Nature of Skin Fragility in Patients Receiving Retinoids for Systemic Effect

Williams, Mary L.; Elias, Peter M.

doi:10.1001/archderm.1981.01650100013019

Cited by 76 publications

(29 citation statements)

References 16 publications

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“…How can sHB-EGF translocate across these cell-cell junctions? It has been reported, both in cultured keratinocytes and in the skin, that retinoids cause fragility of this cell-cell contact through decreased numbers of tonofilaments in keratinocytes and desmosomal attachments in the epidermis (Hatakeyama et al, 2004;Peck et al, 1977;Wanner et al, 1999;Williams et al, 1981). This suggests that tRA treatment induces epidermal fragility, and as a result, sHB-EGF might be able to translocate through gaps between the keratinocytes to the basal layer.…”

Section: Discussionmentioning

confidence: 99%

Soluble Form of Heparin-binding EGF-like Growth Factor Contributes to Retinoic Acid-induced Epidermal Hyperplasia

Kimura

Iwamoto

Mekada

2005

Cell Struct. Funct.

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ABSTRACT. Heparin-binding EGF-like growth factor (HB-EGF), a member of the EGF-family, is thought to be important for keratinocyte functions. HB-EGF is first synthesized as a membrane-anchored form, and its soluble form is released by ectodomain shedding. Here we investigate the role of HB-EGF in epidermal hyperplasia induced by all-trans retinoic acid (tRA) treatment. HB-EGF is normally expressed in epidermis of normal adult mice at very low levels, but topical tRA treatment results in epidermal hyperplasia, concomitant with the strong induction of HB-EGF expression in the suprabasal layer. tRA-induced epidermal hyperplasia was reduced both in the keratinocyte-specific HB-EGF null mice (K5-HB del/del ) and knock-in mice expressing the uncleavable mutant form of HB-EGF (HB uc/uc ), as compared with wild-type HB-EGF knock-in mice (HB lox/lox ). Among ErbB tyrosine kinase receptors, EGF receptor (EGFR) and ErbB2 were selectively activated by tRA treatment in skin from wild-type mice, while the activation of these ErbB receptors was significantly reduced in the skin of HB-EGF null mice. These results indicate that expression of HB-EGF and generation of its soluble form, followed by activation of EGFR and ErbB2, are pivotal processes in tRA-induced epidermal hyperplasia.

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Section: Discussionmentioning

confidence: 99%

Soluble Form of Heparin-binding EGF-like Growth Factor Contributes to Retinoic Acid-induced Epidermal Hyperplasia

Kimura

Iwamoto

Mekada

2005

Cell Struct. Funct.

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“…Epidermal changes after topical application of all-trans retinoic acid include hyperplasia (42,43), coupled with decreased elaboration of desmosomal proteins (44 -46) and other factors that support cell-matrix attachment (47). Decreased cell-cell and cell-matrix adhesion leads to enhanced keratinocyte sloughing and barrier disruption (48,49), which in turn results in elaboration of proinflammatory cytokines such as interleukin-1 (50,51). Whereas this is an undesirable consequence of retinoid therapy (and may be particularly so in skin that is already compromised), recent studies suggest that it will be possible to separate negative epidermal effects from the beneficial effects of topical retinoid use.…”

Section: ϫ2mentioning

confidence: 99%

Topical Pretreatment of Diabetic Rats With All-trans Retinoic Acid Improves Healing of Subsequently Induced Abrasion Wounds

et al. 2005

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In the current study, rats were made diabetic with streptozotocin (STZ) and maintained for 8 weeks, during which time they were treated topically on alternative days with a solution of 0.1% all-trans retinoic acid in a vehicle of 70:30% ethanol/propylene glycol. STZinduced diabetic rats treated with vehicle served as controls. Additional nondiabetic rats were treated with all-trans retinoic acid or vehicle in parallel. At the end of the 8-week period, rats from all four treatment groups were subjected to abrasion wound formation. Wounds healed more rapidly in vehicle-treated nondiabetic skin than in vehicle-treated diabetic skin (96% of the wound surface area closed in nondiabetic rats within 6 days vs. 41% closed in diabetic rats). Wounds in all-trans retinoic acid-treated diabetic skin healed more rapidly than wounds in vehicle-treated diabetic skin (85% of the wound surface area closed in all-trans retinoic acid-treated diabetic rats vs. 41% closed in vehicle-treated diabetic rats). At the histological level, recently healed skin from vehicle-treated diabetic rats was shown to contain a thin, wispy provisional matrix in which many of the embedded cells were rounded and some were pycnotic. In contrast, a much denser provisional matrix with large numbers of embedded spindleshaped cells was observed in healed wounds from diabetic skin that had been pretreated with all-trans retinoic acid. The all-trans retinoic acid-treated diabetic skin was histologically similar to vehicle-treated (or all-trans retinoic acid-treated) skin from nondiabetic animals. In light of these findings, we suggest that prophylactic use of retinoid-containing preparations might be useful in preventing the development of nonhealing skin ulcers resultant from minor traumas in at-risk skin. Diabetes 54:855-861, 2005 D iabetes is responsible for delayed or impaired wound healing, leading in many instances to chronic ulcer formation. Diabetic ulcers of the lower limbs and feet, in particular, are associated with high morbidity and often lead to amputation (1-3). Peripheral neuropathy and peripheral vascular disease are thought to be underlying factors in diabetic wound formation (2-6), but dermal atrophy is likely to be a contributing factor in many cases (6,7). Reduced fibroblast growth, increased expression of matrix-degrading matrix metalloproteinases (MMPs), and decreased matrix synthesis are consequences of chronic vascular disease in diabetic skin as well as in other situations where peripheral vascular disease is present (7-15). Atrophic skin is less resistant than healthy skin to wound formation. In addition, scanty extracellular matrix production during the proliferative phase of wound repair undoubtedly contributes to poor healing (16,17).Past studies have shown that all-trans retinoic acid has the capacity to repair photodamaged skin (18 -19). The repair response includes both increased procollagen production and decreased elaboration of tissue-destructive MMPs. In addition, there is epidermal thickening caused by retinoid-induced ke...

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“…One of the side effects of the retinoid therapy is excessive fragility of the skin (4). Although the skin fragility has been suggested to be of the epidermal origin (4), it is also possible that the connective tissue matrix of the dermis might be affected by the treatment.…”

Section: Introductionmentioning

confidence: 99%

Modulation of procollagen gene expression by retinoids. Inhibition of collagen production by retinoic acid accompanied by reduced type I procollagen messenger ribonucleic acid levels in human skin fibroblast cultures.

Oikarinen¹,

Oikarinen²,

Tan³

et al. 1985

J. Clin. Invest.

116

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Recent clinical observations have suggested that retinoids, which are in frequent use in dermatology, can affect the connective tissue metabolism in skin and other tissues. In this study, we examined the effects of several retinoids on the metabolism of collagen by human skin fibroblasts in culture. Incubation of cultured fibroblasts with all-trans-retinoic acid or 13-cis-retinoic acid, in 10-5 M or higher concentrations, markedly reduced the procollagen production, as measured by synthesis of radioactive hydroxyproline. The effect was selective in that little, if any, inhibition was noted in the incorporation of [Hjleucine into the noncollagenous proteins, when the cells were incubated with the retinoids in 10-5 M concentration. Similar reduction in procollagen production was noted with retinol and retinal, whereas an aromatic analogue of retinoic acid ethyl ester (RO-10-9359) resulted in a slight increase in procollagen production in these cultures. The reduction in procollagen production by all-trans-retinoic acid was accompanied by a similar reduction in proa2(I) of type I procollagen specific messenger RNA (mRNA), as detected by dot blot and Northern blot hybridizations. Hybridizations with human fibronectin and fl-actin specific DNA probes indicated that the levels of the corresponding mRNAs were not affected by the retinoids, further suggesting selectivity in the inhibition of procollagen gene expression. Further control experiments indicated that all-trans-retinoic acid, under the culture conditions employed, did not affect the posttranslational hydroxylation of prolyl residues, the mannosylation of newly synthesized procollagen, the specific radioactivity of the intracellular prolyltransfer RNA pool, or DNA replication. All-trans-retinoic acid also elicited a reduction in trypsin-activatable collagenase, but not in the activity of prolyl hydroxylase or an elastaselike neutral protease in the fibroblast cultures. Incubation of three fibroblast lines established from human keloids with all-transretinoic acid or 13-cis-retinoic acid also resulted in a marked reduction in procollagen production. The results, therefore, suggest that further development of retinoids might provide a novel means of modulating collagen gene expression in patients with various diseases affecting the connective tissues.

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Nature of Skin Fragility in Patients Receiving Retinoids for Systemic Effect

Cited by 76 publications

References 16 publications

Soluble Form of Heparin-binding EGF-like Growth Factor Contributes to Retinoic Acid-induced Epidermal Hyperplasia

Soluble Form of Heparin-binding EGF-like Growth Factor Contributes to Retinoic Acid-induced Epidermal Hyperplasia

Topical Pretreatment of Diabetic Rats With All-trans Retinoic Acid Improves Healing of Subsequently Induced Abrasion Wounds

Modulation of procollagen gene expression by retinoids. Inhibition of collagen production by retinoic acid accompanied by reduced type I procollagen messenger ribonucleic acid levels in human skin fibroblast cultures.

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