Article

The mineralization of hair follicle tissue

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Abstract

Previous histological investigations have shown that the hair follicle is particularly susceptible to mineralization when the skin of hypercalcaemic rats is injured. Direct chemical and X-ray diffraction analyses of follicle tissue have now confirmed this finding. As judged by increases in both calcium and phosphorus, mineral deposits began to form in hair follicle tissue 6–12 h after a mild crush injury to the skin of rats dosed with dihydrotachysterol (DHT), and 24–48 h after a similar injury to the skin of non-dosed rats. X-ray diffraction gave a diffuse apatite pattern. Within 3 h of injury there was a rise in the calcium content of follicle tissue which was not related to DHT-dosing and which was probably a reflection of calcium binding rather than mineral deposition.

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... Since these proteins are well known to be associated with calcium deposition in bone and dentin leading to tissue mineralization, we speculate that DSP, PP, OPN and BSP might contribute to calcium deposition, which strengthens the hardness of the hair root sheath. This possibility is supported by the findings of Pearce et al [18], who used direct chemical and Xray diffraction to demonstrate that hair follicles are susceptible to mineralization when the skin of hypercalcaemic rats is injured. The X-ray diffraction image of the hair follicles in the injured region showed a diffuse apatite pattern. ...
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ATP has been found in the fluid from distilled water washes of the dorsum of epilated and non-epilated rats. However, considerably more ATP was found in the epilated rats. Based upon these and previously reported results demonstrating that calcium adenosine 5′ triphosphate initiates subcutaneous calcification in rats, a hypothesis is proposed for the mechanism of topical cutaneous calcinosis as follows: Feeding DHT results in generalized hypercalcemia. When this is followed by epilation, tissue trauma occurs, resulting in destruction and/or enhanced permeability of cell membranes and release of ATP. The CaATP which forms hydrolyzes to produce a calcium orthophosphate nucleating seed for the calcification process. The ground substance necessary to form with calcium phosphate, the organized plaque, are the collagen fibers and muccopolysaccarides in the inter-fibrillar matrix in the dermal layer or the hair follicle itself.
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Hair follicle tissue from uninjured skin induced mineral formation in calcium phosphate solutions at a level of supersaturation equal to the lowest level resulting in the crystal growth and secondary nucleation of synthetic hydroxypatite. This indicates that follicle tissue contains an effective nucleator of calcium phosphate; a nucleator which could be responsible for the initial localization of mineral deposits to this tissue during skin calcificationin vivo. Hair clippings devoid of follicle tissue showed only a moderate nucleating ability. Follicle tissue which had been lyophilized and stored lost its nucleating ability, but the fact that the ability could be partly restored by treatment of the tissue with mercaptoethanol suggested that sulphydryl groups could be involved in the mechanism. The mineral precipitated from the barbitone-buffered calcifying solutions was nodular in appearance and showed the presence of octacalcium phosphate as well as hydroxyapative by X-ray diffraction. Inhibition of crystal growth and secondary nucleation by soluble follicle protein extracted into calcifying solutions was demonstrated and distinguished from the nucleation of solid mineral, phase by insoluble follicle proteins.
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Historically, the term 'keratin' stood for all of the proteins extracted from skin modifications, such as horns, claws and hooves. Subsequently, it was realized that this keratin is actually a mixture of keratins, keratin filament-associated proteins and other proteins, such as enzymes. Keratins were then defined as certain filament-forming proteins with specific physicochemical properties and extracted from the cornified layer of the epidermis, whereas those filament-forming proteins that were extracted from the living layers of the epidermis were grouped as 'prekeratins' or 'cytokeratins'. Currently, the term 'keratin' covers all intermediate filament-forming proteins with specific physicochemical properties and produced in any vertebrate epithelia. Similarly, the nomenclature of epithelia as cornified, keratinized or non-keratinized is based historically on the notion that only the epidermis of skin modifications such as horns, claws and hooves is cornified, that the non-modified epidermis is a keratinized stratified epithelium, and that all other stratified and non-stratified epithelia are non-keratinized epithelia. At this point in time, the concepts of keratins and of keratinized or cornified epithelia need clarification and revision concerning the structure and function of keratin and keratin filaments in various epithelia of different species, as well as of keratin genes and their modifications, in view of recent research, such as the sequencing of keratin proteins and their genes, cell culture, transfection of epithelial cells, immunohistochemistry and immunoblotting. Recently, new functions of keratins and keratin filaments in cell signaling and intracellular vesicle transport have been discovered. It is currently understood that all stratified epithelia are keratinized and that some of these keratinized stratified epithelia cornify by forming a Stratum corneum. The processes of keratinization and cornification in skin modifications are different especially with respect to the keratins that are produced. Future research in keratins will provide a better understanding of the processes of keratinization and cornification of stratified epithelia, including those of skin modifications, of the adaptability of epithelia in general, of skin diseases, and of the changes in structure and function of epithelia in the course of evolution. This review focuses on keratins and keratin filaments in mammalian tissue but keratins in the tissues of some other vertebrates are also considered.
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The composition of the mineralized matrix of the calcifying epithelioma of Malherbe (pilomatrixoma) and the process of mineralization have been investigated in two different tumors, one largely calcified and the other only slightly calcified. Fractionation of the tissue has been performed by isopycnic centrifugation. Whatever the mineral content of the fractions, their matrix is composed of a small proportion of collagen and a large proportion of keratin. The amino acid composition of this keratin is closer to that of nail than of hair. The hydroxylapatite crystals are associated with the keratin and the process of mineralization is accompanied by a progressive reduction in this polypeptide matrix. The chemical composition of this keratin, the known examples of calcification of hard keratin and the analogy of the ultrastructural pathways in the keratinization of pilomatrixoma and nails, suggest that the pilomatrixoma arises from the differentiation of ectopic ectodermal cells under the influence of an inducing system similar to that of nail.
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When the skin of rats is middly injured, mineral deposits form in some hair follicles in the injured area (Cousins and Smillie 1965). It was suggested that this could have resulted from the injury-induced modification of hair follicle proteins to form an efficient nucleator from a normally inactive precursor. S-carboxymethyl kerateine derivatives of follicle proteins were subjected to chromatography on diethylaminoethyl cellulose and to starch gel electrophoresis. No differences could be detected by these techniques between follicle keratins from injured skin and those from uninjured skin. This indicated that efficient nucleating material is normally present in hair follicles and is not formed following injury. This is discussed in relation to previous work on follicular mineralization.
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REPORTS of metastatic calcification in the skin are uncommon, even though it was described by Jadassohn1 as long ago as 1910. Metastatic calcification is seen in diseases associated with chronically elevated blood calcium and phosphorus levels. In contrast, dystrophic calcification occurs in diseases associated with local tissue injury, in which serum calcium and phosphorus levels remain normal.2 Recently, Selye3 described an experimental form of soft-tissue calcification called "calciphylaxis." This form of calcification occurred in rats when acute calcium mobilization, which of itself would not induce metastatic calcification, was followed by an injury or challenge, which also of itself would not . . .
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The hypercalcemic and hyperphosphatemic effects of equivalent dosages of crystalline dihydrotachysterol (DHT), Hytakerol (AT-10) and vitamin D2 are reported. In rats, DHT at high levels was more toxic than Hytakerol or vitamin D2. It produced marked hypercalcemia, hyperphosphatemia and high serum urea nitrogen levels, the latter probably on the basis of renal damage. In dogs, the onset and decline of hypercalcemia with orally administered DHT was very rapid, requiring only 3 days for maximal effect or for return to control levels upon discontinuance. On a weight basis, Hytakerol was less potent, with a more gradual decline upon cessation of administration, and vitamin D2 produced the least hypercalcemia, which, however, persisted for over 3 weeks after the vitamin was discontinued. The hypercalcemic sterol in Hytakerol (identified physicochemically as dihydrovitamin D2-II in a previous report) is to as potent as its isomer, DHT. The inadequacy of serum calcium levels as a measure of relative potencies of ...
Article
1.1. The development of orientation in the presumptive cortex of the follicle of the human hair has been studied by means of birefringence measurements and X-ray photographs.2.2. The birefringence rises very rapidly at the constriction of the follicle, and at the same level the typical α-keratin X-ray diagram appears.3.3. The presumptive cortex is divided into the following regions: the isotropic bulb, the fibrous but unconsolidated pre-keratin, the zone of progressive hardening, and the fully hardened hair.4.4. The unconsolidated pre-keratin is distinguished by easy digestion by enzymes, dispersion in saturated urea, and disorientation by warming with a fall in birefringence and the appearance of a disoriented β-ray pattern.Résumé1.1. L'évolution de l'orientation du cortex du follicule du cheveu humain a été étudiée au moyen de mesures de biréfringence et de photographie aux rayons X.2.2. La biréfringence devient rapidement très forte là où le follicule se trouve resserré, en même temps qu'apparaît le diagramme de rayons X caractéristique de la kératine α.3.3. Le cortex se divise en les régions suivantes: le bulbe isotrope, la pré-kératine fibreuse mais encore peu stable, la zone de durcissement progressif et le cheveu dont le durcissement est achevé.4.4. La pré-kératine encore peu stable se caractérise par la facilitéde sa dégradation par les enzymes, par son aptitude à se disperser dans une solution saturée d'urée, et par la désorientation qu'elle subit lors de son chauffage, désorientation accompagnée d'une diminution de biréfringence et de l'apparition d'un spectre β désorienté.Zusammenfassung1.1. Die Entwicklung der Orientierung im Cortex des Follikels des Menschenhaars wurde mit Hilfe von Doppelbrechungsmessungen und Röntgenaufnahmen untersucht.2.2. Die Doppelbrechung steigt bei der Einschnürung des Follikels sehr schnell, und in demselben Masse erscheint das typische Röntgendiagramm von α-Keratin.3.3. Der Cortex wird in die folgenden Gebiete eingeteilt: die isotrope Kugel, das faserige, aber nicht konsolidierte Präkeratin, die Zone fortschreitender Härtung, und das vollgehärtete Haar.4.4. Das nicht konsolidierte Präkeratin ist gekennzeichnet durch leichte Verdaulichkeit durch Enzyme, Dispersion in gesättigter Harnstofflösung, und Aufhebung der Orientierung durch Erwärmung mit einer Abnahme der Doppelbrechung und dem Auftreten des β-Röntgendiagrams
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Data were presented which show that the particle size of a precipitate ; is influenced by the past history of the water used in preparing a reagent ; solution. On the basis of these data and previously published information it is ; proposed that the nucleation process in practical analytical precipitation ; reactions is one of induced nucleation on sites which are inevitably available. ; It was shown that such a mechanism is free of inconsistencies encountered with ; other proposals concerning the origin of nuclei. (auth);
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The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.
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In the calcified deposits of the experimental cutaneous calcinosis, the apatite crystals measure approximately 5 nm in diameter and 50 nm in length; they are associated with the collagen fibrils but without any preferential orientation.
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1. The histochemical changes of cellular and extracellular components during the development of experimental heterotopic calcifications (provoked in rats by dihydrotachysterol-(DHT)-feeding and local mechanical injury after Selye, 1962) were investigated. Non-DHT-sensitized animals with skin injuries served as controls. In both groups the first reactions were similar. An edema and heavy synthetic activities of connective tissue cells developed. The discharge of mast cell granules, and increased alkaline phosphatase activity were also observed. Only in DHT-sensitized animals fine mineral deposits appeared and developed into large calcifying plaques. 2. Rats with developing heterotopic calcifications were also injected with a fluorochrome labeled homologous serum protein fraction containing albumin, α1-globulin, transferrin, and haptoglobin. Fluorescence microscopy revealed the specific and selective uptake and binding of this protein by the connective tissue matrix simultaneously with the inorganic calcium deposition. 3. These findings suggest together with the results reported by Lipp (1966, 1967) on bones and our preliminary observations on coronary arteries and kidneys that serum protein may function as a calcium carrier which reacts specifically with the calcifiable ground substance.
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The ascorbic acid method of Ammon and Hinsberg, modified by Lowry and associates, has been applied to the determination of phosphorus in whole blood, plasma, serum, and urine. A sensitivity about eight times that of the aminonaphtholsulfonic acid method permits the use of much smaller samples for measurement in conventional cells (as little as 0.15 γ of phosphorus can be determined in ordinary 3-ml. cuvettes.) A comparison with an accepted procedure on a number of samples showed that the ascorbic acid method gave essentially the same results.
Histological changes and the accretion of calcium and phosphorus in an experimentally induced calcification of rat skin (“topical calciphylaxis”) have been described. The appearance of mineral deposits was rapid and mild injury (epilation or light squeezing) was sufficient stimulus to cause a sparse, restricted mineralisation which, with prior treatment of the animal with an hypercalcaemic agent, progressed to give a grossly mineralised skin area. The initial mineralisation was restricted to the hair follicle, and the deposition of hydroxyapatite crystallites within cells of the inner root sheath of the follicle and within the cortex of the hair was demonstrated by electron microscopy. This preferential mineralisation of the follicle was not associated with obvious degenerative changes and the follicle remained functional. The low-level calcification was not species restricted and could also be demonstrated in rachitic rats in which a full “calciphylactic” response could not be elicited.The implications of keratin mineralisation are discussed, and the findings of this study are considered in relation to current concepts on the calcification mechanism.
Article
Calcinosis cutis is an idiopathic deposition of calcium phosphate (apatite) in skin and subcutaneous tissues. Two cases of eight months' and 14 years' duration were studied. Analysis of the calcium in sweat of advanced case showed levels greater than 15 times normal. X-ray diffraction studies showed large well-crystallized apatite mineral the size of enamel crystals. Electron micrographs showed crystals to be plate-like structures. Histochemical techniques showed no dermal acid mucopolysaccharides about early sites of calcification. Electron microscopy showed crystals in tissue that were not demonstrable by light microscopy. Electron micrographs of early tissue deposits of calcium showed apatite crystals lying parallel and tangential to collagen fibrils, but no small crystals were noted in ground substance. Larger crystal aggregates appeared to cut across collagen fibrils and to have areas of electron lucency about them. It is suggested that collagen fibrils are involved in the laying down of apatite particles. The presence of sharp spicules of apatite lying among moving collagen fibrils results in a possible injury to the tissue.
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Zusammenfassung Grahamsalz, ein langkettiges Polyphosphat, ist bei subcutaner Verabreichung imstande, eine pathologische Verkalkung der Haut (Calciphylaxe) bei der Ratte zu hemmen. Der Wirkungsmechanismus dieser Hemmung wird kurz diskutiert.
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The uptake of radiocalcium by specific regions of the skin, eye, cartilage and mucous glands has been demonstrated with the help of integrated autoradiographs. Most of the calcium that enters the hair follicle is found in the keratogenous zone. In the skin and eye, it appears that Ca ⁴⁵ has entered by bio-synthesis while in the cartilage and mucous glands, that uptake of labelled Ca might represent cation adsorption by the sulfopolysaccharides. The autoradiographic record of Ca ⁴⁵ follows the distribution of the blue/white dust in the spodograms of skin, cartilage and mucous glands.
Article
Introduction Solitary asymptomatic nodules in the skin often are given a vague provisional clinical diagnosis such as "sebaceous cyst." Occasionally such a "cyst," when examined histologically, proves to be a calcifying epithelioma, a designation not indicating its benign nature. The name has persisted, however, due to the lack of information on the histogenesis. Much of the information about this lesion is from continental Europe, although recently scattered reports have occurred in the English literature. In 1954 Castigliano and Rominger1 noted that 243 cases had been reported since 1880. Since that time about 60 more have been recorded.In view of the obvious inadequacies of the term "calcifying epithelioma," the name "pilomatrixoma" is suggested. This name may be offensive to the language-purist, but it has the advantage of conveying the histogenesis of the tumor and avoids the use of the word "epithelioma," which generally indicates a malignant tumor.It is
Article
In rats, a cutaneous calcinosis with sclerosis, not unlike that seen in certain types of clinical scleroderma, can be produced at will in predetermined regions of the skin. This is best accomplished if, at a critical time of systemic dihydrotachysterol overdosage, the selected cutaneous area is lightly traumatized by epilation.
I-Iistochemistry. Theoretical and applied Inhibition of skin calcification (calciphylaxis) by polyphosphates
  • A G E Pearse
Pearse, A. G. E. : I-Iistochemistry. Theoretical and applied, 2nd ed., p. 934. London: Churchill 1960. Schibler, D., Fleisch, H. : Inhibition of skin calcification (calciphylaxis) by polyphosphates. Experientia (Basel) 22, 367-373 (1966).
Mineralization of Hair Follicle Tissue in vivo Belanger, L. F. : The entry of 4~Ca into the skin and other soft tissues of the rat: an auto-radiographic and spodographic study
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E.I.F. Pearce et al. : Mineralization of Hair Follicle Tissue in vivo Belanger, L. F. : The entry of 4~Ca into the skin and other soft tissues of the rat: an auto-radiographic and spodographic study. J. Histochem. Cytochem. 5, 65-71 (1957).
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  • A G Fincham
Calcification of keratin In: Progress in the biological sciences in relation to dermatology
  • F G E Pautard
Soluble prekeratin In: Biology of the skin and hair growth
  • A G Matoltsy
Calcification of keratin
  • F G E Pautard
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