Stimulate Keratinocyte Proliferation Research Articles

Induction of secretory leukocyte protease inhibitor (SLPI) in estradiol valerate (EV) induced polycystic ovary

The excessive administration of estradiol valerate induces polycystic ovary syndrome by formation of follicular cysts. Secretory leukocyte protease inhibitor (SLPI) promotes wound healing by decreasing the excessive inflammatory response, stimulating keratinocyte proliferation and increasing collagen deposition through the inhibition of protease activity. In this study, SLPI expression was high in the ovarian stroma, corpus luteum, unilaminar primary follicle, multilaminar primary follicle and granulose layer of the antral follicle in polycystic ovary (PCO) compared to the normal ovary. SLPI was expressed strongly in the theca around the cyst in PCO compared to the mature follicle in the normal ovary. The levels of SLPI mRNA and protein expression were higher in PCO than in the normal ovary, and the level of MMP-2 expression was lower in PCO. These results showed that the formation of a cyst was initiated from a multilaminar primary follicle and SLPI expression was increased depending on the morphological changes in the follicle and ovarian stroma. Therefore, an increase in SLPI may be related to the suppression of tissue disruption, and act as a protease inhibitor in PCO, suggesting that SLPI increases independently of the estrogen concentration in pathological tissues.

Evaluation of the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol, In vitro, ex vivo and in vivo studies

Three studies were performed to investigate the mechanism of action and evaluate the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol. The Ex vivo study on skin explants showed that caffeine and forskolin both stimulated glycerol release and demonstrates for the first time that retinol and carnitine in combination synergistically stimulated keratinocyte proliferation, which leads to an increase epidermal thickness. The double-blind, randomized, placebo-controlled clinical study associating circumference measurements on five selected parts of the body, cutaneous hydration measurements as well as blinded expert grading of skin aspect was conducted on 78 women who applied the product or placebo twice daily for 12 consecutive weeks. After 4 weeks of twice-daily application of the product, significant reductions in circumference of abdomen, hips-buttocks and waist were already observed. Improvements concerned all the measured body parts after 12 weeks. Orange peel and stubborn cellulite decreased significantly from 4 weeks of treatment and tonicity improved from 8 weeks, demonstrating that the product improved skin aspect. At the end of the study, eight parameters of the thirteen evaluated were significantly improved in the active group and compared with placebo.

The Prostaglandin E2 Receptor, EP2, Stimulates Keratinocyte Proliferation in Mouse Skin by G Protein-dependent and β-Arrestin1-dependent Signaling Pathways

The prostaglandin E(2) (PGE(2)) G protein-coupled receptor (GPCR), EP2, plays important roles in mouse skin tumor development (Chun, K. S., Lao, H. C., Trempus, C. S., Okada, M., and Langenbach, R. (2009) Carcinogenesis 30, 1620-1627). Because keratinocyte proliferation is essential for skin tumor development, EP2-mediated signaling pathways that contribute to keratinocyte proliferation were investigated. A single topical application of the EP2 agonist, butaprost, dose-dependently increased keratinocyte replication via activation of epidermal growth factor receptor (EGFR) and PKA signaling. Because GPCR-mediated activation of EGFR can involve the formation of a GPCR-β-arrestin-Src signaling complex, the possibility of a β-arrestin1-Src complex contributing to EP2-mediated signaling in keratinocytes was investigated. Butaprost induced β-arrestin1-Src complex formation and increased both Src and EGFR activation. A role for β-arrestin1 in EP2-mediated Src and EGFR activation was demonstrated by the observation that β-arrestin1 deficiency significantly reduced Src and EGFR activation. In agreement with a β-arrestin1-Src complex contributing to EGFR activation, Src and EGFR inhibition (PP2 and AG1478, respectively) indicated that Src was upstream of EGFR. Butaprost also induced the activation of Akt, ERK1/2, and STAT3, and both β-arrestin1 deficiency and EGFR inhibition (AG1478 or gefitinib) decreased their activation. In addition to β-arrestin1-dependent EGFR activation, butaprost increased PKA activation, as measured by phospho-GSK3β (p-GSK3β) and p-cAMP-response element-binding protein formation. PKA inhibition (H89 or R(P)-adenosine-3',5'-cyclic monophosphorothioate (R(P)-cAMPS)) decreased butaprost-induced cAMP-response element-binding protein and ERK activation but did not affect EGFR activation, whereas β-arrestin1 deficiency decreased EGFR activation but did not affect butaprost-induced PKA activation, thus indicating that they were independent EP2-mediated pathways. Therefore, the results indicate that EP2 contributed to mouse keratinocyte proliferation by G protein-independent, β-arrestin1-dependent activation of EGFR and G protein-dependent activation of PKA.

Human lactoferrin stimulates skin keratinocyte function and wound re-epithelialization

Human lactoferrin (hLF), a member of the transferrin family, is known for its antimicrobial and anti-inflammatory effects. Recent studies on various nonskin cell lines indicate that hLF may have a stimulatory effect on cell proliferation. To study the potential role of hLF in wound re-epithelialization. The effects of hLF on cell growth, migration, attachment and survival were assessed, with a rice-derived recombinant hLF (holo-rhLF), using proliferation analysis, scratch migration assay, calcein-AM/propidium iodide staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) method, respectively. The mechanisms of hLF on cell proliferation and migration were explored using specific pathway inhibitors. The involvement of lactoferrin receptor low-density lipoprotein receptor-related protein 1 (LRP1) was examined with RNA interference technique. An in vivo swine second-degree burn wound model was also used to assess wound re-epithelialization. Studies revealed that holo-rhLF significantly stimulated keratinocyte proliferation which could be blocked by mitogen-activated protein kinase (MAPK) kinase 1 inhibitor. Holo-rhLF also showed strong promoting effects on keratinocyte migration, which could be blocked by either inhibition of the MAPK, Src and Rho/ROCK pathways, or downregulation of the LRP1 receptor. With cells under starving or 12-O-tetradecanoylphorbol-13-acetate exposure, the addition of holo-rhLF was found greatly to increase cell viability and inhibit cell apoptosis. Additionally, holo-rhLF significantly increased the rate of wound re-epithelialization in swine second-degree burn wounds. Our studies demonstrate the direct effects of holo-rhLF on wound re-epithelialization including the enhancement of keratinocyte proliferation and migration as well as the protection of cells from apoptosis. The data strongly indicate its potential therapeutic applications in wound healing.

Acne vulgaris

Peripherally active androgens control cellular functions by binding to androgen receptors. Follicular keratinocytes and sebocytes are target cells for androgens, which, directly or indirectly, stimulate keratinocyte proliferation and the volume of sebaceous glands as well as the sebum secretion rate. Acne often begins with the adrenarche, namely with the up- regulation of adrenal synthesis of dehydroepiandrosterone sulfate, a hormone that is upstream to testosterone. The majority of acne patients exhibit normal levels of circulating androgens, while sebaceous glands from acne regions exhibit a stronger sensitivity to androgens than the sebaceous glands from other parts of the body. Hormone-like active lipids, hormones in diet and neuropeptides may also play a role in the development of acne lesions. The target of antiandrogen treatment of the skin is mainly the sebaceous gland and the primary effect is sebostasis.

Bovine colostrum promotes growth and migration of the human keratinocyte HaCaT cell line

Bovine colostrum represents a rich source of growth factors, which are known to play a central role in wound healing. The aim of our study was to investigate the possible mitogenic and motogenic effects induced by colostrum on human keratinocytes. Cell proliferation evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide test and 5-Bromo-2′-deoxyuridine incorporation revealed that colostrum exerts a growth promoting activity. Scratch assay and immunofluorescence of actin cytoskeleton showed its effectiveness also in inducing cell migration. Furthermore, colostrum treatment increases the levels of tyrosine phosphorylated proteins and the activated forms of the extracellular signal-regulated kinases 1 and 2 and such effects appear to be repressed by the tyrosine kinase inhibitor genistein. Our results indicate that the biological activities of colostrum are specifically mediated by the growth factor-induced activation of tyrosine kinase receptors and underline the relevance of the synergistic action exerted by the growth factors in stimulating keratinocyte proliferation and migration essential for tissue repair.

Hair Follicles Are Required for Optimal Growth during Lateral Skin Expansion

The hair follicles (HFs) and the interfollicular epidermis (IFE) of intact mature skin are maintained by distinct stem cell populations. Upon wounding, however, emigration of HF keratinocytes to the IFE plays a role in acute stages of healing. In addition to this repair function, rapidly cycling cells of the upper HF have been observed transiting to the IFE in neonatal skin. Here we report that an absence of HF development leads to shortening and kinking of the mouse tail. These skeletal defects are reduced by stimulating keratinocyte proliferation, suggesting that they arise from impaired epidermal expansion. We confirm that rapidly cycling cells of the HF emigrate to the IFE of the neonatal tail. These results suggest that an absence of HFs results in impaired skin growth that is unable to keep pace with the rapidly elongating axial skeleton of the tail. Thus, in addition to their role in wound repair, HFs can make a significant contribution to lateral expansion of the IFE in the absence of trauma.

Mesenchymal–epithelial interactions involving epiregulin in tuberous sclerosis complex hamartomas

Patients with tuberous sclerosis complex (TSC) develop hamartomas containing biallelic inactivating mutations in either TSC1 or TSC2, resulting in mammalian target of rapamycin (mTOR) activation. Hamartomas overgrow epithelial and mesenchymal cells in TSC skin. The pathogenetic mechanisms for these changes had not been investigated, and the existence or location of cells with biallelic mutations ("two-hit" cells) was unclear. We compared TSC skin hamartomas (angiofibromas and periungual fibromas) with normal-appearing skin of the same patient, and we observed more proliferation and mTOR activation in hamartoma epidermis. Two-hit cells were not detected in the epidermis. Fibroblast-like cells in the dermis, however, exhibited allelic deletion of TSC2, in both touch preparations of fresh tumor samples and cells grown from TSC skin tumors, suggesting that increased epidermal proliferation and mTOR activation were not caused by second-hit mutations in the keratinocytes but by mesenchymal-epithelial interactions. Gene expression arrays, used to identify potential paracrine factors released by mesenchymal cells, revealed more epiregulin mRNA in fibroblast-like angiofibroma and periungual fibroma cells than in fibroblasts from normal-appearing skin of the same patient. Elevation of epiregulin mRNA was confirmed with real-time PCR, and increased amounts of epiregulin protein were demonstrated with immunoprecipitation. Epiregulin stimulated keratinocyte proliferation and phosphorylation of ribosomal protein S6 in vitro. These results suggest that hamartomatous TSC skin tumors are induced by paracrine factors released by two-hit cells in the dermis and that proliferation with mTOR activation of the overlying epidermis is an effect of epiregulin.

Keratinocyte–Fibroblast Interactions in Wound Healing

Cutaneous tissue repair aims at restoring the barrier function of the skin. To achieve this, defects need to be replaced by granulation tissue to form new connective tissue, and epithelial wound closure is required to restore the physical barrier. Different wound-healing phases are recognized, starting with an inflammation-dominated early phase giving way to granulation tissue build-up and scar remodeling after epithelial wound closure has been achieved. In the granulation tissue, mesenchymal cells are maximally activated, cells proliferate, and synthesize huge amounts of extracellular matrix. Epithelial cells also proliferate and migrate over the provisional matrix of the underlying granulation tissue, eventually closing the defect. This review focuses on the role of keratinocyte-fibroblast interactions in the wound-healing process. There is ample evidence that keratinocytes stimulate fibroblasts to synthesize growth factors, which in turn will stimulate keratinocyte proliferation in a double paracrine manner. Moreover, fibroblasts can acquire a myofibroblast phenotype under the control of keratinocytes. This depends on a finely tuned balance between a proinflammatory or a transforming growth factor (TGF)-beta-dominated environment. As the phenotype of fibroblasts from different tissues or body sites becomes better defined, we may understand their individual contribution in wound healing in more detail and possibly explain different clinical outcomes.

Granulocyte–Macrophage Colony-Stimulating Factor Is Essential for Normal Wound Healing

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multipotent growth factor, which plays an important role during the process of wound healing. In clinical settings it has occasionally been employed in the treatment of cutaneous wounds of diverse etiologies. In a previous study, we have shown the positive influence of GM-CSF on full thickness excisional wounds in transgenic mice overexpressing GM-CSF in the basal layer of the epidermis. Direct GM-CSF action as well as indirect processes through the induction of secondary cytokines were proposed to contribute towards the beneficial effects. In this study, we analyzed the process of wound healing in transgenic mice overexpressing a GM-CSF antagonist in the epidermis. These mice not only exhibited a delayed scab rejection and reepithelialization but also neovascularization was reduced. The newly formed tissue was of poor quality as exhibited by the presence of extensive fibrosis. We suggest that the presence of GM-CSF in the repair process is of basic importance and its absence leads not only to delayed wound healing but it is also detrimental for the quality of the newly formed tissue.

Fibroblast-keratinocyte interactions in psoriasis: failure of psoriatic fibroblasts to stimulate keratinocyte proliferation in vitro

We have tested in two ways the hypothesis that dermal fibroblasts direct the hyperproliferation of the overlying epidermis in psoriasis. First, culture medium from psoriatic and from normal skin fibroblasts was added to monolayer cultures of foreskin keratinocytes. Second, psoriatic and normal fibroblasts embedded in hydrated collagen lattices were co-cultured with monolayers of foreskin keratinocytes. There was no evidence in either study that psoriatic fibroblast products could stimulate the proliferation of the keratinocytes, or that normal fibroblast products inhibited their proliferation. A positive control for the fibroblasts was provided by leucocyte supernatants, which stimulated keratinocyte proliferation by up to 65%. Our data do not support a primary role for dermal fibroblasts in psoriasis.

Cytokine-mediated effects of peripheral blood mononuclear cells from patients with atopic eczema on keratinocytes (HaCaT) in a new coculture system.

Interactions between keratinocytes and mononuclear cells via cytokines and adhesion molecules are thought to play a crucial part in inflammatory skin diseases. The cytokine-mediated effects of peripheral blood mononuclear cells (PBMC) from patients with atopic eczema (AE) and healthy individuals on keratinocytes (HaCaT) were investigated in vitro. A new coculture model (Transwell system) which consists of a lower and an upper compartment, which are separated by a polycarbonate-treated membrane, was established. 3[H]thymidine incorporation of keratinocytes and lymphocytes, as well as IL-6, IL-8 and IFN-gamma synthesis, were measured. Keratinocyte proliferation was significantly enhanced in the presence of PBMC from patients with AE. In contrast, PBMC from normal donors did not enhance HaCaT cell proliferation when they were cocultured. Lymphocytes from patients with AE showed a significantly enhanced proliferation after coculture with keratinocytes. However, PBMC from normal donors did not proliferate in the presence of HaCaT cells. Keratinocyte supernatants incubated with PBMC from either atopic or normal volunteers induced a suppression of lymphocyte 3[H]thymidine incorporation. In supernatants from cocultures of PBMC from patients with AE and keratinocytes, significantly enhanced amounts of IL-6 and IL-8, compared with normal donor's lymphocytes and HaCaT cells, were measured. No differences in IFN gamma production were observed. When PBMC were cultured without HaCaT cells, supernatants contained equal levels of IL-6, IL-8 and IFN-gamma in normal donors and in patients with AE. Interestingly, HaCaT cells spontaneously secrete measurable amounts of IL-6, IL-8 and IFN-gamma. Blocking experiments with neutralizing antibodies against these interleukins showed a complete inhibition of keratinocyte proliferation when PBMC from normal donors were used whereas the proliferative potency of PBMC supernatants from patients with AE on keratinocytes remained. Our data indicate that (i) PBMC from patients with AE stimulate keratinocyte proliferation via soluble factor(s) that are different from IL-6, IL-8 and IFN-gamma; (ii) probably, HaCaT cells spontaneously produce lymphocyte/monocyte inhibitory soluble factors and IL-6, IL-8 as well as IFN-gamma; and (iii) secretion and/or activity of keratinocyte-derived inhibitory mediators is regulated via cytokines of PBMC infiltrating inflammatory skin.

Epidermal and Dermal Characteristics in Skin Equivalent after Systemic and Topical Application of Skin Care Ingredients

Effects of active ingredients from topical and systemic skincare products on structure and organization of epidermis, dermal-epidermal junction (DEJ), and dermis were examined using an in vitro reconstructed skin equivalent (SE). Imedeen Time Perfection (ITP) ingredients (a mixture of BioMarine Complex, grape seed extract, tomato extract, vitamin C) were supplemented systemically into culture medium. Kinetin, an active ingredient from Imedeen Expression Line Control Serum, was applied topically. Both treatments were tested separately or combined. In epidermis, all treatments stimulated keratinocyte proliferation, showing a significant increase of Ki67-positive keratinocytes (P < 0.05). Kinetin showed a twofold increase of Ki67-positive cells, ITP resulted in a fivefold, and ITP+kinetin showed a nine-fold increase. Differentiation of keratinocytes was influenced only by kinetin since filaggrin was found only in kinetin and kinetin+ITP samples. At the DEJ, laminin 5 was slightly increased by all treatments. In dermis, only ITP increased the amount of collagen type I. Both kinetin and ITP stimulated formation of fibrillin-1 and elastin deposition. The effect of kinetin was seen in upper dermis. It stimulated not only the amount of deposited fibrillin-1 and elastin fibers but also their organization perpendicularly to the DEJ. ITP stimulated formation of fibrillin-1 in deeper dermis. In summary, the combination of topical treatment with kinetin and systemic treatment with ITP had complementary beneficial effects in the formation and development of epidermis and dermis.

Smad3 Mediates Angiotensin II– and TGF-β1–Induced Vascular Fibrosis

See related article, pages 1032–1039 Hypertension, diabetes, and atherosclerosis are three diseases responsible for the majority of cardiovascular morbidity in humans. Not only are they independent risk factors, but they clearly potentiate and complement each other in the pathogenesis of cardiovascular disease. The first manifestation of end-organ damage in these diseases is the vascular remodeling of small (resistance) and large (conductance), and this precedes the development of cardiac hypertrophy, renal insufficiency or stroke.1 This vascular remodeling is characterized by hyperplasia, hypertrophy, and apoptosis of smooth muscle cells (SMCs) and vascular fibrosis, caused by increased extracellular matrix deposition of total collagen, and changes in ratio of type I/III collagen, fibronectin, and proteoglycans.1 Angiotensin II (Ang II) has recently emerged as a key mediator of vascular fibrosis (sclerosis) both in humans and animal models of hypertension because of its pleiotropic effects of SMCs, fibroblasts, and inflammatory cells. Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor antagonists (ARB) diminish cardiac hypertrophy and vascular fibrosis in animal models of hypertension.1,2 In human clinical trials of hypertension, ARBs reverse vascular remodeling in resistance arteries and new incidence of strokes more potently than any other antihypertensive agents (beta-blockers or calcium channel blockers), despite similar reduction in blood pressure.3,4 This provides strong evidence that targeting the mechanisms involved in arterial remodeling process may provide the key in preventing the long-term consequences of hypertension or atherosclerosis in humans. However, deciphering the intimate mechanisms of in vivo vascular remodeling has become very complex because of enormous reciprocal interactions between Ang II and other growth factors. Ang II exerts its effects not only by activating its specific receptors, but also by transactivating other growth factor receptors such as epidermal growth factor …

Possible association of psoriasis and reduced bone mineral density due to increased TNF-α and IL-6 concentrations

Psoriasis is a chronic erythematosquamous disease affecting about 2-3% of the population. It is generally considered to be a T cell-mediated disorder. Psoriasis is characterized by Th1-type cytokine pattern with the predominant secretion of IL-2, IL-6, IFN-gamma and TNF-alpha. Such cytokine pattern is sufficient in inducing keratinocyte hyperproliferation, a hallmark of psoriasis. It seems that development of psoriatic lesions is mediated by TNF-alpha and proliferation of local T cells is dependent on local TNF-alpha production. IL-6 enhances activation, proliferation and chemotaxis of T cells into psoriatic lesions. It is also a direct keratinocyte mitogen that could directly stimulate keratinocyte proliferation. Data of possible association between psoriasis and reduced bone mineral density (BMD) are limited and therefore, not fully conclusive. The major limitation of two studies reported so far was small sample size. Based on increased concentrations of TNF-alpha and IL-6 in psoriasis we hypothesized that these patients are more prone to osteoporosis than healthy subjects. TNF-alpha enhances bone resorption via stimulating osteoclast development and activity as well as bone formation. On the other hand, IL-6 is also a potent stimulator of bone resorption. Moreover, increased production of TNF-alpha and IL-6 has been found in postmenopausal women with osteoporosis. Several lines of evidence support our hypothesis; higher value of IL-6 was recorded in children with idiopathic osteoporosis than in healthy controls; TNF-alpha knock-out mice do not lose bone after ovariectomy; polymorphism of TNFRSF1B gene which encodes 75 Kd TNF receptor is associated with BMD; treatment with anti-TNF-alpha antibody exert beneficial effect on bone metabolism in patients with rheumatoid arthritis and finally, raloxifene inhibit osteoclast activity by reducing TNF-alpha and IL-6 synthesis. However, our hypothesis raised number of questions. Are increased serum concentrations of TNF-alpha and IL-6 mirrored by increased concentrations of these cytokines on the local level? Furthermore, could other cytokines relevant in the pathogenesis of the psoriasis, first of all IFN-gamma, modulate the risk of osteoporosis? Thus, a large prospective, case-control study with the data on BMD, biochemical parameters of bone turnover and fractures have to be done to test our hypothesis.

Pomegranate as a cosmeceutical source: Pomegranate fractions promote proliferation and procollagen synthesis and inhibit matrix metalloproteinase-1 production in human skin cells

Pomegranate ( Punica granatum) is an ancient fruit with exceptionally rich ethnomedical applications. The peel (pericarp) is well regarded for its astringent properties; the seeds for conferring invulnerability in combat and stimulating beauty and fertility. Here, aqueous fractions prepared from the fruit's peel and fermented juice and lipophilic fractions prepared from pomegranate seeds were examined for effects on human epidermal keratinocyte and human dermal fibroblast function. Pomegranate seed oil, but not aqueous extracts of fermented juice, peel or seed cake, was shown to stimulate keratinocyte proliferation in monolayer culture. In parallel, a mild thickening of the epidermis (without the loss of ordered differentiation) was observed in skin organ culture. The same pomegranate seed oil that stimulated keratinocyte proliferation was without effect on fibroblast function. In contrast, pomegranate peel extract (and to a lesser extent, both the fermented juice and seed cake extracts) stimulated type I procollagen synthesis and inhibited matrix metalloproteinase-1 (MMP-1; interstitial collagenase) production by dermal fibroblasts, but had no growth-supporting effect on keratinocytes. These results suggest heuristic potential of pomegranate fractions for facilitating skin repair in a polar manner, namely aqueous extracts (especially of pomegranate peel) promoting regeneration of dermis, and pomegranate seed oil promoting regeneration of epidermis.

Immunohistochemical analysis of keratinocyte growth factor and fibroblast growth factor 10 expression in psoriasis

The pathogenic mechanism underlying the hyperproliferation of keratinocytes in psoriasis is still not completely clarified. The production of cytokines released by activated T lymphocytes infiltrating the upper dermis probably has a crucial role. Even dermal fibroblasts can participate in the process through the secretion of growth factors, and some studies have reported an increased expression of the insulin-like growth factor 1. Few studies, however, have focused on the possible involvement of the keratinocyte growth factor (KGF/FGF-7) and the fibroblast growth factor 10 (FGF-10/KGF-2), which are secreted by fibroblasts and stimulate keratinocyte proliferation acting through a receptor specifically expressed by epithelial cells. The aim of this study was to investigate the expression of KGF and FGF-10 on the skin of patients with psoriasis by immunohistochemical analysis and to evaluate the correlation with the lymphocyte infiltrate and the epidermal proliferation. Immunostaining for KGF and FGF-10 showed that both the growth factors are upregulated in the upper dermis of psoriatic skin, and that the expression is correlated with the presence of T-cell infiltrate and with keratinocyte proliferation. Our data suggest that in psoriatic lesions activated lymphocytes can stimulate fibroblasts to produce KGF and FGF-10, which in turn contribute to sustain the hyperproliferative status of the keratinocytes.

The neurotrophin network in human skin

The neurotrophin (NT) family includes nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), neurotrophin‐3 (NT‐3) and NT‐4/5. Keratinocytes synthesize and release all NTs. Keratinocytes express the low‐affinity p75 receptor which binds all NTs, the high‐affinity NGF receptor trkA and the NT‐3 receptor trkC. By contrast, keratinocytes express only a truncated form of trkB, the BDNF high‐affinity receptor. NT‐3 stimulates keratinocyte proliferation. NTs other than NGF fail to protect keratinocytes from UVB‐induced apoptosis. While NGF decreases upon UVB irradiation, NT‐3 and NT‐4 are upregulated. UVA dose dependently increases NT‐3 levels. NT‐3 and NGF stimulate each other release. Both fibroblasts and myofibroblasts synthesize and release all NTs, as well as their trk receptors except for trkC. p75 is more expressed in myofibroblast than in fibroblasts. NGF reduces secretion of collagen I in myofibroblasts. Myofibroblasts secrete more collagen I than fibroblasts. NGF reduces production of metalloproteinase 2 (MMP2) in myofibroblasts. Melanocytes synthesize and release all NTs. UVB irradiation upregulates the release of NT‐3, while it downregulates the release of NT‐4. Melanocytes express p75, which is downregulated by UVB. Melanocytes also express trkA and the extracellular domain of trkB. Taken together, these data indicate that a complex NT network exists in human skin with potential functions, partly to be determined.

Nerve growth factor and its role in epidermal homeostasis

Nerve growth factor (NGF) belongs to the neurotrophin (NT) family which also includes brain‐derived neurotrophic factor (BDNF), neurotrophin‐3 (NT‐3) and NT‐4/5. Human keratinocytes synthesize and release all NT and express both the low‐ (p75NTR) and the high‐affinity receptor (trk). Keratinocyte stem cells (KSCs) express higher levels of NGF as compared with young transit amplifying (TA) cells, while NGF levels are almost undetectable in TA cells. While trk is expressed in all basal keratinocytes in a homogeneous pattern, p75 is expressed only in a subpopulation of basal keratinocytes. p75 is strongly expressed in young TA cells, whereas it is scarcely visible in TA cells and absent in KSCs. Moreover, Ca++ strongly enhances p75 expression in subconfluent cells. NGF stimulates keratinocyte proliferation and protects keratinocytes from spontaneous and UVB‐induced apoptosis. These activities are performed through trk receptor, while the role of p75 is more controversial. p75 belongs to the TNF receptor superfamily, and it shares with other members of this family a death domain which signals apoptosis upon binding to the ligands. BDNF or NT‐4 induces keratinocyte apoptosis through p75, while the trk inhibitor K252 augments cell death in p75‐overexpressing keratinocytes. BDNF also activates c‐JUN kinase (JNK) in p75‐transfected keratinocytes. Taken together, these data point to a dual role of NT in epidermal homeostasis.

Taming psoriatic keratinocytes--PTHs' uses go up another notch.

The native parathyroid hormone (PTH) and several of its N-terminal adenylyl cyclase-activating fragments and their analogs have become the star stimulators of bone growth for treating osteoporosis, accelerating fracture healing, and strengthening the anchorage of prosthetic bone implants and one of them (Lilly's Forteo--recombinant hPTH-(1-34) has recently arrived in the clinic. But something entirely different has been lurking in the background-the ability of the adenylyl cyclase stimulating hPTH-(1-34) to calm hyperproliferating keratinocytes and reduce psoriatic lesions. By contrast PTH-(7-34) which cannot stimulate adenylyl cyclase actually stimulates keratinocyte proliferation. Normal keratinocytes make PTHrP after they lift off the basal lamina and have stopped cycling. But they have an unconventional PTH/PTHrP receptor which is not coupled to adenylyl cyclase. Psoriatic keratinocytes do not make PTHrP and have only a broken-down, proliferation-limiting terminal differentiation-driving Notch-Notch ligand mechanism. Putting these and other facts together produces a possible picture of an exogenously applied adenylyl cyclase-activating PTH pinch hitting for the missing PTHrP and restoring normal keratinocyte proliferative activity epidermal structure by stimulating dermal fibroblasts which do have the conventional adenylyl cyclase-linked PTHR1 and in response directly or indirectly restore the overlying basal keratinocytes' Notch-Notch ligand terminal differentiation-driving mechanism and consequently a normal epidermal structure.