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Biomedical subjects

A G Messenger

Publications and source records attributed to A G Messenger.

At least 37 records · Page 2Linked to original sources
PubMed2000

The hair follicle: a paradoxical androgen target organ.

Androgens are the main regulator of normal human hair growth. After puberty, they promote transformation of vellus follicles, producing tiny, unpigmented hairs, to terminal ones, forming larger pigmented hairs, in many areas, e.g. the axilla. However, they have no apparent effect on the eyelashes, but can cause the opposite transformation on the scalp leading to the replacement of terminal hairs by vellus ones and the gradual onset of androgenetic alopecia. This paradox appears to be an unique hormonal effect. Hair follicles are mainly epithelial tissues, continuous with the epidermis, which project into the dermis. A mesenchyme-derived dermal papilla enclosed within the hair bulb at the base controls many aspects of follicle function. In the current hypothesis for androgen regulation, the dermal papilla is also considered the main site of androgen action with androgens from the blood binding to receptors in dermal papilla cells of androgen-sensitive follicles and causing an alteration of their production of paracrine factors for target cells e.g. keratinocytes. Studies of cultured dermal papilla cells from sites with different responses to androgens in vivo have confirmed the paradoxical responses. All dermal papilla cells from androgen-sensitive sites contain low capacity, high affinity androgen receptors. However, only some cells formed 5alpha-dihydrotestosterone, e.g. beard but not axillary cells, in line with hair growth in 5alpha-reductase deficiency. Incubation with androgens also stimulated the mitogenic capacity of beard cell media, but inhibited that produced by scalp cells. This suggests that the paradoxical differences are due to differential gene expression within hair follicles, presumably caused during embryogenesis.

Androgens↗
PubMed1999

Diffuse female hair loss: are androgens necessary?

Diffuse hair loss in women is generally regarded as the female equivalent of male balding and is often referred to as female androgenetic alopecia. In this article we report the case of a young woman with hypopituitarism who presented with the clinical and histological features of female androgenetic alopecia in the absence of detectable levels of circulating androgens or other signs of postpubertal androgenization, showing that this pattern of hair loss is not necessarily androgen dependent.

Adolescent↗
PubMed1999

Identification of novel mutations in basic hair keratins hHb1 and hHb6 in monilethrix: implications for protein structure and clinical phenotype.

Monilethrix is an hereditary hair dystrophy recently shown to be due to mutations in the helix termination motif of two type II (basic) human hair keratin genes, hHb1 and hHb6. It has been suggested that mutation in hHb1 produces a less severe phenotype. We have studied hair keratin genes and clinical features in 18 unrelated pedigrees of monilethrix from Germany, Scotland, Northern Ireland, and Portugal, in 13 of which mutations have not previously been identified. By examining the rod domains of hHb1, hHb3 and hHb6, we have identified mutations in nine of the new pedigrees. We again found the glutamine-lysine substitution (E413K) in the helix termination motif of hHb6 in two families, and in another, the corresponding E413K substitution in the hHb1 gene. In four families a similar substitution E402K was present in a nearby residue. In addition two novel mutations within the helix initiation motif of hHb6 were found in Scottish and Portuguese cases, in whom the same highly conserved asparagine residue N114 was mutated to histidine (N114H) or aspartic acid (N114D) residues, respectively. In four other monilethrix pedigrees mutations in these domains of hHb1, hHb3, and hHb6 were not found. The mutations identified predict a variety of possible structural consequences for the keratin molecule. A comparison of clinical features and severity between cases with hHb1 and hHb6 mutations does not suggest distinct effects on phenotype, with the possible exception of nail dystrophy, commoner with hHb1 defects. Other factors are required to explain the marked variation in clinical severity within and between cases.

Amino Acid Sequence↗
PubMed1999

Differences in hair follicle dermal papilla volume are due to extracellular matrix volume and cell number: implications for the control of hair follicle size and androgen responses.

The size of a hair follicle is thought to be determined by the volume of its dermal papilla. The volume of the dermal papilla depends on the number of cells it contains and on the volume of the extracellular matrix. To establish which of these two variables is related to differences in hair follicle size we performed a stereologic study on 235 hair follicles from different sites, including male facial skin (beard), female facial skin, and scalp. In facial follicles there was a strong correlation between the area of the hair cortex and the volume of the dermal papilla. The area of the hair cortex also correlated with the number of cells in the dermal papilla and with the volume of dermal papilla per cell. In scalp hair follicles, where there was a smaller range of sizes, the correlations between these variables were weaker. In large male facial follicles the mean total dermal papilla volume was almost 40-fold higher than in vellus follicles from female facial skin. This difference was associated with a mean 17-fold greater number of cells in the dermal papilla and a 2.4-fold greater volume associated with each cell. Intermediate results were obtained in scalp follicles. In many regions of the skin hair follicles enlarge in response to androgens during adult life hair. Our results imply that the increase in the volume of the dermal papilla in these follicles is due to an increase in the number of cells, either through proliferation or through the migration of cells from the follicular dermal sheath, and to an increase in the amount of extracellular matrix per cell. As androgens are thought to act primarily on the dermal papilla, these changes may have a direct bearing on the mechanism of androgen-mediated alterations in hair follicle size.

Adolescent↗
PubMed1998

A mutational hotspot in the 2B domain of human hair basic keratin 6 (hHb6) in monilethrix patients.

Monilethrix is an inherited hair dystrophy in which affected, fragile, hairs have an unique beaded morphology. Ultrastructural studies suggest a defect in filament structure in the cortex of the hair, and the hard keratins of hair and nail are thus candidate genes. In several families with autosomal dominant monilethrix, the disorder has been linked to the type II keratin gene cluster at chromosome 12q13. Recently, causative mutations in the critical helix termination motif in the 2B domain of the human hair basic keratin 6 (hHb6) have been identified. We now report the results of sequencing this domain in 13 unrelated families or cases with monilethrix. Five of the 13 had the same mutation as previously found, a G to A transversion leading to a lysine for glutamic acid substitution (E413K) in the 2B domain (residue 117 of the 2B helix) of hHb6. The mutation was confirmed by a restriction fragment length polymorphism assay developed for this purpose, and, as this mutation is evidently a common cause of the syndrome, for use in screening other cases. In eight families or cases, however, including three in whom linkage data are consistent with a defect at the type II keratin locus, no mutation was found in this domain of hHb6.

Family Health↗
PubMed1998

Androgen-dependent beard dermal papilla cells secrete autocrine growth factor(s) in response to testosterone unlike scalp cells.

Androgens stimulate many hair follicles, e.g., beard, but may cause regression on the scalp; occipital areas are considered androgen independent. The mesenchyme-derived dermal papilla that regulates the hair follicle is considered the site of androgen action. Because hair size has been clearly related to dermal papilla size, one of the key functions androgens must regulate is the size of the dermal papilla. This implies that androgens stimulate dermal papilla cells to divide or to secrete autocrine mitogenic factors. As physiologic levels of androgens do not stimulate mitogenesis in cultured dermal papilla cells, this study was designed to determine whether dermal papilla cells cultured from human hair follicles with different responses to androgens in vivo, i.e., androgen-dependent beard and androgen-independent nonbalding scalp, produce soluble autocrine mitogenic factors and, if so, whether either cell type altered their secretion in response to testosterone in vitro. Conditioned medium was prepared by incubating individual primary lines of cells for 24 h with, and without, testosterone (10(-10)-10(-5) M). All conditioned media significantly increased [3H] thymidine incorporation by other dermal papilla cells; trypsin treatment significantly reduced the effect. Although both beard and scalp cell conditioned media had a similar stimulatory potential, beard cells incorporated approximately double the [3H]thymidine of scalp cells, in both types of media. Physiologic levels of testosterone increased mitogenic factor production by beard, but not scalp cells; only beard cells responded to these factor(s). Testosterone added after conditioning had no effect, indicating stimulation was not a synergistic effect of testosterone and conditioned medium. Thus, both beard and scalp cells release similar autocrine growth factor(s), but their response to these factor(s) is determined by their in vivo origin. Testosterone in vitro stimulates secretion of an autocrine growth factor(s) by beard, but not scalp cells, to which only beard cells are able to respond, reflecting the responses to androgens in vivo. These factors may be involved in the key increase of dermal papilla size necessary for androgen-induced changes in hair size.

Adult↗
PubMed1998

Foot dermatitis in children: causative allergens and follow-up.

Allergic contact dermatitis from shoes may have a typical pattern of presentation, but we have found that the distribution of dermatitis is often unhelpful in establishing the diagnosis. In this study, we aimed to define the features of foot dermatitis in children and to assess its outcome, in comparison to adults with foot eruptions. Relevant allergens were found in 15 out of 29 children and 26 out of 57 adults with foot eruptions. The most common allergens in children were rubber chemicals and topical medicaments. Adults showed a similar pattern, but also reacted to clothing dyes. The prognosis in both groups was good, with the dermatitis improving or resolving in 2/3.

Adolescent↗
PubMed1998

Hair follicles: kinetic concepts and human disease.

The hair follicle is a dynamic structure in which vigorous cell proliferation and protein synthesis occur on an intermittent basis during the course of the hair growth cycle. This article reviews how the kinetics of hair growth are altered in common physiological and pathological hair disorders and how these changes can be related to the clinical features.

Alopecia Areata↗
PubMed1997

Mapping of monilethrix to the type II keratin gene cluster at chromosome 12q13 in three new families, including one with variable expressivity.

Monilethrix is an autosomal dominant disorder chiefly affecting hair. The degree of hair dystrophy is highly variable, as is the presence of additional features, such as follicular keratoses. In three British families of monilethrix, linkage has recently been reported to the type II keratin gene cluster at chromosome 12q13, and it has been suggested that the disease is due to a defect in the hard keratins of hair and nail. If monilethrix is a keratin disorder, we would predict that some pedigrees might map to the type I keratin gene cluster on 17q where hard keratin genes are also found. We have now studied clinically and by linkage analysis three new and unrelated pedigrees from England, Scotland and Spain, the first of which showed a variant phenotype. In this family the disease was expressed in four of 12 cases only as a follicular-keratosis of the neck, elbows and knees, and without clinical or historical evidence of hair anomalies; non-penetrance in an obligate carrier was also observed. In all three families, we have established linkage to a series of microsatellite markers at the type II locus at 12q13 (Zmax = 6.34 at theta = 0.00 for D12S368) and have excluded linkage from the type I keratin gene cluster on 17q. It remains probable that monilethrix is a disorder of hard keratins, but at present there is no evidence that it is due to defects in type I keratins.

Alopecia↗
PubMed1996

Dermal papilla cells derived from beard hair follicles secrete more stem cell factor (SCF) in culture than scalp cells or dermal fibroblasts.

As stem cell factor (SCF) and its receptor, c-kit, are involved in hair pigmentation, SCF is probably produced in the skin, possibly by the regulatory follicular dermal papilla. Since androgens often alter the type and color of hair, probably via the dermal papilla, they may regulate its SCF production. SCF produced by beard and non-balding scalp dermal papilla cells in the presence, or absence, of 10nM testosterone was assayed by ELISA. After 24 h, beard cells produced significantly (p = 0.001) more SCF than scalp cells, while beard and scalp fibroblasts secreted significantly (p = 0.04) less SCF. Testosterone in vitro had no effect on SCF secretion. These results support the hypotheses that the dermal papilla is a local source of SCF in hair follicles and that androgens would alter SCF production only at specific points of the hair cycle.

Cells, Cultured↗
PubMed1996

The pathogenesis of alopecia areata.

Knowledge of the disease mechanisms in alopecia areata is discussed in the light of progress in hair biology, immunology, and genetics. A disease model is presented incorporating polygenic determination of disease severity and susceptibility with largely unknown trigger factors responsible for initiating clinical disease expression. Experimental systems including animal models for alopecia areata offer new opportunities for investigation of alopecia areata and developing novel therapies.

Alopecia↗
PubMed1996

The metabolism of testosterone by dermal papilla cells cultured from human pubic and axillary hair follicles concurs with hair growth in 5 alpha-reductase deficiency.

Androgens regulate the growth of many human hair follicles, but only pubic, axillary, and scalp hair growth occur in men with 5 alpha-reductase deficiency. This suggests that 5 alpha-dihydrotestosterone is the active intracellular androgen in androgen-dependent follicles, except in the axilla and pubis. Since the dermal papilla plays a major regulatory role in hair follicles and may be the site of androgen action, we have investigated androgen metabolism in six primary lines of cultured dermal papilla cells from pubic and axillary hair follicles; previous studies have shown that beard cells take up and metabolize testosterone, retaining and secreting 5 alpha-dihydrotestosterone. After 24 h preincubation in serum-free Eagle's medium 199, 100-mm dishes of confluent cells were incubated for 2 h with 5 nM [1,2,6,7-3H]testosterone. Media were collected and the cells washed with phosphate-buffered saline and extracted with chloroform: methanol (2:1). After the addition of unlabeled and 14C-labeled marker steroids, the extracts were analyzed by a two-step thin-layer chromatography system; steroid identity was confirmed by recrystallization to a constant 3H/14C ratio. Beard and pubic dermal papilla cells were also incubated for 24 h, and the medium was analyzed at various times. The results from pubic and axillary primary cell lines were similar. In both cells and media the major steroid identified was testosterone, but significant amounts of androstenedione were present, indicating 17 beta-hydroxysteroid dehydrogenase activity; androstenedione was also identified within the cells, but a small amount of 5 alpha-dihydrotestosterone was only identified in one pubic cell line. Beard dermal papilla cells secreted large amounts of 5 alpha-dihydrotestosterone into the medium over 24 h in contrast to pubic cells, which produced only very small amounts. The pubic and axillary cell results contrasts with the observations of pronounced 5 alpha-dihydrotestosterone in beard cells and confirm that androgen metabolism in cultured dermal papilla cells reflects the parent follicle's ability to respond to androgen in the absence of 5 alpha-reductase type II in vivo. This supports our hypothesis that androgen acts on hair follicles via the dermal papilla and suggests that cultured dermal papilla cells may offer an important model system for studies of androgen action.

Cells, Cultured↗
PubMed1994

The aetiology and pathogenesis of alopecia areata.

In common with a number of inflammatory autoimmune diseases, genetic factors including HLA class II associations have been identified in alopecia areata. No consensus has been reached on the identity of a specific disease target within the hair follicle in alopecia areata. Suggested candidate cell types include the dermal papilla cells, the keratinocytes of the matrix and presumptive cortex and the hair bulb melanocytes, but these need not be mutually exclusive. The pathogenesis is known to involve disturbance of immune function but there is no proof that an autoimmune mechanism is fundamental. We propose a pathogenetic model incorporating polygenic determination of disease susceptibility and severity with additional, possibly environmental, factors as triggers for disease expression.

Alopecia Areata↗