Impact of Specific Bioactive Collagen Peptides on Joint Discomforts in the Lower Extremity during Daily Activities: A Randomized Controlled Trial.

The intake of specific collagen peptides (SCPs) has been shown to decrease activity-related knee pain in young, physically active adults. This trial investigated the effect of a 12-week SCP supplementation in a wider age range of healthy men and women over 18 years with functional knee and hip pain during daily activities. A total of 182 participants were randomly assigned to receive either 5 g of specific collagen peptides (CP-G) or a placebo (P-G). Pain at rest and during various daily activities were assessed at baseline and after 12 weeks by a physician and participants using a 10-point numeric rating scale (NRS). The intake of 5 g SCP over 12 weeks significantly reduced pain at rest (p = 0.018) and during walking (p = 0.032) according to the physician's evaluation. Participants in the CP-G also reported significantly less pain when climbing stairs (p = 0.040) and when kneeling down (p < 0.001) compared to the P-G. Additionally, after 12 weeks, restrictions when squatting were significantly lower in the CP-G compared with the P-G (p = 0.014). The daily intake of 5 g of SCP seems to benefit healthy adults with hip and knee joint discomforts by reducing pain during daily activities.

Oral supplementation with specific bioactive collagen peptides improves nail growth and reduces symptoms of brittle nails.

BACKGROUND: Brittle nail syndrome is a common problem among women and refers to nails that exhibit surface roughness, raggedness, and peeling. AIM: The goal of this study was to investigate whether daily oral supplementation with collagen peptides alleviates the symptoms of brittle nails and improves nail growth rate. METHODS: In this open-label, single-center trial, 25 participants took 2.5 g of specific bioactive collagen peptides (BCP, VERISOL® ) once daily for 24 weeks followed by a 4-week off-therapy period. Nail growth rate and the frequency of cracked and/or chipped nails as well as an evaluation of symptoms and global clinical improvement score of brittle nails were assessed by a physician during treatment and 4 weeks after discontinuation. RESULTS: Bioactive collagen peptides treatment promoted an increase of 12% nail growth rate and a decrease of 42% in the frequency of broken nails. Additionally, 64% of participants achieved a global clinical improvement in brittle nails, and 88% of participants experienced an improvement 4 weeks post-treatment. The majority of participants (80%) agreed that the use of BCP improved their nails' appearance, and were completely satisfied with the performance of the treatment. CONCLUSIONS: This study demonstrated that the daily ingestion of BCP increased nail growth and improved brittle nails in conjunction with a notable decrease in the frequency of broken nails.

Dietary Supplementation with Specific Collagen Peptides Has a Body Mass Index-Dependent Beneficial Effect on Cellulite Morphology.

In this double-blind, placebo-controlled clinical study, we investigated the efficacy of specific bioactive collagen peptides (BCP) on the cellulite treatment of normal and overweight women. In total, 105 women aged 24-50 years with moderate cellulite were randomized to orally receive a daily dosage of 2.5 g BCP or a placebo over 6 months. The degree of cellulite was evaluated before starting the treatment and after 3 and 6 months of intake. In addition, skin waviness, dermal density, and the length of subcutaneous borderline were assessed. BCP treatment led to a statistically significant decrease in the degree of cellulite and a reduced skin waviness on thighs (P < 0.05) in normal weight women. Moreover, dermal density was significantly improved (P < 0.05) compared to placebo. The subcutaneous borderline showed a significant shortening after BCP intake compared to the beginning of the study, indicating cellulite improvement, but the data failed to reach statistical significance compared to placebo. The efficacy of BCP treatment was also confirmed in overweight women, although the impact was less pronounced in comparison with women of normal body weight. The results of the study demonstrated that a regular ingestion of BCP over a period of 6 months led to a clear improvement of the skin appearance in women suffering from moderate cellulite. Based on the current data, it can be concluded that a long-term therapy with orally administered BCP leads to an improvement of cellulite and has a positive impact on skin health.

Mechanical and metabolic injury to the skin barrier leads to increased expression of murine ß-defensin-1, -3, and -14.

Protection of the skin against microbiological infection is provided by the permeability barrier and by antimicrobial proteins. We asked whether the expression of murine ß-defensins (mBDs)-1, -3, and -14-orthologs of human ß-defensins hBD-1, -2, and -3, respectively--is stimulated by mechanically/physicochemically (tape stripping or acetone treatment) or metabolically (essential fatty acid-deficient (EFAD) diet) induced skin barrier dysfunction. Both methods led to a moderate induction of mBD-1 and mBD-14 and a pronounced induction of mBD-3 mRNA. Protein expression of the mBDs was increased as shown by immunohistology and by western blotting. Artificial barrier repair by occlusion significantly reduced the increased expression of mBD-14 after mechanical injury and of all three mBDs in EFAD mice, supporting an interrelationship between permeability and the antimicrobial barrier. mBD-3 expression was stimulated in vitro by tumor necrosis factor-α (TNF-α), and a neutralizing anti-TNF-α antibody significantly reduced increased mBD-3 expression after barrier injury in mouse skin, indicating that induction of mBD-3 expression is mediated by cytokines. The expression of mBD-14 was stimulated by transforming growth factor-α and not by TNF-α. In summary, we demonstrated upregulation of mBD1, -3, and -14 after mechanically and metabolically induced skin barrier disruption, which may be an attempt to increase defense in the case of permeability barrier dysfunction.

Distinct roles of JNK-1 and ERK-2 isoforms in permeability barrier repair and wound healing.

c-Jun N-terminal kinases (JNKs, also called stress activated protein kinases) and the extra-cellular signal responsive kinases (ERKs) exert different functions in mitogenesis, maturation and differentiation of immune and epithelial cells. We investigated specific functions of individual JNK and ERK isoforms in skin permeability barrier repair and in wound healing. JNK1, but not JNK2 or JNK3, deficient mice revealed a delay in the permeability barrier repair after superficial injury to the skin (tape-stripping) as well as a delay in the healing of full skin thickness wounds. Skin barrier injury induced an increase in epidermal JNK1 enzyme activity in mouse skin in vivo, and JNK1 activity correlated with the degree of differentiation in organotypic keratinocyte cultures. Skin injury activated epidermal ERK2 enzyme activity with biphasic maxima after 30 min and 3h, and the activity was independent from the differentiation state in keratinocyte culture. In summary, superficial and deep wound healing depends on the differential activity of MAP kinases such as JNK1 in epidermal differentiation and ERK2 in proliferation.

Artificial barrier repair in wounds by semi-occlusive foils reduced wound contraction and enhanced cell migration and reepithelization in mouse skin.

The repair of the permeability barrier to prevent the entry of harmful substances into the body is a goal in wound healing. Semi-occlusive foils, which provide an artificial barrier, are commonly used for the treatment of wounds. We examined the effects of foils on wound contraction, cell migration, and reepithelization. Full-thickness skin wounds in mice were covered with occlusive latex foils or semi-occlusive water vapor-permeable hydrocolloid foils for either the entire, the first half, or the second half of the wound-healing period. We found that application of foils for the entire healing period initially reduced wound healing during the first week of treatment, whereas healing was enhanced during the second week. Foils were found to reduce wound contraction, but enhanced reepithelization during the second week of wound healing because of increased proliferation and migration of keratinocytes. These effects were also noted when the hydrocolloid foils were applied for the second part of the healing period, only. The fully occlusive latex foil led to irritation of the skin, whereas less irritation occurred under semi-occlusive conditions. In summary, we found that artificial barrier repair with semi-occlusive foils in wounds reduced wound contraction and enhanced cell migration and reepithelization without irritation.

Acid and neutral sphingomyelinase, ceramide synthase, and acid ceramidase activities in cutaneous aging.

In aged skin, decreased levels of stratum corneum ceramides have been described. Epidermal ceramides are generated by sphingomyelin hydrolysis or synthesis from sphingosin and fatty acids and are degraded by ceramidase. We recently showed that epidermal acid sphingomyelinase (A-SMase) generates ceramides with structural function in the stratum corneum lipid bilayers, which provide for the permeability barrier function of the skin. Here, we examined the activities of epidermal A-SMase, ceramide synthase, and ceramidase in chronologically aged versus young hairless mouse skin. We found reduced A-SMase and ceramide synthase activities in the epidermis of aged mice. However, studies on enzyme localization revealed unchanged, ongoing high A-SMase activity in the outer epidermis, which correlated with reported normal barrier function found in aged skin under basal conditions. Reduced A-SMase and ceramide synthase activity was noted in the inner epidermis, correlating with reduced capacity for permeability barrier repair in aging. Ceramidase activity was not age dependent. In summary, we found reduced activities of ceramide-generating SMase and ceramide synthase in the inner epidermis of aged skin, explaining its reduced capacity in barrier repair. In contrast, A-SMase activity in the outer epidermis was unchanged, indicating that this enzyme is crucially involved in basal permeability barrier homeostasis.

The interleukin-6 cytokine system regulates epidermal permeability barrier homeostasis.

Interleukin-6 (IL-6) is involved in the growth and differentiation of numerous cell types. In the skin it is produced primarily by keratinocytes. The transcription factor STAT3 is activated by cytokines of the IL-6 family. In this study, we examined the involvement of IL-6, soluble IL-6-receptor, and STAT3 in epidermal barrier repair after injury to the stratum corneum by tape-stripping. After barrier disruption in wild-type mice we found an increased immunostaining of IL-6 and IL-6R on epidermal keratinocytes at 15 min to 5 h after treatment. The increase in IL-6 and IL-6R was confirmed by western blotting using epidermal homogenates and was partially prevented by occlusion immediately after barrier disruption. In IL-6-deficient mice, epidermal barrier repair was reduced at 3-24 h after treatment. Topical application of IL-6 or Hyper-IL-6, a complex of IL-6 linked to the soluble IL-6 receptor, enhanced epidermal barrier repair in wild-type mice. Application of the fusion protein gp130-FC, a specific inhibitor of the agonist IL-6/sIL-6 receptor complex, delayed barrier repair in wild, but not in IL-6-deficient mice. STAT3 tyrosine phosphorylation was induced after barrier disruption in wild-type, but markedly reduced in IL-6-deficient mice. Our results indicate that the IL-6 cytokine system, particularly transsignalling via the soluble IL-6R, is critically involved in barrier repair after skin injury.

Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis.

A defective permeability barrier leads to the penetration of environmental allergens into the skin and initiates immunological reactions and inflammation crucially involved in the pathogenesis of atopic dermatitis (AD). Decreased stratum corneum ceramide content may cause the defect in permeability barrier function consistently found in AD. Acid and neutral sphingomyelinase (A- and N-SMase) generate ceramides with structural and signal transduction functions in epidermal proliferation and differentiation. We determined epidermal SMase activities, DNA synthesis, involucrin, loricrin, filaggrin, and keratin expression in lesional and non-lesional skin of AD patients. We found decreased epidermal A-SMase activity in lesional and non-lesional skin, correlating with reduced stratum corneum ceramide content and disturbed barrier function. N-SMase activity was reduced in non-lesional skin and more significantly reduced in lesional skin, correlating with impaired expression of cornified envelope proteins and keratins, important for skin barrier function. Changes in involucrin, loricrin, filaggrin, keratin K 5 (basal) and K 16 (proliferation associated) were noticed in non-lesional and lesional skin, whereas changes in K 10 (suprabasal), K 6 (proliferation associated), and K 17 (inflammation associated) were found only in lesional skin. In summary, reduction in SMase-generating ceramides and impaired differentiation are involved in the defective barrier function found in AD.

Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation.

We previously demonstrated that the aspartate protease cathepsin D is activated by ceramide derived from acid sphingomyelinase. Increased expression of cathepsin D in the skin has been reported in wound healing, psoriasis and skin tumors. We explored specific functions of cathepsin D during epidermal differentiation. Protein expression and enzymatic activity of cathepsin D increased in differentiated keratinocytes in both stratified organotypic cultures and in mouse skin during epidermal barrier repair. Treatment of cultured keratinocytes with exogenous cathepsin D increased the activity of transglutaminase 1, known to cross-link the cornified envelope proteins involucrin and loricrin during epidermal differentiation. Inhibition of cathepsin D by pepstatin A suppressed the activity of transglutaminase 1. Cathepsin D-deficient mice revealed reduced transglutaminase 1 activity and reduced protein levels of the cornified envelope proteins involucrin and loricrin. Also, amount and distribution of cornified envelope proteins involucrin, loricrin, filaggrin, and of the keratins K1 and K5 were significantly altered in cathepsin D-deficient mice. Stratum corneum morphology in cathepsin D-deficient mice was impaired, with increased numbers of corneocyte layers and faint staining of the cornified envelope only, which is similar to the human skin disease lamellar ichthyosis. Our findings suggest a functional link between cathepsin D activation, transglutaminase 1 activity and protein expression of cornified envelope proteins during epidermal differentiation.

Matrix metalloproteinase-19 expression in normal and diseased skin: dysregulation by epidermal proliferation.

Most of the matrix metalloproteinases (MMP) are not expressed in normal intact skin but they are upregulated in inflamed or diseased skin. The recently cloned MMP-19 is one of the few MMP members that are also expressed in healthy epidermis. In this study, we found that MMP-19 is generally coexpressed with cytokeratin 14 that is confined to keratinocytes of the stratum basale. MMP-19 was also detected in hair follicles, sebaceous glands, and eccrine sweat glands. Its expression, however, changed in cutaneous diseases exhibiting increased alternations of epidermal proliferation, such as psoriasis, eczema, and tinea. In the affected area, MMP-19 was also found in suprabasal and spinous epidermal layers. We also studied the regulation of MMP-19 expression at the protein level, as well as by using a promoter assay. The constitutive expression of MMP-19 was upregulated with phorbol myristate acetate and downregulated with retinoic acid and dexamethasone. Tumor necrosis factor-alpha, interleukin (IL)-6, TGF-beta, IL-15, IL-8, and RANTES as well as the bacterial compounds lipopolysaccharide and lipoteichoic acid did not show any profound effect in HaCaT cells. In contrast, type IV and type I collagens upregulated MMP-19 significantly. The dysregulation of MMP-19 expression in epidermis suggests its possible involvement in the perpetuation of cutaneous infections and proliferative disorders such as psoriasis.