Quantification of human tissue kallikreins in the stratum corneum: dependence on age and gender.
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Human tissue kallikreins are a family of 15 trypsin or chymotrypsin-like secreted serine proteases (hK1-hK15). hK5, hK6, hK7, hK8, and hK13 have been identified in the stratum corneum (SC), stratum granulosum, and skin appendages. It has been reported that hK5 and hK7 degrade desmosomes/corneodesmosomes, suggesting that kallikreins are responsible for desquamation. We report the quantification of hK5, hK6, hK7, hK8, hK10, hK11, hK13, and hK14 in the SC by ELISA and their variation among age groups. The total SC trypsin and chymotrypsin-like activities were also measured. The amount of hK7, hK8, and hK11 (ng per mg dry weight) were high, and varied from 6 to 14, hK5 (2.0-4.0) was present at intermediate levels, and hK10 (0.65-1.0), hK14 (0.1-0.3), hK6 (0.1-0.3), and hK13 (0.02-0.1) were present at lower levels. hK6 and hK14 were significantly lower in females between 20 and 59 y. hK5, hK7, hK10, hK11, and hK14 were not significantly different across the age groups. hK8 was lowest at extremes of age (highest at 30-39 y), hK6 was lower at >30 y, and hK13 was lower at >20 y. Overall trypsin-like activity did not differ across age groups but was higher in subjects <11 y. Overall chymotrypsin-like activity was not related to age. In conclusion, we found multiple kallikreins in the SC and suggest that these enzymes may be responsible for desquamation through an enzymatic cascade pathway. (+info)
Different consequences of beta1 integrin deletion in neonatal and adult mouse epidermis reveal a context-dependent role of integrins in regulating proliferation, differentiation, and intercellular communication.
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There are conflicting reports of the consequences of deleting beta1 integrins from the epidermis of transgenic mice. Epidermal thinning with normal differentiation and lack of inflammation has been observed; conversely, epidermal thickening, abnormal differentiation, and dermal fibrosis can occur. beta1 integrin deletion results in decreased epidermal proliferation, yet on wounding the proliferative defect is overcome. To distinguish primary from secondary consequences of beta1 integrin loss, we compared epidermal beta1 deletion at E14.5 via K5Cre and 4-hydroxy-tamoxifen induced deletion in adulthood via K14CreER. As reported previously, there was dermo-epidermal splitting, inflammation, reduced proliferation, and hair follicle and sebaceous gland loss in 30-d-old K5Cre beta1-null mice. These changes were not observed 30 d after beta1 integrin deletion in adult epidermis, however, and there were no changes in the hair follicle stem cell compartment. Deletion in adult epidermis revealed a previously unreported correlation between the level of beta1 integrins and proliferation in the interfollicular epidermis that was remarkably consistent with human epidermis. In addition, the number of melanocytes in interfollicular epidermis was greatly increased. Our results highlight the context-dependent effects of beta1 integrin deletion and suggest that inflammation may be responsible for some of the K5Cre beta1-null phenotype. (+info)
Mitochondrial DNA deletions serve as biomarkers of aging in the skin, but are typically absent in nonmelanoma skin cancers.
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The potential role of mitochondrial DNA (mtDNA) deletions in nonmelanoma skin cancer (NMSC) and in cutaneous photoaging was explored using a genetic approach. Tumors and photodamaged tumor-free "margin" skin were obtained from NMSC patients undergoing excision and the mtDNA from these specimens was screened for the presence of deletions using long extension PCR. mtDNA deletions were abundant in margin tissue specimens from older patients and their number correlated with the patient age. There was a statistically significant difference between the number of mtDNA deletions in tumors and margins. Fewer deletions were detected in the tumors than the margins and the tumors often had no deletions, implying a potential selection for full-length mtDNA or perhaps a protective role for mtDNA deletions in the process of tumorigenesis. The observed mtDNA deletions from skin were often unreported (19 of 21 deletions), but typically shared structural features with mtDNA deletions reported in other tissues. Some mtDNA deletions were detected from the skin of multiple individuals, including 3,715 and 6,278-base pair (bp) deletions, whose frequencies approached that of the previously well-characterized 4977-bp "common" deletion. These data support the use of mtDNA mutations as biomarkers of photoaging in the skin. (+info)
The receptor for advanced glycation end products is highly expressed in the skin and upregulated by advanced glycation end products and tumor necrosis factor-alpha.
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Advanced glycation end products (AGEs) form non-enzymatically from reactions of proteins with reducing sugars. In the skin, AGEs were reported to accumulate in dermal elastin and collagens and to interact nonspecifically with the cell membrane of dermal fibroblasts. Therefore, AGEs may influence the process of skin aging. We investigated the presence of the AGE receptor RAGE in skin and the influence of AGEs on receptor expression and the formation of extracellular matrix (ECM). Sections of sun-protected and sun-exposed skin were analyzed with monoclonal antibodies against (RAGE), heat-shock protein 47, factor XIIIa, CD31, and CD45. RAGE was mainly expressed in fibroblasts, dendrocytes, and keratinocytes and to a minor extent in endothelial and mononuclear cells. Human foreskin fibroblasts (HFFs) highly expressed RAGE on the protein and mRNA level when analyzed by quantitative Western blotting and real-time PCR. Incubation of HFFs with the specific RAGE ligand Nepsilon-(carboxymethyl)lysine-modified BSA (CML-BSA) and tumor necrosis factor-alpha resulted in significant upregulation of RAGE expression. CML-BSA induced a mildly profibrogenic pattern, increasing connective tissue growth factor, transforming growth factor-beta (TGF-beta) 1, and procollagen-alpha1(I) mRNA, whereas expression of matrix metalloproteinase (MMP)-1, -2, -3, and -12 was unaffected. We conclude that in HFFs, AGE-RAGE interactions may influence the process of skin aging through mild stimulation of ECM gene expression. (+info)
A genome scan for epidermal skin pattern in adolescent twins reveals suggestive linkage on 12p13.31.
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Deterioration in stratum corneum reticular patterning (skin pattern or skin wrinkling) has been associated with increased rates of solar keratoses and skin cancer. A previous analysis of data from the twin sample used in this investigation has shown that 86% of the variation in skin pattern is genetic at age 12 and 62% in an adult sample (mean age = 47.5). Variation due to genetic influences is likely to be influenced by more than one locus. Here, we present results of a genome-wide linkage scan of skin pattern in adolescent twins and siblings from 428 nuclear twin families. Sib-pair linkage analysis was performed on skin pattern data collected from twins at age 12 (378 informative families) and 14 (316 families). Suggestive linkage was found at marker D12S397 (12p13.31, logarithm of the odds (lod) 1.94), when the effect of the trait locus was modelled to influence the skin pattern equally at both ages 12 and 14. In the same analysis, a peak was seen at 4q23 with a lod score of 1.55. A possible candidate for the peak at 12p13.31 is the protease inhibitor, alpha-2-macroglobulin. (+info)
Chemical peeling by SA-PEG remodels photo-damaged skin: suppressing p53 expression and normalizing keratinocyte differentiation.
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Chemical peeling with salicylic acid in polyethylene glycol vehicle (SA-PEG), which specifically acts on the stratum corneum, suppresses the development of skin tumors in UVB-irradiated hairless mice. To elucidate the mechanism through which chemical peeling with SA-PEG suppresses skin tumor development, the effects of chemical peeling on photodamaged keratinocytes and cornified envelopes (CEs) were evaluated in vivo. Among UVB-irradiated hairless mice, the structural atypia and expression of p53 protein in keratinocytes induced by UVB irradiation were intensely suppressed in the SA-PEG-treated mice 28 days after the start of weekly SA-PEG treatments when compared to that in the control UVB-irradiated mice. Incomplete expression of filaggrin and loricrin in keratinocytes from the control mice was also improved in keratinocytes from the SA-PEG-treated mice. In photo-exposed human facial skin, immature CEs were replaced with mature CEs 4 weeks after treatment with SA-PEG. Restoration of photodamaged stratum corneum by treatment with SA-PEG, which may affect remodeling of the structural environment of the keratinocytes, involved the normalization of keratinocyte differentiation and suppression of skin tumor development. These results suggest that the stratum corneum plays a protective role against carcinogenesis, and provide a novel strategy for the prevention of photo-induced skin tumors. (+info)
Influence of environmental factors on facial ageing.
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BACKGROUND: A recent twin study has shown that 'looking old for one's age' is associated with increased mortality. Approximately 40% of the variation in perceived age is due to non-genetic factors. OBJECTIVE: To examine environmental factors influencing perceived age controlling for diseases. DESIGN: A twin study. SETTING: In the 2001 wave of the population-based survey--the Longitudinal Study of Aging Danish Twins--participants provided information on a wide range of exposures and health indicators. Additionally, they were asked to have a face photograph taken. SUBJECTS: A total of 1826 elderly (70+) twins who had a high-quality face photograph taken. METHODS: Ten nurses assessed the visual age of each twin from the face photograph. The mean of the nurses' age estimates for each twin was used as the twin's perceived age. Multivariate linear regression and intrapair comparison (for intact twin pairs) were used for analyses. RESULTS: Statistically significant determinants of facial ageing associated with high perceived age for men were smoking (P = 0.01), sun exposure (P = 0.02) and low body mass index (BMI) (P<0.005), while for women they were low BMI (P = 0.05) and low social class (P<0.005). The number of children (men) and marital status (P = 0.08) and depression symptomatology score (women) were borderline significantly associated with facial ageing. CONCLUSION: Our study confirms previous findings of a negative influence of sun exposure, smoking and a low BMI on facial ageing. Furthermore, our study indicates that high social status, low depression score and being married are associated with a younger look, but the strength of the associations varies between genders. (+info)
Photoprotective and anti-skin-aging effects of eicosapentaenoic acid in human skin in vivo.
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Skin aging can be attributed to photoaging (extrinsic) and chronological (intrinsic) aging. Photoaging and intrinsic aging are induced by damage to human skin attributable to repeated exposure to ultraviolet (UV) irradiation and to the passage of time, respectively. In our previous report, eicosapentaenoic acid (EPA) was found to inhibit UV-induced matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. Therefore, we investigated the effects of EPA on UV-induced skin damage and intrinsic aging by applying EPA topically to young and aged human skin, respectively. By immunohistochemical analysis and Western blotting, we found that topical application of EPA reduced UV-induced epidermal thickening and inhibited collagen decrease induced by UV light. It was also found that EPA attenuated UV-induced MMP-1 and MMP-9 expression by inhibiting UV-induced c-Jun phosphorylation, which is closely related to UV-induced activator protein-1 activation, and by inhibiting JNK and p38 activation. EPA also inhibited UV-induced cyclooxygenase-2 (COX-2) expression without altering COX-1 expression. Moreover, it was found that EPA increased collagen and elastic fibers (tropoelastin and fibrillin-1) expression by increasing transformin growth factor-beta expression in aged human skin. Together, these results demonstrate that topical EPA has potential as an anti-skin-aging agent. (+info)