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Androgen responsive genes as they affect hair growth
Abstract
Finasteride has been shown to be an effective treatment for men with androgenetic alopecia (AGA) as it restores hair growth to miniaturized hair follicles on the top of the scalp [1]. Caspases are regulators of programmed cell death, and very likely some specific caspases may function as mediators of the hair growth cycle. It is unclear whether finasteride influences the regulation of apoptosis via caspases in the hair follicle. Very little information is available regarding the role of caspases present in human hair follicles in normal scalp and in androgenetic alopecia. In this study we have analyzed the family of caspases, 1-10 along with usurpin, and XIAP, in men with normal scalp and in men with androgenetic alopecia before and after 6 months treatment with 1 mg oral finasteride treatment. Caspases 1, 3, 8 and 9 were detected predominantly within the isthmic and infundibular hair follicle area for both normal and AGA patients, however the expression of all factors, especially caspase 3 was greater in the AGA group than in the normal scalp group. AGA men had the same caspase factors but with greater expression. In the same AGA men treated with finasteride for 6 months, the expression of these factors was similar to levels in the normal group. Results from our study indicate caspase 3 to be of primary importance in normal hair homeostasis and that DHT may be signaling greater expression of caspases, inducing apoptosis in androgenetic alopecia. In conclusion, DHT may selectively regulate the caspase genes which play an important role in signaling programmed cell death, affecting the hair growth cycle.
... Androgenetic alopecia (AGA) is one of the hair cycle disorders affecting both males and females and causes inconvenience in modern social life. Hair loss is generally accompanied by thinned skin areas in the bald region [3,4]. This alopecia is generally caused by various internal factors such as a genetic problem or hormonal balance [3][4][5]. ...
... Hair loss is generally accompanied by thinned skin areas in the bald region [3,4]. This alopecia is generally caused by various internal factors such as a genetic problem or hormonal balance [3][4][5]. The major pathologic alteration of hair follicles in AGA exhibits a gradual shortening of the anagen phase in hair cycle dynamics. ...
... 5α-reductase plays an important role in the conversion of testosterone to dihydrotestosterone (DHT) in dermal papilla cells. After DHT binds to androgen receptors, the following signaling pathways disturb hair growth and eventually miniaturize hair follicles [3,4,6]. However, the precise molecular mechanism underlying AGA has not yet been fully elucidated. ...
Hair loss is a common status found among people of all ages. Since the role of hair is much more related to culture and individual identity, hair loss can have a great influence on well-being and quality of life. It is a disorder that is observed in only scalp patients with androgenetic alopecia (AGA) or alopecia areata caused by stress or immune response abnormalities. Food and Drug Administration (FDA)-approved therapeutic medicines such as finasteride, and minoxidil improve hair loss temporarily, but when they stop, they have a limitation in that hair loss occurs again. As an alternative strategy for improving hair growth, many studies reported that there is a relationship between the expression levels of prostaglandins (PGs) and hair growth. Four major PGs such as prostaglandin D2 (PGD2), prostaglandin I2 (PGI2), prostaglandin E2 (PGE2α), and prostaglandin F2 alpha (PGF2α) are spatiotemporally expressed in hair follicles and are implicated in hair loss. This review investigated the physiological roles and pharmacological interventions of the PGs in the pathogenesis of hair loss and provided these novel insights for clinical therapeutics for patients suffering from alopecia.
... The pivotal role of 5-reductase in dermal papilla cells is central to these changes, facilitating the conversion of testosterone (T) into DHT. Subsequently, strong binding of DHT to androgen receptors (AR) triggers a cascade of signaling events that disrupt normal hair growth, ultimately leading to the miniaturization of affected hair follicles [5,6]. Despite these insights, the precise mechanisms underlying AGA remain incompletely elucidated. ...
Prostaglandin E2 (PGE2) is known to be effective in regenerating tissues, and bimatoprost, an analog of PGF2α, has been approved by the FDA as an eyelash growth promoter and has been proven effective in human hair follicles. Thus, to enhance PGE2 levels while improving hair loss, we found dihydroisoquinolinone piperidinylcarboxy pyrazolopyridine (DPP), an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using DeepZema®, an AI-based drug development program. Here, we investigated whether DPP improved hair loss in human follicle dermal papilla cells (HFDPCs) damaged by dihydrotestosterone (DHT), which causes hair loss. We found that DPP enhanced wound healing and the expression level of alkaline phosphatase in DHT-damaged HFDPCs. We observed that DPP significantly down-regulated the generation of reactive oxygen species caused by DHT. DPP recovered the mitochondrial membrane potential in DHT-damaged HFDPCs. We demonstrated that DPP significantly increased the phosphorylation levels of the AKT/ERK and activated Wnt signaling pathways in DHT-damaged HFDPCs. We also revealed that DPP significantly enhanced the size of the three-dimensional spheroid in DHT-damaged HFDPCs and increased hair growth in ex vivo human hair follicle organ culture. These data suggest that DPP exhibits beneficial effects on DHT-damaged HFDPCs and can be utilized as a promising agent for improving hair loss.
... The results suggest that the single-compound catechin-glycoside and its extract have hair growth-promoting effects. DHT is generated, and eventually, hair loss proceeds [27]. Male hormones promote the positive function of masculinity and cause seborrheic dandruff to worsen the symptoms of alopecia [28]. ...
This study was conducted to examine the anti-hair loss mechanism of the supercritical fluid extraction-residues extract of Ulmus davidiana by the regulation of cytokine production and hormone function in human dermal follicle papilla cells (HDFPCs). To investigate the modulatory effects on H2O2-induced cytokines, we measured transforming growth factor-beta and insulin-like growth factor 1 secreted from HDFPCs. To investigate the regulatory effects of supercritical extraction-residues extract of Ulmus davidiana on dihydrotestosterone hormone production, cells were co-incubated with high concentrations of testosterone. The supercritical extraction-residues extract of Ulmus davidiana significantly inhibited the secretion of transforming growth factor-beta but rescued insulin-like growth factor 1 in a dose-dependent manner. The supercritical extraction-residues extract of Ulmus davidiana markedly reduced dihydrotestosterone production. These results suggest that the supercritical fluid extract residues of Ulmus davidiana and their functional molecules are candidates for preventing human hair loss.
... Additionally, apoptosis in hair follicle is believed to be an important contributor to the process of androgenic hair loss [80]. Hair follicle apoptosis can be induced by androgens such as testosterone and dihydrotestosterone, leading to reduced matrix cell growth, increased hair cell death, early induction of catagen-like transition of hair follicles, and ultimately, hair loss [81,82]. Topical application of RGO, linoleic acid, or b-sitosterol inhibited testosterone-induced apoptosis in a mouse model of androgenic alopecia by decreasing the Bax/Bcl-2 ratio and the level of TGF-b [83]. ...
Red ginseng oil (RGO), rather than the conventional aqueous extract of red ginseng, has been receiving much attention due to accumulating evidence of its functional and pharmacological potential. In this review, we describe the key extraction technologies, chemical composition, potential health benefits, and safety of RGO. This review emphasizes the proposed molecular mechanisms by which RGO is involved in various bioactivities. RGO is mainly produced using organic solvents or supercritical fluid extraction, with the choice of method greatly affecting the yield and quality of the end products. RGO contains a high unsaturated fatty acid levels along with considerable amounts of lipophilic components such as phytosterols, tocopherols, and polyacetylenes. The beneficial health properties of RGO include cellular defense, antioxidation, anti-inflammation, anti-apoptosis, chemoprevention, hair growth promotion, and skin health improvement. We propose several molecular mechanisms and signaling pathways that underlie the bioactivity of RGO. In addition, RGO is regarded as safe and nontoxic. Further studies on RGO must focus on a deeper understanding of the underlying molecular mechanisms, composition–functionality relationship, and verification of the bioactivities of RGO in clinical models. This review may provide useful information in the development of RGO-based products in nutraceuticals, functional foods, and functional cosmetics.
... 5α-reductase plays the key role in dermal papillar cells for the transformation of testosterone (T) to dihydrotestosterone (DHT). After strong binding of DHT to androgen receptors (AR), following cascade signaling alters hair growth and affected hair follicles are miniaturized after all [2,3]. However, the mechanisms underlying AGA are not fully understood. ...
Prostaglandin D2 (PGD2) and prostaglandin D2 receptor 2 (DP2) is known to be an important factor in androgenetic alopecia (AGA). However, the effect of PGD2 in human dermal papilla cells (hDPCs) is not fully understood. The function of PGD2-induced expression of the androgen receptor (AR), DP2, and AKT (protein kinase B) signal were examined by using real time-PCR (qRT-PCR), western blot analysis, immunocytochemistry (ICC), and siRNA transfection system. PGD2 stimulated AR expression and AKT signaling through DP2. PGD2 stimulated AR related factors (transforming growth factor beta 1 (TGFβ1), Creb, lymphoid enhancer binding factor 1 (LEF1), and insulin-like growth factor 1, (IGF-1)) and AKT signaling (GSK3β and Creb) on the AR expression in hDPCs. However, these factors were down-regulated by DP2 antagonist (TM30089) and AKT inhibitor (LY294002) as well as DP2 knockdown in hDPCs decreased AR expression and AKT signaling. Finally, we confirmed that PGD2 stimulates the expression of AR related target genes, and that AKT and its downstream substrates are involved in AR expression on hDPCs. Taken together, our data suggest that PGD2 promotes AR and AKT signal via DP2 in hDPCs, thus, PGD2 and DP2 signal plays a critical role in AR expression. These findings support the additional explanation for the development of AGA involving PGD2-DP2 in hDPCs.
... The first target is obviously androgenic: the aim is to slow production of dihydrotestosterone (DHT) by 5α-reductase. DHT acts by atrophying the hair follicle and, according to a recently advanced hypothesis [7], through a pro-apoptotic mechanism via caspase 3. ...
Synopsis : Excessive hair loss in men is a multifactorial problem that needs holistic treatment. The stimulation of matrix regeneration by a specifically designed peptide – biotinyl-GHK-was investigated ex vivo on human hair follicle biopsies, by immune fluorescence tagging and histology. Increased synthesis of collagen IV, laminin 5 and mitosis marker Ki67 was observed. The inhibition of 5-α-reductase by oleanolic acid was concomitantly observed in vitro. The combination of biotinyl-GHK, oleanolic acid and the well known vasoactive substance apigenin was then tested in a vehicle controlled clinical study of hair loss in a male panel of patients with high telogen ratio. Significant improvement in the A/T ratio was observed after four months in the treated group. The combined activities of activated microcirculation, inhibition of DHT production and matrix stimulation and repair clearly show measurable benefits for the anchoring and growth behaviour of the hairs on the scalp.
... Although finasteride, a synthetic type II 5α-reductase inhibitor, reduces the conversion of testosterone to DHT. 4) Also, finasteride suppressed caspase 1, 3, 8 and 9 expression. 5) But, it has adverse sexual side effects. 4) We wanted to find natural plant components having less severe side effects that could be used instead of finasteride. ...
This study was conducted to test whether ginsenoside F2 can reduce hair loss by influencing sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and the transforming growth factor beta (TGF-β) pathway of apoptosis in dihydrotestosterone (DHT)-treated hair cells and in a DHT-induced hair loss model in mice. Results for ginsenoside F2 were compared with finasteride. DHT inhibits proliferation of hair cells and induces androgenetic alopecia and was shown to activate an apoptosis signal pathway both in vitro and in vivo. The cell-based 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the proliferation rates of DHT-treated human hair dermal papilla cells (HHDPCs) and HaCaTs increased by 48% in the ginsenoside F2-treated group and by 12% in the finasteride-treated group. Western blot analysis showed that ginsenoside F2 decreased expression of TGF-β2 related factors involved in hair loss. The present study suggested a hair loss related pathway by changing SCAP related apoptosis pathway, which has been known to control cholesterol metabolism. SCAP, sterol regulatory element-binding protein (SREBP) and caspase-12 expression in the ginsenoside F2-treated group were decreased compared to the DHT and finasteride-treated group. C57BL/6 mice were also prepared by injection with DHT and then treated with ginsenoside F2 or finasteride. Hair growth rate, density, thickness measurements and tissue histotological analysis in these groups suggested that ginsenoside F2 suppressed hair cell apoptosis and premature entry to catagen more effectively than finasteride. Our results indicated that ginsenoside F2 decreased the expression of TGF-β2 and SCAP proteins, which have been suggested to be involved in apoptosis and entry into catagen. This study provides evidence those factors in the SCAP pathway could be targets for hair loss prevention drugs.
... Hair color, size, and location may change with race, age, and body region [2]. Rate of whitening is slower in eyelashes and eyebrows when compared with hair in humans because of different amounts of outer sheath melanocytes, enzymes, and stem cells in different hair follicles [19][20][21]. Onset and progression of whitening of hair follicles depends on chronological age and occurs to various degrees independent of gender and race. Age of onset is under genetic control and hereditary. ...
Background
The aim of this study was to determine whether eyebrow and eyelash whitening is an effective parameter in age estimation.
Material/Methods
We evaluated 1545 patients. Age groups were 1–10, 11–20, 21–30, 31–40, 41–50, 51–60, 61–70, 71–80, and 81–90 years. Level of whitening was categorized as level 0: no whitening, level 1: 1–3 strands, level 2: 3–10 strands, level 3: 10 strands–2/3 whitening, level 4: >3/4 whitening.
Results
Mean age was 42.39±20.01. While there was no eyebrow whitening in 87% of the subjects, level 4 whitening of eyebrows was observed in 0,8% of the subjects. There was no eyelash whitening in 97,7% of the subjects and no level 4 eyelash whitening was detected in any subject. Men had significantly more level 1, 2, 3, and 4 eyebrow whitening compared with women. There was no gender difference in terms of eyelash whitening level. There was no eyebrow and eyelash whitening in subjects age 1–40 years; whitening began in the 41–50 years age group and increased with age in other groups. Mean age was 39.59±19.63 years in subjects with no eyebrow whitening; 59 years in level 1, 61 years in level 2, 63 years in level 3, and 69 years in level 4 eyebrow whitening. Mean age was 41.85±19.87 in subjects with no eyelash whitening; and 63.57±10.75 in those with whitening.
Conclusions
Particularly after 41–50 years of age, level of eyebrow and eyelash whitening may be among a useful age estimation parameter.
... Since the hair cycle and its turning points have been largely identified [14,18,25,67], molecular mechanisms controlling hair chronobiology have been progressively disclosed [14,68]. The complex interactions between hair growth, sebaceous gland functions, angiogenesis [69,70], micro-inflammation and its counterpart immuno-suppression [51][52][53][54][55][56][57] and neuroendocrine influences [41,71] are incompletely characterized. The environmental impact including solar irradiation [49,50] and commensal microorganisms [56,59,72,73] cannot be neglected either. ...
Knowledge of the hair follicle anatomy and the dynamics of hair cycling is substantial. Recognizing the anagen, catagen and telogen phases as well as teloptosis and the hair eclipse phenomenon clearly characterizes the typical hair chronobiology. Physiological modulators include hormones, neuromediators, miscellaneous biomolecules, seasons, micro-inflammation and ageing. For individuals who present with the complaint of increased hair shedding or alopecia, a host of evaluation techniques are available in addition to history, physical examination and laboratory assessment. Various clinical hair techniques can help in assessing the efficacy of drugs and cosmetics on hair growth. The methods are quite similar to those used to establish a definite diagnosis in dermatological practice. Great strides have been made during the recent decades in the methodology of hair growth trials in dermatology and cosmetology. Clinical evaluations benefit from a few additional specific techniques that enhance the perception of hair (re-) growth, shedding and alopecia. These assessments include the determination of hair patterning and density that may be helped by the 'black-and-white felt' examination. Daily hair counts, the 'hair pull test' and the 'hair feathering test' are also available. Instrumental methods provide reliable quantitative information that is useful if there are adequate controls. Some photographic methods, the trichogram, hair weighing and variants of the hair growth window technique including the phototrichogram, videotrichogram and tractio-phototrichogram provide insight into the complexities of hair cycling and shedding. Skin biopsy is indicated for diagnostic purposes, especially when the hair loss is accompanied by scarring.
... Dihydrotestosterone is thought to be responsible for the gradual miniaturization of genetically marked hair follicles by shortening the duration of the anagen growth phase and reducing the cellular hair matrix volume [25][26][27] . Previous work in young balding men has shown a substantial increase in the production of DHT in frontal anagen hair follicles compared to frontal hair follicles in nonbalding men 28,29 . ...
Human hair morphogenesis is a dynamic process caused by the remodelling of the skin. Hair growth is cyclic in mammals consisting of three distinct stages: an active stage (anagen), a regressive stage (catagen), and a resting stage (telogen). One disorder in this process is gradual balding of the scalp called androgenetic alopecia. Little is known about the cell biological or molecular mechanisms involved and thus very little treatment is currently available. In this review we focus on the most significant parameters affecting hair growth which participate in baldness.
The therapy with anti-5-α-reductase substances is definitely effective to treat androgenetic alopecia. Several studies have shown that the conversion of testosterone to dihydrotestosterone by hair follicle cells can be reduced by inhibiting the enzyme II - but also I - receptors. This process generates a reduction in the gene expression of the factors leading hair bulbs to miniaturize and die. Two studies have demonstrated that finasteride can also reduce the gene expression of the caspase cascade activation and especially of caspase 3, which induce the apoptosis of follicle keratinocytes and fibroblasts. As already advanced by several Authors, we believe that the oxidative stress induced by inflammatory factors and the oxidative stress-induced apoptosis of hair follicles can participate in altering the physiological hair cycle clock of hair bulbs. Any noxa underlying this alteration brings some damage to hair follicles, thus inducing androgenetic alopecia and some other trichological diseases, such as telogenic defluvium. As already advanced by Mahe, Paus and Philpott, we believe the therapy of androgenetic alopecia requires a new and more complete approach, with the use of specific substances to inhibit androgenic receptors and active principles to reduce the inflammation process with the subsequent apoptosis of hair follicle cells. We have therefore tested two natural active principles whose use is known to be effective and safe, beta-glucan and superoxide dismutase, administered systemically in a complete pool in conjunction with a specific polyunsaturated acid mixture with an anti-5-α-reductase action. The results of this blinded randomized study have demonstrated that the anti-inflammatory and anti-apoptotic action has a greater effect on the clinical symptonts of AGA in comparison with the anti AR principle alone and, obviously, the placebo. Moreover, after the suspension of the therapy, this complete pool has resulted to bring a significant reduction in the progression of AGA (miniaturization, phlogosis) for a longer period than the AR inhibitor alone and, obviously, the placebo.
Desde los inicios de la humanidad el cabello ha tenido una importancia trascendental desde el punto de vista religioso, racial, sexual y ornamental. En los seres humanos el pelo es un vestigio evolutivo, a diferencia de otros seres vivos, que cumple funciones de protección y regulación de la temperatura.
El número de pelos que se desprenden normalmente es de aproximadamente 100 por día y esta tasa aumenta al final del verano y principios de otoño, quizás debido a efectos de la mayor radiación solar y temperatura.
La alopecia es la pérdida anormal del cabello, resultado de un proceso patológico. Las causas de alopecia son diversas y representan un desafío tanto para el médico como para el paciente.
El objetivo de esta revisión es profundizar en la fisiopatología del cabello, las causas de alopecia y su tratamiento.
Although hair forms (straight, curly, wavy, etc.) are present in apparently infinite variations, each fibre can be reduced to a finite sequence of tandem segments of just three types: straight, bent/curly, or twisted. Hair forms can thus be regarded as resulting from genetic pathways that induce, reverse or modulate these basic curvature modes. However, physical interconversions between twists and curls demonstrate that strict one-to-one correspondences between them and their genetic causes do not exist. Current hair-curvature theories do not distinguish between bending and twisting mechanisms. We here introduce a multiple papillary centres (MPC) model which is particularly suitable to explain twisting. The model combines previously known features of hair cross-sectional morphology with partially/completely separated dermal papillae within single follicles, and requires such papillae to induce differential growth rates of hair cortical material in their immediate neighbourhoods. The MPC model can further help to explain other, poorly understood, aspects of hair growth and morphology. Separate bending and twisting mechanisms would be preferentially affected at the major or minor ellipsoidal sides of fibres, respectively, and together they exhaust the possibilities for influencing hair-form phenotypes. As such they suggest dialectic for hair-curvature development. We define a natural-dialectic (ND) which could take advantage of speculative aspects of dialectic, but would verify its input data and results by experimental methods. We use this as a top-down approach to first define routes by which hair bending or twisting may be brought about and then review evidence in support of such routes. In particular we consider the wingless (Wnt) and mammalian target of rapamycin (mTOR) pathways as paradigm pathways for molecular hair bending and twisting mechanisms, respectively. In addition to the Wnt canonical pathway, the Wnt/Ca(2+) and planar cell polarity (PCP) pathways, and others, can explain many alternatives and specific variations of hair bending phenotypes. Mechanisms for hair papilla budding or its division by bisection or fission can explain MPC formation. Epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions, acting in collaboration with epithelial-mesenchymal communications are also considered as mechanisms affecting hair growth and its bending and twisting. These may be treated as sub-mechanisms of an overall development from neural-crest stem cell (NCSC) lineages to differentiated hair follicle (HF) cell types, thus providing a unified framework for hair growth and development.
—Once stated the current situation of Spanish dermatology in their chapters of classical dermatosis, diseases caused by infectious agents, including Venereology, cancer and precancer of the skin, photobiology, diseases of the adnexals and dermatologic surgery, the future possibilities are evaluated. Although our current situation is very acceptable, the future norms of the European Union, and the constant scientific evolution can do that some parts of the current Dermatology passes to other specialities or to general practitioners being indispensable the creation of Reference and Control Units for dermatological patients, as well as clinics and surgicals ones, always with the most high scientific and assistential quality, with the purpose that governments consider the need of Dermatology as a medical speciality that contribute to social benefits and therefore indispensable to improve the social life quality.
Introduction:
Androgenetic alopecia (AGA) is the most common form of hair loss, however current treatment options are limited and moderately effective. In the past few years, there has been an increased interest in deciphering the molecular mechanisms responsible for this disorder, which has opened the possibility of novel treatments that promise to not only stimulate hair growth, but also to induce formation of new hair follicles.
Areas covered:
The future holds more effective topical treatments with less systemic side effects (such as topical 5-alfa-reductase inhibitors), prostaglandin analogs and antagonists, medications which act through the Wnt signaling pathway, stem cells for hair regeneration, platelet-rich plasma (PRP) and more effective ways of transplanting hair. A comprehensive search was made using PubMed, GoogleScholar and Clinicaltrial.gov using different combination of key words, which included AGA treatment, new treatments for AGA, Wnt pathway, prostaglandins, PRP and stem cells for hair regrowth.
Expert opinion:
In the near future, treatments with topical 5-alfa-reductase inhibitors and prostaglandin agonists or antagonists are expected. More evidence is needed to verify the efficacy of PRP. Although hair follicle bioengineering and multiplication is a fascinating and promising field, it is still a long way from being available to clinicians.
During the last years, an increased misuse of doping substances in sport has been observed. The action of doping substances characterized by the stimulation of blood flow and metabolic processes is also reflected in the hair structure. In the present study it was demonstrated that optical coherent tomography is well suited for the analysis of hair parameters influenced by doping.
Analyzing 20 patients, systemically treated with steroids which also represent doping substances, it was found that in all cases a significant increase in the cross-section of the hairs could be detected. The results obtained in the study are not only important for the screening of doping substances but also for medical diagnostics and control of compliance of patients.
Zusammenfassung: Die androgenetische Alopezie (AGA) ist die häufigste Form des Haarausfalls bei Männern. Die relativ ausgeprägte Konkordanz der Glatzenausprägung bei Vätern und ihren Söhnen unterliegt keinem gewöhnlichen Mendelschen Erbgang, sondern beruht wahrscheinlich auf einer polygenen Vererbung. Die prädisponierenden Gene für eine AGA sind bis heute unbekannt und die molekularen Grundlagen des Androgen-abhängigen Bartwuchses versus Androgen-abhängigen Haarausfalls sind ungeklärt, die AGA kann jedoch als Dihydrotestosteron (DHT)-abhängiger Prozess mit kontinuierlicher Miniaturisierung der empfindlichen Haarfollikel beschrieben werden. Die 2, 5-α-Reduktase spielt eine zentrale Rolle bei der intrafollikulären Konversion von Testosteron (T) zu Dihydrotestosteron. Da das Wissen auf diesem Gebiet ständig zunimmt, soll diese Arbeit aktuelle Erkenntnisse kritisch beleuchten.
Summary: Androgenetic alopecia (AGA) is the most common type of hair loss in men. The relative strong concordance of the degree of baldness in fathers and sons is not consistent with a simple Mendelian trait and a polygenic basis is considered to be most likely. So far the predisposing genes for AGA are unknown and we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss, but AGA can be defined as a DHT-dependent process with continuous miniaturization of sensitive hair follicles. The type 2 ,5-α-R plays a central role by the intrafollicular conversion of T to DHT. Due to the increasing knowledge in this field, this article shall provide an critical overview of recent discoveries.
No The word “gerontology” is familiar to most of us as a term that captures the study of the social, psychological, and biological aspects of aging. However, its derivative “gerontobiology” as applied to the hair follicle is more concerned with the latter aspect – the biology of aging in the hair follicle mini-organ. As with any complex multicellular tissue system, the hair follicle is prone to broadly similar underlying processes that determine the functional longevity of organs and tissues. No matter how complex the tissue system is, it will contain cells that eventually lose functionality, reproductive potential and will ultimately die. The hair follicle is somewhat unusual among mammalian tissues in that it is a veritable histologic mélange of multiple cell types (e.g., epithelial, mesenchymal and neuro-ectodermal) that function contemporaneously in all stages of their life histories e.g., stem cells, transit-amplifying cells, and terminally differentiating cells. Some of these interactive cell systems appear to be nonessential for overall hair follicle survival (e.g., melanocytes). However, strikingly graying hair follicles may grow even more vigorously than their pigmented predecessors. Moreover, the hair follicle is unique in the adult mammal in that it follows a tightly regulated script of multiple lifelong cycles of cellular birth, proliferation, differentiation, and death. Powerful evolutionary selection ensures that the hair follicle is, in the main, hardwired against significant aging-related loss of function, even after 12 or more decades of life – although some would argue with this view, if only on purely cosmetic grounds. Processes underlying aging in general, e.g., oxidative damage, telomere shortening, age-relating deficiencies related to nuclear/mitochondrial DNA damage and repair as well as age-related reductions in the cells’ energy supply, will all impact on whether some follicular cell subpopulations will enter cellular senescence. This chapter will focus on how gerontobiology of the hair follicle may impact on certain aspects of hair fiber phenotype.
We explored the molecular correlates of the effect of finasteride on prostate tissue in patients undergoing radical prostatectomy.
Patients undergoing radical prostatectomy for localized prostate cancer were eligible for study. After providing informed consent patients were randomized to receive 5 mg finasteride or placebo daily for at least 30 days before surgery. At surgery prostate tissue was harvested from the surgical specimen and sent for analysis. Tissue samples were analyzed for the pro-apoptotic factors caspase-3, caspase-7 and IGFBP-3. Samples were also analyzed for the tumor suppressor/proto-oncoproteins bcl-2, p53 and p21. Finally, tissues were analyzed for androgen receptor density and insulin growth factor-1.
A total of 22 study and 20 placebo samples were collected and analyzed. Negligible staining for bcl-2 or caspase-3 was noted in each group. Statistical differences were not observed for bcl-2, p53, p21 or insulin growth factor-1 between the groups. There was a statistically significant difference in caspase-7 and IGFBP-3. A mean of 77% and 99.9% of cells stained for caspase-7 in the treatment and placebo groups, respectively (p = 0.007). In 3 patients caspase-7 staining disappeared completely and it was decreased by 70% and 50% in 1 patient each. Mean intensity staining for IGFBP-3 was 1.03 in the treatment group and 1.54 in the placebo group (p = 0.005). The staining intensity of nuclear androgen receptors on benign and cancerous cells was not significantly different between the treatment and placebo groups. However, there was a significant difference in androgen receptor staining between benign and cancer cells in the 2 populations. Mean nuclear androgen receptor staining intensity in all cancer and all benign tissue samples was 119.3 and 151.8, respectively (0.001).
Finasteride administered 30 days before surgery appears to decrease the apoptotic factors caspase-7 and IGFBP-3 in cancer cells, while having little to no effect on caspase-3, insulin growth factor-1, bcl-2, p53 and p21. This short-term study may have interesting implications for interpreting Prostate Cancer Prevention Trial data on the molecular level. No differences were noted between the treatment and placebo groups in the expression of nuclear androgen receptor. However, decreased expression of androgen receptors was present in cancer cells compared to that in benign prostate cells in the 2 groups.
Roxithromycin (RXM) is a 14-member macrolide antibiotics, with a variety of bioregulatory functions including anti-apoptotic activity to keratinocytes. Therefore, RXM has been used for many kinds of skin diseases. In this study, human and murine hair follicles were treated with RXM in order to find the possibility to cure hair loss disease such as androgenetic alopecia (AGA). In AGA, dihydrotestosterone signals apoptosis in dermal papilla cells in susceptible individuals, resting in premature termination of anagen and early entry into catagen. Therefore, anti-apoptotitic drug has a possibility of new candidate for AGA. This study revealed RXM antagonized the in vitro inhibitory effect of IFN-gamma on proliferation of keratinocytes and induction of apoptosis in murine and human hair bulb. RXM increases hair elongation and inhibits catagen-like changes induced in vitro with IFN-gamma in murine and human hair follicles. Furthermore, topical 5% RXM solution effectively restores hair growth in about half of individuals with AGA without any local and systemic adverse effects. Therefore, RXM is new candidate as a hair restoration drug for AGA.
Androgenetic alopecia (AGA) is the most common type of hair loss in men. The relative strong concordance of the degree of baldness in fathers and sons is not consistent with a smiple Mendelian trait and a polygenic basis is considered to be most likely. So far the predisposing genes for AGA are unknown and we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss, but AGA can be defined as a DHT-dependent process with continuous miniaturization of sensitive hair follicles. The type 2 5aR plays a central role by the intrafollicular conversion of T to DHT. Due to the inceasing knowledge in this field, this article shall privide an critical overwiew of recent discoveries.
Androgenetic alopecia (AGA) is the most common type of hair loss. The relatively strong concordance of the degree of baldness in fathers and sons is not consistent with a simple Mendelian trait, and a polygenic basis is considered to be most likely. So far, the predisposing genes for AGA are unknown and we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss, but AGA can be defined as a dihydrotestosterone (DHT)-dependent process with continuous miniaturization of sensitive hair follicles. The type 2 5alpha-reductase plays a central role by the intrafollicular conversion of testosterone to DHT. However, due to the increasing knowledge in this field, we now know that there are many more steroidogenic enzymes involved in the onset and development of AGA, and this article shall provide a critical overview of recent discoveries.
The tight coupling of hair follicle melanogenesis to the hair growth cycle dramatically distinguishes follicular melanogenesis from the continuous melanogenesis of the epidermis. Cyclic re-construction of an intact hair follicle pigmentary unit occurs optimally in all scalp hair follicles during only the first 10 hair cycles, i.e. by approximately 40 years of age. Thereafter there appears to be a genetically regulated exhaustion of the pigmentary potential of each individual hair follicle leading to the formation of true gray and white hair. Pigment dilution results primarily from a reduction in tyrosinase activity within hair bulbar melanocytes. Thereafter, 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 follicular papilla of the hair bulb, will all disrupt normal function of the pigmentary unit.
Pathogenetic mechanisms in androgenetic alopecia are not yet fully understood; however, it is commonly accepted that androgens like testosterone (T) and 5alpha-dihydrotestosterone (5alpha-DHT) inhibit hair follicle activity with early induction of the catagen. Thus, we investigated the influence of T and 5alpha-DHT on proliferation, cell death and bcl-2/bax expression in cultured dermal papilla cells (DPC) from nonbalding scalp regions of healthy volunteers. T and 5alpha-DHT induced apoptosis in DPC in a dose-dependent and time-related manner; in addition a necrotic effect due to T at 10(-5) M was found. Interestingly, bcl-2 protein expression was decreased in T- and 5alpha-DHT-treated cells, leading to an increase in the bax/bcl-2 ratio. In addition, T and 5alpha-DHT induced proteolytic cleavage of caspase 8 and inhibited proliferation of DPC at 10(-5) M. High concentrations of T and 5alpha-DHT were needed to induce apoptotic effects in DPC. These data suggest that DPC from nonbalding scalp regions do have the capacity to undergo apoptosis, but need a high androgen stimulus. The present study provides an interesting new pathogenetic approach in androgenetic alopecia.
Synopsis
Hair shedding and hair thinning have been reported to be affected by dandruff and seborrhoeic dermatitis. The present study was conducted in 150 men presenting with telogen effluvium related to androgenic alopecia associated with dandruff. They were randomly allocated to three groups receiving each one of the three shampoos in the market containing either 1% ketoconazole (KTZ), 1% piroctone olamine (PTO) or 1% zinc pyrithione (ZPT). Shampoos had to be used 2–3 times a week for 6 months. Hair shedding during shampoo was evaluated semiquantitatively. Hair density on the vertex was evaluated on photographs using a Dermaphot. Trichograms were used for determining the anagen hair percentage and the mean proximal hair shaft diameter using computerized image analysis. The sebum excretion rate (SER, μg cm ⁻² h ⁻¹ ) was also measured using a Sebumeter ® .
The three treatments cleared pruritus and dandruff rapidly. At end point, hair density was unchanged, although hair shedding was decreased (KTZ: −17.3%, PTO: −16.5%, ZPT: −10.1%) and the anagen hair percentage was increased (KTZ: 4.9%, PTO: 7.9%, ZPT: 6.8%). The effect on the mean hair shaft diameter was contrasted between the three groups of volunteers (KTZ: 5.4%, PTO: 7.7%, ZPT: −2.2%). In conclusion, telogen effluvium was controlled by KTZ, PTO and ZPT shampoos at 1% concentration. In addition, KTZ and PTO increased the mean hair shaft thickness while discretely decreasing the sebum output at the skin surface.
Interleukin-1 beta converting enzyme (ICE) is a mammalian homolog of CED-3, a protein required for programmed cell death in
the nematode Caenorhabditis elegans. The activity of ICE can be specifically inhibited by the product of crmA, a cytokine
response modifier gene encoded by cowpox virus. Microinjection of the crmA gene into chicken dorsal root ganglion neurons
was found to prevent cell death induced by deprivation of nerve growth factor. Thus, ICE is likely to participate in neuronal
death in vertebrates.
The protease responsible for the cleavage of poly(ADP-ribose) polymerase and necessary for apoptosis has been purified and characterized. This enzyme, named apopain, is composed of two subunits of relative molecular mass (M
r) 17K and 12K that are derived from a common proenzyme identified as CPP32. This proenzyme is related to interleukin-lβ-converting enzyme (ICE) and CED-3, the product of a gene required for programmed cell death in Caenorhabditis elegans. A potent peptide aldehyde inhibitor has been developed and shown to prevent apoptotic events in vitro, suggesting that apopain/CPP32 is important for the initiation of apoptotic cell death.
The baculovirus protein p35 inhibits programmed cell death in such diverse animals as insects, nematodes and mammals. Here we show that p35 protein is a substrate for and inhibitor of the Caenorhabditis elegans cell-death protease CED-3 (refs 6, 7) and a substrate for four CED-3-like vertebrate cysteine protease activities implicated in apoptosis in mammals. A p35 mutation that greatly reduced p35 activity in vitro as a CED-3 substrate and inhibitor abolished p35 activity in vivo in protecting against cell death in C. elegans. Introduction of the CED-3 cleavage site in p35 into the cowpox virus protein crmA, which inhibits mammalian apoptosis but not programmed cell death in C. elegans, caused crmA to block CED-3-mediated cell death. These observations suggest that p35 may prevent programmed cell death in C. elegans and other species by acting as a competitive inhibitor of cysteine proteases.
There is compelling evidence that members of the caspase (interleukin-1β converting enzyme/CED-3) family of cysteine proteases
and the cytotoxic lymphocyte-derived serine protease granzyme B play essential roles in mammalian apoptosis. Here we use a
novel method employing a positional scanning substrate combinatorial library to rigorously define their individual specificities.
The results divide these proteases into three distinct groups and suggest that several have redundant functions. The specificity
of caspases 2, 3, and 7 andCaenorhabditis elegans CED-3 (DEXD) suggests that all of these enzymes function to incapacitate essential homeostatic pathways during the effector phase of
apoptosis. In contrast, the optimal sequence for caspases 6, 8, and 9 and granzyme B ((I/L/V)EXD) resembles activation sites in effector caspase proenzymes, consistent with a role for these enzymes as upstream components
in a proteolytic cascade that amplifies the death signal.
Background: Androgenetic alopecia (male pattern hair loss) is caused by androgen-dependent miniaturization of scalp hair follicles, with scalp dihydrotestosterone (DHT) implicated as a contributing cause. Finasteride, an inhibitor of type II 5α-reductase, decreases serum and scalp DHT by inhibiting conversion of testosterone to DHT. Objective: Our purpose was to determine whether finasteride treatment leads to clinical improvement in men with male pattern hair loss. Methods: In two 1-year trials, 1553 men (18 to 41 years of age) with male pattern hair loss received oral finasteride 1 mg/d or placebo, and 1215 men continued in blinded extension studies for a second year. Efficacy was evaluated by scalp hair counts, patient and investigator assessments, and review of photographs by an expert panel. Results: Finasteride treatment improved scalp hair by all evaluation techniques at 1 and 2 years (P < .001 vs placebo, all comparisons). Clinically significant increases in hair count (baseline = 876 hairs), measured in a 1-inch diameter circular area (5.1 cm2 ) of balding vertex scalp, were observed with finasteride treatment (107 and 138 hairs vs placebo at 1 and 2 years, respectively; P < .001). Treatment with placebo resulted in progressive hair loss. Patients’ self-assessment demonstrated that finasteride treatment slowed hair loss, increased hair growth, and improved appearance of hair. These improvements were corroborated by investigator assessments and assessments of photographs. Adverse effects were minimal. Conclusion: In men with male pattern hair loss, finasteride 1 mg/d slowed the progression of hair loss and increased hair growth in clinical trials over 2 years. (J Am Acad Dermatol 1998;39:578-89.)
Members of the interleukin-1β-converting enzyme (ICE)/CED-3 protease family have been implicated in apoptosis in both vertebrates and invertebrates. Using primary culture methods, we report that neurons and astrocytes require the activity of the ICE/CED-3 family of proteases to undergo apoptosis induced by staurosporine, ceramide, and serum-free media. We show that specific inhibitors of ICE/CED-3 proteases can inhibit apoptosis and that cytosolic fractions from apoptosing neurons, but not healthy cells, induced apoptosis in a cell-free system. Cell extracts from neurons induced to undergo apoptosis contained ICE/CED-3 protease activity. To determine which member of the ICE/CED-3 family was activated in neurons and astrocytes during apoptosis, we developed a novel affinity-labeling technique that labeled the active site cysteine and identified a 17-kDa subunit of the activated protease. The affinity-labeled 17-kDa protease subunit shares antigenic and molecular mass identity with the processed form of CPP32 on immunoblots, suggesting that CPP32 may be the prinicipal effector in the apoptotic pathway in neurons and astrocytes. In time-course experiments, the activation of CPP32 preceded the detection of PARP cleavage and DNA laddering, suggesting that processing of CPP32 is a very early event in apoptosis of neurons and astrocytes and may be involved in the proteolytic action on specific cellular targets. The affinity-labeling technique developed and used in this report with neural cells allows for the sensitive detection, purification, and identification of ICE/CED-3 proteases that may be activated in other cells types under a variety of conditions, including certain diseased states. J. Neurosci. Res. 48:168–180, 1997. © 1997 Wiley-Liss, Inc.
Depilatory infusions of mouse epidermal growth factor (mEGF) induced regressive involution (catagen) in the wool follicles of Merino sheep. The follicles were examined by transmission electron microscopy prior to infusion and at intervals during catagen regression in order to determine the mechanism(s) involved in follicle involution. Cell deletion by apoptosis occurred in all cell types in the proximal region of catagen follicles between 12 h and 6 days after the beginning of infusion. Apoptosis also occurred in the basal layer of involuting sebaceous glands at 2 and 3 days, following earlier mEGF-induced proliferation. This process involved nuclear chromatin condensation and margination in single, scattered cells which subsequently fragmented and were ultimately phagocytosed and degraded by adjacent unaffected cells. It was concluded that during mEGF-induced catagen, wool follicle involution was accomplished largely through cell death and deletion by apoptosis.
The proliferative activities of germinative cells of the wool follicles and the epidermis have been determined in sheep treated with epidermal growth factor (EGF). Infusions of 0.17-0.72 mg EGF/kg metabolic body weight (MBW) for 28 h resulted in marked declines in the mitotic indices (MI) of the follicle bulb cell populations 24 h after the beginning of treatment, the lowest values being recorded at 48 h. Follicular activity subsequently recovered and the MI returned to preinfusion levels after 3-8 days. The inhibition of fiber production resulting from the decline in bulb cell division caused the development of a break in the fleece. By contrast, the MI of the peripheral cells of the sebaceous gland acini and the basal cells of the epidermis increased after EGF treatment, reaching peaks 48-72 h after the beginning of infusion. The degree to which all of these responses were observed appeared to be approximately correlated with the amount of EGF administered.
The baculovirus antiapoptotic protein p35 inhibited the proteolytic activity of human interleukin-1 beta converting enzyme (ICE) and three of its homologs in enzymatic assays. Coexpression of p35 prevented the autoproteolytic activation of ICE from its precursor form and blocked ICE-induced apoptosis. Inhibition of enzymatic activity correlated with the cleavage of p35 and the formation of a stable ICE-p35 complex. The ability of p35 to block apoptosis in different pathways and in distantly related organisms suggests a central and conserved role for ICE-like proteases in the induction of apoptosis.
Programmed cell death is central to hair biology, as the hair follicle undergoes cycles of growth (anagen), regression (catagen), and rest (telogen). During catagen, the hair follicle shortens via a pathway of programmed cell death and apoptosis. The molecular mechanisms involved in this process have not been elucidated yet. Using reverse transcriptase-polymerase chain reaction, we examined in this study the expression in total skin, throughout one hair cycle, of a series of regulatory genes associated with apoptosis. We show that gene expression within skin is hair-cycle-dependent. Transforming growth factor-beta was expressed immediately before catagen; therefore, it might be involved in the early signaling of this process. Tumor necrosis factor-beta was expressed during catagen and might be involved in follicular apoptosis. Several proto-oncogenes and transcription factors have been described in the regulation of apoptosis in other systems. Here we show that the transcript levels of c-myc, c-myb, and c-jun changed immediately before or during early catagen and thus could be involved in the signaling or regulation of catagen. Levels of p53 remained constant throughout anagen and catagen, suggesting that p53 is not involved in the developmentally induced apoptosis of the hair follicle. The variable expression throughout the hair cycle of the genes described demonstrates the dynamic changes of the skin and underscores the importance of studying the complete hair cycle when characterizing any molecule in skin.
During the development of the vertebrate nervous system, up to 50 percent or more of many types of neurons normally die soon after they form synaptic connections with their target cells. This massive cell death is thought to reflect the failure of these neurons to obtain adequate amounts of specific neurotrophic factors that are produced by the target cells and that are required for the neurons to survive. This neurotrophic strategy for the regulation of neuronal numbers may be only one example of a general mechanism that helps to regulate the numbers of many other vertebrate cell types, which also require signals from other cells to survive. These survival signals seem to act by suppressing an intrinsic cell suicide program, the protein components of which are apparently expressed constitutively in most cell types.
Three of the predominant features of apoptosis are internucleosomal DNA fragmentation, plasma membrane bleb formation, and retraction of cell processes. We demonstrate that actin is a substrate for the proapoptotic cysteine protease interleukin 1beta-converting enzyme. Actin cleaved by interleukin 1beta-converting enzyme can neither inhibit DNase I nor polymerize to its filamentous form as effectively as intact actin. These findings suggest a mechanism for the coordination of the proteolytic, endonucleolytic, and morphogenetic aspects of apoptosis.
It is now clear that members of the ICE/CED-3 protease family play key biological roles in inflammation and mammalian apoptosis. To date, ten homologs of human origin have been published (Figure 1Figure 1). The frenetic pace of identification of new homologs has led to inconsistent and multiple names for many of these enzymes. As a consequence, the general scientific community is finding it increasingly difficult to follow this provocative and rapidly moving field. In an effort to remedy this situation, several of us who have been involved in the identification and characterization of these enzymes have formed a committee, with the objective of proposing a nomenclature for the human members of this protease family that is sensible and easy to use. The purpose of this letter is to outline our recommendations.Figure 1Caspase Designations for Human Members of the ICE/CED3 Protease Family and Phylogenic Relationships among these ProteasesThe phylogenic relationships were determined using the PILEUP algorithm (version 8.1; gap weight = 3.0; gap length weight = 0.1) (Program Manual for the Wisconsin Package, Version 8, September 1994, Genetics Computer Group, 575 Science Drive, Madison, Wisconsin 53711). This figure was contributed by Don Nicholson, Merck Frosst.View Large Image | View Hi-Res Image | Download PowerPoint SlideWe propose to use the trivial name “caspase” as a root for serial names for all family members. The selection of caspase was based on two catalytic properties of these enzymes. The “c” is intended to reflect a cysteine protease mechanism, and “aspase” refers to their ability to cleave after aspartic acid, the most distinctive catalytic feature of this protease family. To designate individual family members, caspase will be followed by an arabic numeral, which will be assigned based on its date of publication. Current assignments are shown in Figure 1Figure 1. The root name for the corresponding gene will be CASP.Each of these enzymes is synthesized as a proenzyme that is proteolytically activated to form a heterodimeric catalytic domain. Proenzymes will be referred to as pro-“enzyme name” (e.g. pro-caspase-1). Subunits of the heterodimer will be described by the enzyme name, followed by the correct molecular size of the subunit (e.g. caspase-1-p10, caspase-1-p20). In a general sense, subunits may be referred to as large and small. The N-terminal peptide that is removed during proteolytic activation of these proteases will be referred to as such.Splice variants will be given a small English character suffix, separated from the name of the protease by a slash, which will be assigned based on order of publication (e.g. caspase-1/a).Please consult one of the members of the committee prior to final publication of any new homolog, so that the appropriate number can be assigned. A new homolog is defined as a fully sequenced protein, cDNA, or gene that has a statistically significant relationship to the large and small subunits of one of the established family members. We strongly encourage all investigators of these proteases to adopt these nomenclature recommendations. It is only through compliance that we will achieve our goal of improving communication between scientists both inside and outside this exciting field.
The mesenchyme-derived dermal papilla plays a major regulatory role in the complex cell biology of the hair follicle. The ability to culture dermal papilla cells from a range of species and particularly a range of normal and disordered human hair follicles has enabled the development of a powerful new model system for investigating hair follicle biology. Already these studies have reinforced the importance of dermal papilla cells in initiating new follicle growth and in androgen action in human hair follicles. The retention of hair growth inducing capabilities and characteristics that reflect their in vivo responsiveness to androgens in culture means that they offer a potentially useful approach despite significant drawbacks in working with the cells themselves. Further studies using dermal papilla cells may well elucidate key molecules involved in hair biology in health and disease and, thereby, lead to better therapeutic regimens.
Research in hair biology has embarked in the pursuit for molecules that control hair growth. Many molecules already have been associated with the controls of hair patterning, hair maturation, and hair cycling and differentiation. Knowing how these molecules work gives us the tools for understanding and treating patients with hair disorders.
Initiation of apopotosis requires the conversion of procaspases to mature caspases. Here we show that oligomerization of pro-caspases is sufficient to induce proteolytic generation of mature caspase subunits and activation of their cell death activity. Deletion of the protein interaction motif DED from pro-caspase-8 greatly suppresses its apoptotic activity. Cell death activity can be restored by oligomerization of pro-caspase-8 protease domains by two heterologous inducible oligomerization systems. Induced oligomerization also activates the apoptotic activity of pro-caspase-1 but not pro-caspase-3. In vitro, oligomerization leads to pro-caspase processing to from the mature caspase subunits; this processing requires the intrinsic caspase activity of zymogens and proceeds via a novel order of cleavage events.
The rapid discovery of a great number of caspases, together with multiple control points of their activation, proceeds well ahead of our knowledge of their physiological roles within the organism. There are still major gaps, but recent gene targeting of caspases provides us with several new and fundamental aspects of their physiological functions. The fact that different lines of KO mice exhibit preferential apoptosis defects rather than a global suppression of apoptosis indicates that caspases play a largely nonredundant apoptotic role in a tissue- and stimulus-dependent manner. Furthermore, despite compelling evidence for a key role of Casp8 and Casp9, the restricted phenotype of both Casp8- and Casp9-deficient mice suggests that other apical caspases must exist regulating apoptotic processes. Casp10, for instance, which is very similar in its structure to Casp8, has been shown to be recruited to death receptors (13xIn vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Fernandes-Alnemri, T, Armstrong, R.C, Krebs, J, Srinivasula, S.M, Wang, L, Bullrich, F, Fritz, L.C, Trapani, J.A, Tomaselli, K.J, Litwack, G, and Alnemri, E.S. Proc. Natl. Acad. Sci. USA. 1996; 93: 7464–7469Crossref | PubMed | Scopus (653)See all References, 72xFas-associated death domain protein interleukin-1beta-converting enzyme 2 (FLICE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling. Vincenz, C and Dixit, V.M. J. Biol. Chem. 1997; 272: 6578–6583Crossref | PubMed | Scopus (239)See all References). Although fibroblasts from Casp8 null mice are almost completely resistant to death receptor–mediated apoptosis, it cannot be excluded that Casp10, having little importance in fibroblasts, exerts crucial functions in other cell types. In addition, since certain cell types such as embryonic fibroblasts from Apaf1 KO mice are still considerably sensitive to a variety of apoptosis inducers, it is very likely that other yet undiscovered key regulators exist. We also have to be aware that the restricted phenotype of most KO mice may underestimate the role of the targeted caspases, because single caspases may substitute other family members. A major obstacle of most KO mice is their prenatal lethality, which precludes manifestations of caspase functions in the adult organism. Therefore, in future research, conditional disruption in a cell type–specific manner or in certain developmental stages will be required to elucidate more precisely the in vivo functional significance of individual caspases in development, immune functions, and pathological forms of apoptosis.*To whom correspondence should be addressed (e-mail: kso@uni-muenster.de).†Present address: Division of Cell Biology, University of Munster, Rontgenweg 21, D-48149 Munster, Germany.