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R Paus

Publications and source records attributed to R Paus.

At least 19 recordsLinked to original sources
PubMed2006

Male New Zealand Black/KN mice: a novel model for autoimmune-induced permanent alopecia?

BACKGROUND: Irreversible, permanent and scarring alopecia is associated with several autoimmune diseases, including all autoimmune connective tissue disorders. The pathogenesis of autoimmune-induced permanent alopecia (APA) is still poorly understood, and instructive, simple mouse models for the study of APA are needed urgently. During the course of our studies in a well-established mouse model for chronic rheumatoid arthritis, the New Zealand Black/KN (NZB/KN) mouse, we noticed that ageing male NZB/KN mice developed spontaneous APA. OBJECTIVES: To study whether alopecia seen in ageing male NZB/KN mice displays key features of human APA and may, thus, be a useful new mouse model for clinically relevant APA research. METHODS: NZB/KN, the F1 hybrid of NZW/N Slc x NZB/KN (W/BKN F1), the F1 hybrid of NZB/KN x NZW/N Slc (BKN/W F1), and the F2 hybrid of W/BKN F1 x W/BKN F1 mice were employed in this study, in order to check which strain carries the highest risk of alopecia development. Besides routine histology, CD3, CD4 and CD8 expression as well as immunoglobulin (Ig) G and IgM deposition in hair follicles were investigated by immunohistology/immunofluorescence. Mast cell distribution/degranulation and Ki-67 (proliferation)/TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling) (apoptosis) positive cells were also analysed. RESULTS: Only F2 male NZB/KN mice were prone to develop alopecia, suggesting that Y chromosome-associated gene(s) are involved in the pathogenesis of APA, which incidence rises with increasing age. The lesional alopecia skin in 12-month-old male NZB/KN mice showed a sharp decline in hair follicle density, thus meeting a key criterion of permanent alopecia. Both macroscopically and histologically, the alopecia seen in these mice resembled in many respects different stages of clinical APA, such as alopecia associated with chronic discoid lupus erythematosus (DLE) in humans. Lesional APA hair follicles in mice displayed intrafollicular and perifollicular mononuclear cell infiltrates, as well as an increased number of activated (degranulated) perifollicular mast cells. In the fully developed lesion, many CD4+ cells were seen in perifollicular locations, including the epithelial stem cell region (bulge), and also contained a few CD8+ T cells. IgM deposits were found in the follicular basement membrane zone (BMZ). Both in the bulge and the hair matrix region of the affected anagen hair follicles, there were signs of massive keratinocyte apoptosis. CONCLUSIONS: Our currently available data suggest that male but not female NZB/KN mice may indeed represent a suitable mouse model for APA, with some similarities to the permanent alopecia seen in human DLE patients, although additional and confirmatory investigations are needed before this mouse strain can be accepted as a murine equivalent of APA in humans.

Aging↗
PubMed2006

Oral zinc sulphate causes murine hair hypopigmentation and is a potent inhibitor of eumelanogenesis in vivo.

BACKGROUND: C57BL/6 a/a mice have been widely used to study melanogenesis, including in electron paramagnetic resonance (EPR) studies. Zinc cations modulate melanogenesis, but the net effect of Zn2+ in vivo is unclear, as the reported effects of Zn2+ on melanogenesis are ambiguous: zinc inhibits tyrosinase and glutathione reductase in vitro, but also enhances the activity of dopachrome tautomerase (tyrosinase-related protein-2) and has agonistic effects on melanocortin receptor signalling. OBJECTIVES: To determine in a C57BL/6 a/a murine pilot study whether excess zinc ions inhibit, enhance or in any other way alter hair follicle melanogenesis in vivo, and to test the usefulness of EPR for this study. METHODS: ZnSO(4).7H2O was continuously administered orally to C57BL/6 a/a mice during spontaneous and depilation-induced hair follicle cycling (20 mg mL-1; in drinking water; mean+/-SD daily dose 1.2+/-0.53 mL), and hair pigmentation was examined macroscopically, by routine histology and by EPR. RESULTS: Oral zinc cations induced a bright brown lightening of new hair shafts produced during anagen, but without inducing an EPR-detectable switch from eumelanogenesis to phaeomelanogenesis. The total content of melanin in the skin and hair shafts during the subsequent telogen phase, i.e. after completion of a full hair cycle, was significantly reduced in Zn-treated mice (P=0.0005). Compared with controls, melanin granules in precortical hair matrix keratinocytes, hair bulb melanocytes and hair shafts of zinc-treated animals were reduced and poorly pigmented. Over the course of several hair cycles, lasting hair shaft depigmentation was seen during long-term exposure to high-dose oral Zn2+. CONCLUSIONS: High-dose oral Zn2+ is a potent downregulator of eumelanin content in murine hair shafts in vivo. The C57BL/6 mouse model offers an excellent tool for further dissecting the as yet unclear underlying molecular basis of this phenomenon, while EPR technology is well suited for the rapid, qualitative and quantitative monitoring of hair pigmentation changes.

Administration, Oral↗
PubMed2006

What is the biological basis of pattern formation of skin lesions?

Pattern recognition is at the heart of clinical dermatology and dermatopathology. Yet, while every practitioner of the art of dermatological diagnosis recognizes the supreme value of diagnostic cues provided by defined patterns of 'efflorescences', few contemplate on the biological basis of pattern formation in and of skin lesions. Vice versa, developmental and theoretical biologists, who would be best prepared to study skin lesion patterns, are lamentably slow to discover this field as a uniquely instructive testing ground for probing theoretical concepts on pattern generation in the human system. As a result, we have at best scraped the surface of understanding the biological basis of pattern formation of skin lesions, and widely open questions dominate over definitive answer. As a symmetry-breaking force, pattern formation represents one of the most fundamental principles that nature enlists for system organization. Thus, the peculiar and often characteristic arrangements that skin lesions display provide a unique opportunity to reflect upon--and to experimentally dissect--the powerful organizing principles at the crossroads of developmental, skin and theoretical biology, genetics, and clinical dermatology that underlie these--increasingly less enigmatic--phenomena. The current 'Controversies' feature offers a range of different perspectives on how pattern formation of skin lesions can be approached. With this, we hope to encourage more systematic interdisciplinary research efforts geared at unraveling the many unsolved, yet utterly fascinating mysteries of dermatological pattern formation. In short: never a dull pattern!

Algorithms↗
PubMed2005

Interferon-gamma is a potent inducer of catagen-like changes in cultured human anagen hair follicles.

BACKGROUND: Interferon (IFN)-gamma appears to be an important hair cycle modulator in mice. It is unclear whether it has similar hair growth modulatory functions in human hair follicles. OBJECTIVES: To study whether IFN-gamma can be exploited to modulate the growth, pigmentation and/or cycling of organ-cultured human anagen scalp hair follicles, as an in vitro indicator system for how IFN-gamma affects human hair growth in vivo. This was correlated with the hair follicle expression patterns of IFN-gamma receptors alpha and beta. In addition, we wanted to establish a new, simple tool for the rapid experimental induction of catagen in vitro. METHODS: Normal human scalp hair follicles in the anagen VI stage of the hair cycle were cultured according to the method of Philpott et al., with or without IFN-gamma (50-1000 IU mL(-1)). Hair shaft elongation and pigmentation changes were measured, complemented by quantitative histomorphometry to assess changes in hair follicle cycling (hair cycle score), proliferation (Ki-67), melanogenesis (Masson-Fontana) and apoptosis (TUNEL). IFN-gamma receptors were also localized by immunofluorescence and EnVision technique. As transforming growth factor (TGF)-beta2 is a recognized key inducer of catagen in human hair follicles, TGF-beta2 expression was investigated by tyramide signal amplification and reverse transcription-polymerase chain reaction in anagen hair follicles treated with vehicle (phosphate-buffered saline) or IFN-gamma. RESULTS: IFN-gamma rapidly inhibited hair elongation in cultured human anagen hair follicles and induced morphological signs of catagen transformation after only 4 days of culture, i.e. faster than with other reported catagen-inducers (e.g. TGF-beta2). Proliferation was inhibited, apoptosis was increased and follicular melanogenesis was switched off in hair bulb keratinocytes treated in situ with IFN-gamma. Anagen hair follicles displayed strong IFN-gamma receptor alpha-like immunoreactivity, while the immunoreactivity for IFN-gamma receptor beta in the hair matrix was only weak. TGF-beta2 immunoreactivity and mRNA transcript levels were enhanced in hair follicles treated with IFN-gamma. CONCLUSIONS: These data suggest that IFN-gamma is a potent catagen inducer in normal human scalp hair follicles, which express cognate receptors, and show that IFN-gamma administration offers an excellent tool for experimental catagen induction in organ-cultured human hair follicles. This catagen induction probably occurs at least in part via upregulation of the recognized catagen-stimulatory growth factor TGF-beta2.

Apoptosis↗
PubMed2004

Towards optimization of an organotypic assay system that imitates human hair follicle-like epithelial-mesenchymal interactions.

BACKGROUND: Human hair growth can currently be studied in vitro by the use of organ-cultured scalp hair follicles (HFs). However, simplified organotypic systems are needed for dissecting the underlying epithelial-mesenchymal interactions and as screening tools for candidate hair growth-modulatory agents. OBJECTIVES: To optimize the design and culture conditions of previously published organotypic systems that imitate epithelial-mesenchymal interactions in the human HF as closely as possible. MATERIALS AND METHODS: Continuous submerged organotypic 'sandwich' cultures were established. These consist of a pseudodermis (collagen I mixed with and contracted by human interfollicular dermal fibroblasts) on which one of two upper layers is placed: either a mixture of Matrigel basement membrane matrix (BD Biosciences, Bedford, MA, U.S.A.) and follicular dermal papilla fibroblasts (DPC), with outer root sheath keratinocytes (ORSK) layered on the top ('layered' system), or a mixture of Matrigel, DPC and ORSK ('mixed' system). Morphological and functional characteristics of these 'folliculoid sandwiches' were then assessed by routine histology, histomorphometry and immunohistochemistry. RESULTS: In both 'layered' and 'mixed' systems, the ORSK formed spheroid epithelial cell aggregates, which retained their characteristic keratin expression pattern (i.e. cytokeratin 6). In the 'mixed' sandwich model the size of the epithelial cell aggregates was smaller, but the numbers of ORSK were significantly higher than in the 'layered' model at day 14 in the culture. ORSK proliferated better in the 'mixed' than in the 'layered' sandwich system, regardless of the calcium or serum content of the media, whereas apoptosis of ORSK was lowest in the 'mixed' system in serum-free, low calcium medium. The kinetics of proliferation and apoptosis of DPC, which retained their characteristic expression of versican, were similar in both systems. However, proliferation and apoptosis of DPC were higher in the presence of serum and/or under high calcium conditions. CONCLUSIONS: Our results underscore the importance of structural design and medium composition for epithelial-mesenchymal interactions as they occur in the human HF. Specifically, we report a new organotypic submerged 'folliculoid sandwich' system with serum-free, low calcium medium and a mixture of interacting human DPC and ORSK, which offers several advantages over previously available assays. This system allows the standardized assessment of the effects of a test agent on the proliferation, apoptosis and key marker expression of human ORSK and DPC under substantially simplified in vitro conditions which approximate the in vivo situation.

Apoptosis↗
PubMed2004

Increased airway responsiveness, allergy-type-I skin responses and systemic anaphylaxis in a humanized-severe combined immuno-deficiency mouse model.

BACKGROUND: In patients with allergic bronchial asthma, a strong relationship between elevated serum IgE antibody titres and the development of increased airway responsiveness (AR) has been demonstrated. To further elucidate the relationship between human (hu) IgE and development of increased AR, we developed an in vivo model utilizing immuno-compromised severe combined immuno-deficiency (SCID) mice. METHODS: SCID mice were either reconstituted with peripheral blood mononuclear cells (PBMC) from non-atopic, healthy or atopic individuals sensitized against house dust mite allergen (Der p), or passively sensitized with plasma from non-atopic, healthy or atopic individuals. RESULTS: In both systems, atopic hu-SCID mice developed increased AR. The following results suggest that these responses were mediated via IgE antibodies: increased AR did not occur after transfer of either PBMC or IgE-negative plasma from non-atopic individuals; increased AR occurred simultaneous with increased serotonin release detected 15 min after allergen-aerosol challenge in bronchoalveolar lavage fluid; and increased AR required at least two allergen-aerosol challenges. SCID mice reconstituted with serum containing anti-Der p IgE antibodies developed positive immediate-type skin test responses to intradermal injection of Der p as well as anti-hu-IgE antibody. In addition, IgE binding to skin mast cells was demonstrated by immunohistochemistry. Furthermore, intravenous challenge of hu anti-Der p positive SCID mice with Der p resulted in systemic anaphylaxis. CONCLUSION: These data provide evidence that passive immunization of SCID mice with hu IgE alters AR and that T cells and eosinophils were not a requirement for the development of increased AR in this model.

Animals↗
PubMed2002

Enhanced inhibition of tumour growth and metastasis, and induction of antitumour immunity by IL-2-IgG2b fusion protein.

Cytokine-immunoglobulin (Ig)-fusion proteins have attracted increasing interest as antitumour agents. Here, we have investigated the antimetastatic and antitumour responses elicited in vivo by mammary adenocarcinoma cells (TS/A) engineered to secrete interleukin (IL)-2-IgG fusion proteins. TS/A cells were transfected with DNA coding for IL-2-IgG2b, IgG2b or IL-2, and injected subcutaneously into syngeneic mice. Animals injected with TS/A-IL-2 or TS/A-IL-2-IgG2b both efficiently rejected tumours, whereas treatment with parental cells or TS/A-IgG2b was lethal. Interestingly, only mice vaccinated with IL-2-IgG2b fusion protein-secreting cells showed a long-lasting protective immunity against a later challenge with parental tumour cells. Moreover, the metastatic potential of TS/A-IL-2-IgG2b-transfected cells was dramatically decreased compared with TS/A-IL-2-cells, with a virtual absence of lung metastases after intravenous injection. Adenocarcinomas secreting IL-2-IgG2b exhibited a more prominent, early and persistent infiltration of CD4+, CD8+ and natural killer (NK) cells than TS/A-IL-2 cells. Therefore, upon transfection into adenocarcinoma cells, the IgG2b part of IL-2 fusion protein exerts intriguing added antitumour properties over IL-2 alone, thus contributing to a long-lasting tumour immunity, probably by the recruitment of specific immune effector cells. These findings suggest a promising new oncotherapeutic strategy for poorly immunogenic tumours: vaccination with tumour cells engineered to secrete IL-2-IgG2b fusion protein.

Adenocarcinoma↗
PubMed2001

The IL-15R alpha chain signals through association with Syk in human B cells.

The alpha-chain of the IL-15R (IL-15Ralpha) serves as the specific, high-affinity receptor for IL-15. It is expressed by lymphoid and nonlymphoid cells, including B cell lymphoma lines. In this study, we have further explored IL-15Ralpha-mediated signaling in activated primary B cells and in Raji cells, a human B-lymphoblastoid cell line which expresses the IL-15Ralpha and IL-2Rgamma chains, but lacks the IL-2Rbeta chain. Stimulation of Raji cells with IL-15 induces their proliferation and rescues them from C2-ceramide-induced apoptosis. By immunoprecipitation and Western blotting, we show that treatment of Raji cells and activated primary B cells with IL-15 induces coprecipitation of Syk kinase with the IL-15Ralpha chain. Upon association, the activated Syk kinase phosphorylates the IL-15Ralpha chain as well as phospholipase Cgamma, which coprecipitates with Syk. Furthermore, transfection of Raji cells with stem-loop Syk antisense oligonucleotides prevents IL-15Ralpha and phospholipase Cgamma phosphorylation as well as the inhibition of apoptosis by IL-15. Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells.

Apoptosis↗
PubMed2001

Indications for a 'brain-hair follicle axis (BHA)': inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P.

It has long been suspected that stress can cause hair loss, although convincing evidence of this has been unavailable. Here, we show that in mice sonic stress significantly increased the number of hair follicles containing apoptotic cells and inhibited intrafollicular keratinocyte proliferation in situ. Sonic stress also significantly increased the number of activated perifollicular macrophage clusters and the number of degranulated mast cells, whereas it down-regulated the number of intraepithelial gd T lymphocytes. These stress-induced immune changes could be mimicked by injection of the neuropeptide substance P in nonstressed mice and were abrogated by a selective substance P receptor antagonist in stressed mice. We conclude that stress can indeed inhibit hair growth in vivo, probably via a substance P-dependent activation of macrophages and/or mast cells in the context of a brain-hair follicle axis.

Acoustic Stimulation↗
PubMed2001

The nude mouse skin phenotype: the role of Foxn1 in hair follicle development and cycling.

The original nude mouse mutation has proven to be an incredibly valuable biomedical tool since its discovery in 1966. Initially its value was as a tool to study the immune system. The immunodeficiency in this mutant mouse made nude mice valuable as hosts for xenografts, primarily for cancer research. More recently, the most obvious clinical feature of this mutant mouse, lack of hair, has been capitalized on to define the role of Foxn1 in normal and pathological skin and hair follicle physiology.

Animals↗
PubMed2001

Graying: gerontobiology of the hair follicle pigmentary unit.

The visual appearance of humans derives predominantly from their skin and hair color. The phylogenetically ancient biochemical [corrected] pathway underling this phenomenon is called melanogenesis and results in the production of melanin pigments in neural crest-derived melanocytes, followed by its transfer to epithelial cells. While melanin from epidermal melanocytes clearly protects human skin by screening harmful ultraviolet radiation, the biologic value of hair pigmentation is less clear. In addition to important roles in social/sexual communication, one potential benefit of pigmented scalp hair in humans may be the rapid excretion of heavy metals, chemicals, toxins from the body by their selective binding to melanin. The hair follicle and epidermal melanogenic systems are broadly distinct, though open. The primary distinguishing feature of follicular melanogenesis, compared to the continuous melanogenesis in the epidermis, is the tight coupling of hair follicle melanogenesis to the hair growth cycle. This cycle appears to involve periods of melanocyte proliferation (during early anagen), maturation (mid to late anagen) and melanocyte death via apoptosis (during early catagen). Thus, each hair cycle is associated with the reconstruction of an intact hair follicle pigmentary unit... at least for the first 10 cycles or so. Thereafter, gray and white hairs appear, suggesting an age-related, genetically regulated exhaustion of the pigmentary potential of each individual hair follicle. Melanocyte aging may be associated with reactive oxygen species-mediated damage to nuclear and mitochondrial DNA with resultant accumulation of mutations with age, in addition to dysregulation of anti-oxidant mechanisms or pro/anti-apoptotic factors within the cells. While the perception of "gray hair" derives in large part from the admixture of pigmented and white hair, it is important to note that individual hair follicles can indeed exhibit pigment dilution or true grayness. This dilution is due to a reduction in tyrosinase activity of hair bulbar melanocytes, sub-optimal melanocyte-cortical keratinocyte interactions, and defective migration of melanocytes from a reservoir in the upper outer root sheath to the pigment-permitting microenvironment close to the dermal papilla of the hair bulb. Animal models with mutations in apoptotic survival factors (e.g. bcl-2) and in melanogenic enzymes (TRP-1) are providing valuable insights into the aging hair pigmentary unit. It is from these and other advances, including our ability to grow hair follicle melanocytes in vitro, that the possibility of reversing canities has been raised. Indeed, it is not too uncommon to see spontaneous repigmentation along the same individual hair shaft in early canities. Moreover, melanocytes taken from gray and white hair follicles can be induced to pigment in vitro. One of the surprising results of pigment loss in canities is the alteration in keratinocyte proliferation and differentiation, providing the tantalizing suggestion that melanocytes in the hair follicle contribute far more that packages of melanin alone. Furthermore, there have been some unconfirmed reports in the literature suggesting that canities may link (although not causally) with more systemic alterations in homeostasis e.g. osteoporosis. Here, we review the current state of knowledge of the development, regulation and control of the human hair follicle pigmentary unit during life.

Aging↗
PubMed2001

Mutant laboratory mice with abnormalities in hair follicle morphogenesis, cycling, and/or structure: annotated tables.

Numerous transgenic, targeted mutagenesis (so-called knockouts), conditional (so-called "gene switch") and spontaneous mutant mice develop abnormal hair phenotypes. The number of mice that exhibit such abnormalities is increasing exponentially as genetic engineering methods become routine. Since defined abnormalities in hair follicle morphogenesis, cycling and/or structure in such mutant mice provide important clues to the as yet poorly understood functional roles of many gene products, it is useful to summarize and classify these mutant mice according to their hair phenotype. This review provides a corresponding, annotated table of mutant mice with hair abnormalities, classifying the latter into 6 categories, 1) abnormally low number of hair follicles, 2) disorders of hair morphogenesis, 3) of hair follicle cycling, 4) of hair follicle structure 5) of sebaceous gland structure, and 6) hair growth disorders as a consequence of immunological abnormalities. This annotated table should serve as a useful source of reference for anyone who is interested in the molecular controls of hair growth, for investigators who are looking for mouse models to explore or compare the functional activities of their gene of interest, and for comparing the hair phenotype of newly generated mouse mutants with existing ones.

Animals↗
PubMed2001

Patterns of proliferation and apoptosis during murine hair follicle morphogenesis.

In this study, we have correlated cutaneous apoptosis and proliferation in neonatal mice during hair follicle morphogenesis. We have applied a novel triple- staining technique that uses Ki67 immunoreactivity as a marker of proliferation as well as TUNEL and Hoechst 33342 staining as apoptosis markers. We have also assessed the immunoreactivity of interleukin-1 beta-converting enzyme, caspase 1, a key enzyme in the execution of apoptosis, and of P-cadherin, which has been suggested as a key adhesion receptor in segregating proliferating keratinocytes. The TUNEL data were systematically compared with high resolution light microscopy and transmission electron microscopy data. Virtually all keratinocytes of the developing hair bud were strongly Ki67(+), suggesting that the hair bud is not an epidermal invagination but primarily the product of localized keratinocyte proliferation. As hair follicle development advanced, three distinct foci of proliferation became apparent: the distal outer root sheath around the hair canal, the mid outer root sheath, and the proximal hair matrix. Of these proliferating hair follicle keratinocytes only defined subsets expressed P-cadherin. TUNEL(+) cells in the hair follicle were not found before stage 5 of murine hair follicle morphogenesis. During the early stages of hair follicle development, interleukin-1 beta-converting enzyme immunoreactivity was present on all keratinocytes, but virtually disappeared from the proximal hair follicle epithelium later on. High resolution light microscopy/transmission electron microscopy revealed scattered and clustered apoptotic keratinocytes in all epithelial hair follicle compartments throughout hair follicle development, including its earliest stages. This highlights striking differences in the demarcation of apoptotic hair follicle keratinocytes between the TUNEL technique and high resolution light microscopy/transmission electron microscopy and suggests a role for apoptosis in sculpting the hair follicle even during early hair follicle development.

Animals↗
PubMed2001

A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages.

Numerous strains of mice with defined mutations display pronounced abnormalities of hair follicle cycling, even in the absence of overt alterations of the skin and hair phenotype; however, in order to recognize even subtle, hair cycle-related abnormalities, it is critically important to be able to determine accurately and classify the major stages of the normal murine hair cycle. In this comprehensive guide, we present pragmatic basic and auxiliary criteria for recognizing key stages of hair follicle growth (anagen), regression (catagen) and quiescence (telogen) in C57BL/6NCrlBR mice, which are largely based on previous work from other authors. For each stage, a schematic drawing and representative micrographs are provided in order to illustrate these criteria. The basic criteria can be employed for all mouse strains and require only routine histochemical techniques. The auxiliary criteria depend on the immunohistochemical analysis of three markers (interleukin-1 receptor type I, transforming growth factor-beta receptor type II, and neural cell-adhesion molecule), which allow a refined analysis of anatomical hair follicle compartments during all hair cycle stages. In contrast to prior staging systems, we suggest dividing anagen III into three distinct substages, based on morphologic differences, onset and progression of melanogenesis, and the position of the dermal papilla in the subcutis. The computer-generated schematic representations of each stage are presented with the aim of standardizing reports on follicular gene and protein expression patterns. This guide should become a useful tool when screening new mouse mutants or mice treated with pharmaceuticals for discrete morphologic abnormalities of hair follicle cycling in a highly reproducible, easily applicable, and quantifiable manner.

Animals↗
PubMed2001

A new strategy for modulating chemotherapy-induced alopecia, using PTH/PTHrP receptor agonist and antagonist.

Parathyroid hormone (PTH) related peptide (PTHrP) and the PTH/PTHrP receptor (PTH/PTHrP-R) show prominent cutaneous expression, where this signaling system may exert important paracrine and/or autocrine functions, such as in hair growth control. Chemotherapy-induced alopecia - one of the fundamental unsolved problems of clinical oncology - is driven in part by defined abnormalities in hair follicle cycling. We have therefore explored the therapeutic potential of a PTH/PTHrP-R agonist and two PTH/PTHrP-R antagonists in a mouse model of cyclophosphamide-induced alopecia. Intraperitoneal administration of the agonist PTH(1-34) or the antagonists PTH(7-34) and PTHrP(7-34) significantly altered the follicular response to cyclophosphamide in vivo. PTH(7-34) and PTHrP(7-34) shifted it towards a mild form of "dystrophic anagen", associated with a significant reduction in apoptotic (TUNEL+) hair bulb cells, thus mitigating the degree of follicle damage and retarding the onset of cyclophosphamide-induced alopecia. PTH(1-34), in contrast, forced hair follicles into "dystrophic catagen", associated with enhanced intrafollicular apoptosis. We had previously shown that an induced shift in the follicular damage-response towards "dystrophic catagen" mitigates cyclophosphamide-induced alopecia, whereas a shift towards "dystrophic catagen" initially enhanced the hair loss, yet subsequently promoted accelerated hair follicle recovery. Therefore, this study in an established animal model of chemotherapy-induced alopecia, which closely mimics human chemotherapy-induced alopecia, strongly encourages the exploration of PTH/PTHrP-R agonists and antagonists as novel therapeutic agents in chemotherapy-induced alopecia.

Alopecia↗
PubMed2001

Hair-cycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides.

As the neuropeptide substance P can manipulate murine hair growth in vivo, we here further studied the role of sensory neuropeptides in hair follicle biology by determining the distribution and hair-cycle-dependent remodeling of the sensory innervation in C57BL/6 mouse back skin. Calcitonin-gene-related peptide, substance P, and peptide histidine methionine (employed as vasoactive intestinal peptide marker) were identified by immunohistochemistry. All of these markers immunolocalized to bundles of nerve fibers and to single nerve fibers, with distinct distribution patterns and major hair-cycle-associated changes. In the epidermis and around the distal hair follicle and the arrector pili muscle, only calcitonin-gene-related peptide immunoreactive nerve fibers were visualized, whereas substance P and peptide histidine methionine immunoreactive nerve fibers were largely restricted to the dermis and subcutis. Compared to telogen skin, the number of calcitonin-gene-related peptide, substance P, and peptide histidine methionine immunoreactive single nerve fibers increased significantly (p < 0.01) during anagen, including around the bulge region (the seat of epithelial stem cells). Substance P significantly accelerated anagen progression in murine skin organ culture, whereas calcitonin-gene-related peptide and a substance-P-inhibitory peptide inhibited anagen (p < 0.05). The inhibitory effect of calcitonin-gene-related peptide could be antagonized by coadministrating substance P. In contrast to substance P, calcitonin-gene-related peptide failed to induce anagen when released from subcutaneous implants. This might reflect a differential functional assignment of the neuropeptides calcitonin-gene-related peptide and substance P in hair growth control, and invites the use of neuropeptide receptor agonists and antagonists as novel pharmacologic tools for therapeutic hair growth manipulation.

Animals↗