Nicotiana benthamiana. The study evaluated the effect of growth factors on UVB-induced skin photoaging. The results of this study showed that rh-FGF1 not only increased cell viability but also cell proliferation. The treatment was also shown to have a significant protective effect against UVB-induced cytotoxicity, in addition to recovering the amount of procollagen lost by the radiation. Therefore,rh-FGF1 has been shown to be highly beneficial for the prevention of UVB-induced oxidative effects on skin cells, possessing the potential as a cosmetic and therapeutic agent that can be applied to preventpho-to aging.

Basic Fibroblastic Growth Factor(FGF-2,bFGF)The basic FGF(FGF-2) reduces and prevents expression lines and wrinkles through the activation of new skin cells and stimulates the proliferation of cells of mesodermal, ectodermal, and endodermal origin, mainly fibroblasts and keratinocytes. All of this suggests that FGF-2 may be important in the modulation of normal processes such as angiogenesis, wound healing, and tissue repair, as well as anti-aging action[4,13,47]. To develop its actions, FGF-2 binds to high-affinity tyrosine kinase receptors, whose activation leads to receptor autophosphorylation and phosphorylation of other substrates, which can stimulate cellular activities such as proliferation, motility, and differentiation [50].

In order to protect FGF-2 from thermal proteolysis in aging skin and preserve its beneficial effects on the proliferation of fibroblasts, a study evaluated the activity of Hibiscus Abelmoschus seed extract as a protective ingredient [51]. The results demonstrated that the extract exhibited a dose-dependent protective activity of FGF-2, which allowed the stimulation of cell turnover through this factor. In this same study, Rival et al.[51]evaluated in 60 healthy human volunteers anti-aging properties of the extract, in a double-blind placebo-controlled clinical study. Significant improvements in wrinkles, texture, elasticity and density of the skin have been demonstrated, at least in part, due heparan sulfate-like properties of this plant and the protection of FGF-2 from thermal degradation. In conclusion, H. Abelmoschus seed extract revealed anti-aging activity by protecting the FGF-2 content present in human skin, so that it can maintain its numerous functions in favor of skin rejuvenation.

In recent years, topical and injectable growth factors have emerged as intriguing therapeutic modalities that can be harnessed for esthetic and medical purposes. A group of researchers, who also studied FGFs, aimed to evaluate an in vivo method for aging skin rejuvenation through direct injection of intradermal FGF-2[52]. The following rejuvenating effects were observed: improvement of skin smoothness, atrophied skin thickness, and improved viscoelasticity. The changes in viscoelasticity pre-and post-treatment were comparable to an age difference of more than 20 years.

Keratinocyte Growth Factor (FGF-7, KGF)

Some anti-aging products containing growth factors have already been developed. An example is the keratinocyte growth factor(KGF), which is a member of the FGF family. While most FGFs influence the proliferation and/or differentiation of various cell types, KGF appears to act specifically on epithelial cells [34].

A study aimed to investigate the efficacy, tolerance, and use of a product containing cycloartenol(a purified extract), antioxidant peptides, and high concentrations of three growth factors: transforming growth factor-beta 1, epidermal growth factor, and KGF. The ability to reduce the visible signs of aging, including fine lines and wrinkles, texture, pore size, elasticity, redness, hydration, and overall skin quality, was evaluated, through the observation of visible signs in photographs. The results showed that eighteen of the twenty subjects experienced significant improvement after only 2 weeks of use for all measured categories and 100% of study subjects noticed an improvement in at least 3 or more of the8 categories as-sessed, concluding that the product is effective for individuals who seek significant improvement in the appearance of aged skin [53].

FGFs and Cosmetic Application

According to the cited evidence about the prevention of cutaneous aging induced by growth factors, pharmaco-logical products containing different types of FGFs were identified and they are listed in Table 1.

Conclusion

The use of growth factors is getting solid in the cosmetic market as a new therapeutic option to prevent and control the aging process, due to its actions in the cellular

differentiation process. FGF plays a relevant role in anti-aging therapy because it is related to the induction of collagen and elastin synthesis responsible for skin elasticity and resistance, characteristics that are diminished with skin aging, both intrinsic and extrinsic. However, further studies are needed to fully understand the mechanisms of the action of growth factors, especially the FGF. A better comprehension of how these substances work would allow the development of more effective and safer pharmacological products with an esthetic aim.

This article is extracted from Darízy Flávia Silva, PhD Institute of Health Sciences, Department of Bioregulation Federal University of Bahia, Avenida Reitor Miguel Calmon S/N, Salvador, Bahia 40110-902 (Brazil) E-Mail darizy.silva@ufba.br