The parotid gland: A new target organ for vitamin D action

Radioactively labelled cholecalciferol was administered continuously to rats which were fed a vitamin D-deficient diet. It has been possible to show that all the metabolites of cholecalciferol which normally occur in known target tissues of vitamin D are present in the parotid gland, and the pattern resembled that obtained for the kidney, a known target tissue for vitamin D action.The accumulation of cholecalciferol metabolites in the parotid gland was shown to be functional, as a calcium-binding protein was found to be present in the gland, possessing similar properties to the renal vitamin D- dependent calcium-binding protein.     

Lymphocyte-increasing action and hypocalcemic action of parotid gland extract.

It has previously been shown in our laboratory that the hypocalcemic substances purified from the thymus have a potent lymphocyte-increasing action in mice. Then, lymphocyte-increasing activity was examined with bovine parotid gland extracts, which showed a hypocalcemic activity as potent as that of the thymus extracts. The lymphocyte-increasing activity was assayed in the littermates of neonatal mice of Swiss-Webster strain; the materials used for this experiment were purified preparations and several fractions obtained from the parotid gland extracts in the course of purification. It was found that the potency of lymphocyte-increasing activity rose approximately in parallel with the rise in hypocalcemic activity with progress in purification. The final product, which was purified from the gland by isoelectric precipitation at pH 5.4, fractional precipitation with ammonium sulfate, chromatography on DEAE-cellulose, gel filtration on Sepharose 6B and preparative disc electrophoresis, gave a single band in polyacrylamide gel electrophoresis. Its intravenous injection in rabbits, in a dose of 10 mug/kg, produced a significant lowering in serum calcium (percent decrease 10.24 +/- 1.06%) compared with control animals given an injection of physiological saline. Intraperitoneal injection of this purified product, in a dose of 0.5 mug/mouse, in the littermates of neonatal mice, also produced a significant increase (ratio of lymphocytes to polymorphs 2.47 +/- 0.07) in lymphocytes compared with control animals injected with physiological saline (L/P ratio 1.57 +/- 0.05). These facts suggest that this purified protein fraction inherently contains both activities, but the possibility cannot be ruled out of slight contamination by a substance having a high activity. On the other hand, a fraction having no activity for lowering serum calcium but which had activity for increasing the lymphocytes was obtained. This is the first paper to report the presence of lymphocyte-increasing substances in the bovine parotid gland and the purification of one of the substances from the gland.     

Response of parotid gland organ culture to radiation

Organ cultures of rhesus parotid tissue in medium enriched with homologous serum and supplemented with low levels of isoproterenol were irradiated with single photon doses of 2.5, 5.0, 7.5, 10.0, 12.5, or 15.0 Gy. Following irradiation, the tissue was incubated while being agitated for 24 h; then it was fixed in formalin. Microscopically, death of serous acinar cells was seen in areas unaltered by autolysis. Based on the numbers of nuclear aberrations, the dose response did not differ significantly from that observed at 24 h in parotid gland irradiated in vivo. The similar rapid response under the two conditions shows that apoptosis of irradiated parotid serous cells is a direct expression of interphase cell death.     

The adrenal: A new target organ of the calciotropic hormone 1,25-dihydroxyvitamin D3

Summary Target cells for 1,25-dihydroxyvitamin D₃ were demonstrated in the adrenal medulla by frozen-section autoradiography. The appearance of these target cells was age-dependent in neonatal mice. Immunocytochemical staining for phenylethanolamine-N-methyltransferase revealed that both epinephrine and non-epinephrine cells concentrate 1,25-dihydroxyvitamin D₃ in their nuclei. In contrast, immunocytochemical staining for vitamin D-dependent calcium-binding protein (D-CaBP) demonstrated that D-CaBP immunoreactivity is localized in only a small percentage of adrenomedullary cells, in mice and rats. Comparison of PNMT and D-CaBP immunoreactivities in sequential sections showed that epinephrine-producing cells do not contain D-CaBP. These results indicate that adrenal medullary cells have receptors for 1,25-dihydroxyvitamin D₃ and that 1,25-dihydroxyvitamin D₃ may directly affect certain functions of these endocrine cells.Supported by US PHS grant PCM8200569 and postdoctoral training grant AM07240-02     

The skeleton as an intracrine organ for vitamin D metabolism

The endocrine hormone, 1alpha,25-dihydroxyvitamin D(3) (1,25D) is an important regulator of calcium and phosphorus homeostasis. In this context, 1,25D is generally recognized as necessary for the maintenance of a healthy skeleton through its actions on the small intestine. In this review, we highlight the direct effects of 1,25D on the constituent cells of the bone, actions that are independent of effects on the intestine and kidney. We also consider the evidence that 25D levels, not 1,25D levels, correlate best with parameters of bone health, and that the bone itself is a site of metabolic conversion of 25D into 1,25D, by virtue of its expression of the 25-hydroxyvitamin D 1alpha-hydroxylase, CYP27B1. We review the evidence that at least osteoblasts and chondrocytes, and possibly also bone resorbing osteoclasts, are capable of such metabolic conversion, and therefore that these cells likely participate in autocrine and paracrine loops of vitamin D metabolism. We conclude that the skeleton is an intracrine organ for vitamin D metabolism, challenging the long-held notion that 1,25D is solely an endocrine hormone.     

A new chromatographic system for vitamin D3 and its metabolites: resoluation of a new vitamin D3 metabolite

A simple yet powerful new chromatographic procedure for vitamin D(3) and its metabolites is described. Liquid-gel partition chromatography on Sephadex LH-20 using a solvent of various percentages of CHCl(3) in Skellysolve B (petroleum ether, bp 67-69 degrees C) permits excellent resolution of vitamin D(3), 25-hydroxyvitamin D(3), and their more polar metabolites. Of special importance is the resolution of the metabolites of vitamin D(3) more polar than 25-hydroxycholecalciferol. Because of this resolution, a new metabolite of vitamin D(3) has been demonstrated in the plasma of rats and in the intestines of chicks given 100 IU of vitamin D(3)-1,2-(3)H.     

Actinobacillus actinomycetemcomitans: a new cause for granuloma of the parotid gland and buccal space

A case of chronic granuloma of the buccal space and parotid gland is described which was caused by the unusual organism Actinobacillus actinomycetemcomitans. A review of the literature describing its pathogenesis and other clinical presentations is offered.     

The lung as a target organ for thyroxine

The isolated perfused in situ rat lung preparation was used to investigate the chronic effect of thyroxine on the intermediary metabolism in the mammalian lung. Treatment with thyroxine caused stimulation of the rate of glucose utilization (91 +/- 11 mumol/g dry weight/hr versus 54 +/- 5 mumol/g dry weight/hr). The increase in the rate of glucose uptake was not accompanied by a similar increase in lactate output. Alanine and pyruvate release were also similar in both groups. The implication is that oxidative metabolism of glucose was increased. This study provides the first unequivocal evidence that the mammalian lung is a target organ for thyroxine.     

The hair follicle: a paradoxical androgen target organ

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

The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action

Vitamin D, the sunshine vitamin, is important for childhood bone health. Over the past two decades, it is now recognized that vitamin D not only is important for calcium metabolism and maintenance of bone health throughout life, but also plays an important role in reducing risk of many chronic diseases including type I diabetes, multiple sclerosis, rheumatoid arthritis, deadly cancers, heart disease and infectious diseases. How vitamin D is able to play such an important role in health is based on observation that all tissues and cells in the body have a vitamin D receptor, and, thus, respond to its active form 1,25-dihydroxyvitamin D. However, this did not explain how living at higher latitudes and being at risk of vitamin D deficiency increased risk of these deadly diseases since it was also known that the 1,25-dihydroxyvitamin D levels are normal or even elevated when a person is vitamin D insufficient. Moreover, increased intake of vitamin D or exposure to more sunlight will not induce the kidneys to produce more 1,25-dihydroxyvitamin D. The revelation that the colon, breast, prostate, macrophages and skin among other organs have the enzymatic machinery to produce 1,25-dihydroxyvitamin D provides further insight as to how vitamin D plays such an essential role for overall health and well being. This review will put into perspective many of the new biologic actions of vitamin D and on how 1,25-dihydroxyvitamin D is able to regulate directly or indirectly more than 200 different genes that are responsible for a wide variety of biologic processes.