Biosynthesis and Function of All-trans- and 9-cis-Retinoic Acid in Parathyroid Cells

Liu, Wei; Hellman, Per; Li, Qing; Yu, Wen-Ru; Juhlin, Claes; Nordlinder, Hans; Rollman, Ola; Åkerström, Göran; Törmä, Hans; Melhus, Håkan

doi:10.1006/bbrc.1996.1903

Cited by 13 publications

(16 citation statements)

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“…Retinoic acids bind to cytoplasmic transport proteins and subsequently to nuclear receptors present in parathyroid tissue (Liu et al 1996). The nuclear receptors for vitamin D 3 and retinoic acids (RAR, RXR) form heterodimers, and different effects of these complexes have been documented.…”

Section: +mentioning

confidence: 99%

“…Thus, 9cRA binding to an RXR/ VDR heterodimer may inhibit or promote the vitamin D 3 /VDR effect on genomic transcription rate (Carlberg et al 1993, Schrader et al 1993. It has recently been demonstrated that 9cRA and atRA have similar effects on PTH mRNA expression as vitamin D 3 and thereby suppress PTH release (MacDonald et al 1994, Liu et al 1996. However, this effect may be indirect, since no actual RAR or RXR binding sites seem to be present in the PTH gene promoter region (G Westin, personal communication).…”

Section: +mentioning

confidence: 99%

“…The effect of vitamin D 3 is the rationale for treatment of hyperparathyroidism secondary to uremia with vitamin D 3 in vivo, resulting in lowering of serum PTH levels as well as signs of reduced tumor progression (Slatopolsky et al 1984). In addition, it is evident that parathyroid cells are targets for retinols and retinoic acids, since metabolic conversion of retinol to retinoic acids take place in parathyroid cells, and that these compounds can reduce mRNA levels as well as the release of PTH (MacDonald et al 1994, Liu et al 1996.…”

Section: Introductionmentioning

confidence: 99%

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Differentiation of human parathyroid cells in culture

Liu¹,

Ridefelt²,

Åkerström³

et al. 2001

Journal of Endocrinology

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Continuous culture of parathyroid cells has proven difficult, regardless from which species the cells are derived. In the present study, we have used a defined serum-free low calcium containing medium to culture human parathyroid cells obtained from patients with parathyroid adenomas due to primary hyperparathyroidism. No fibroblast overgrowth occurred, and the human parathyroid chief cells proliferated until confluent. After the first passage the cells ceased to proliferate, but still retained their functional capacity up to 60 days, demonstrated by Ca 2+ -sensitive changes in the release of parathyroid hormone (PTH) and as adequate cytoplasmic calcium ([Ca 2+ ] i ) responses to changes in ambient calcium as measured by microfluorimetry. Low calcium concentrations enhanced, and vitamin D 3 and retinoic acids (RA) dose-dependently inhibited cell proliferation during the first passage, as determined by [ 3 H]thymidine incorporation, immunohistochemistry for proliferating cell nuclear antigen and cell counting. Signs of differentiation were present as the set-points, defined as the external calcium concentration at which half-maximal stimulation of [Ca 2+ ] i (set-point c ), or half-maximal inhibition of PTH release (set-point p ) occur, were higher in not proliferating compared with proliferating cells in P0. Inhibition of cell proliferation was accompanied by signs of left-shifted set-points, indicating a link between proliferation and differentiation.The results demonstrate that human parathyroid chief cells cultured in a defined serum-free medium can be kept viable for a considerable time, and that signs of differentiation occur after proliferation has ceased. The low calcium stimulated cell proliferation may also be inhibited by vitamin D and RA.

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Section: +mentioning

confidence: 99%

Section: +mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differentiation of human parathyroid cells in culture

Liu¹,

Ridefelt²,

Åkerström³

et al. 2001

Journal of Endocrinology

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“…The interplay, therefore, between these 3 proteins and the affinities that the different proteins exhibit for each other and to specific target DNA sequences (VDR/RXR-VDRE, RAR␥2/RXR-RARE, VDR/RAR␥2-VDRE) could theoretically produce a wide range of responses depending on ligand availability and the relative amounts of expressed receptors in a given target cell. Age-and disease-dependent declines in VDR expression have been noted previously [27][28][29][30], thus it is possible to speculate that a contributing factor to vitamin D 'resistance' could arise from a decrease in the relative expression of VDR to RAR␥2 in co-expressing cell types, such as skin [31][32][33] and parathyroid glands [34], so long as sufficient quantities of both ligands are present in circulation. However, ablation of RAR␥2 expression in the mouse did not produce an obvious phenotypic change [35,36], while VDR knockout mice develop a number of striking abnormalities, including alopecia, hypocalcemia and hyperparathyroidism [37].…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid receptor gamma 2 interactions with vitamin D response elements

Koszewski

Herberth

Malluche

2010

The Journal of Steroid Biochemistry and Molecular Biology

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“…These observations are consistent with the findings of Sass et al (47) and Kraft et al (50), who reported that all-trans and 9-cis RA are the predominant in vivo metabolites of administered all-trans and 9-cis retinal, respectively. Furthermore, Liu et al (51) demonstrated that parathyroid cells do not convert all-trans RA to 9-cis RA, but synthesize 9-cis RA from all-trans retinol. Taken together, these observations suggest that RA isomers are generated in target cells from different precursor retinoids rather than by isomeric exchange.…”

Section: Discussionmentioning

confidence: 99%

Cloning of monkey RALDH1 and characterization of retinoid metabolism in monkey kidney proximal tubule cells

Brodeur¹,

Gagnon²,

Mader³

et al. 2003

Journal of Lipid Research

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All-trans and 9-cis retinoic acids function as ligands for retinoic acid receptors (RARs and RXRs), which are ligand-dependent transcription factors and play important roles in development and cellular differentiation. Several retinal dehydrogenases are likely to contribute to the production of all-trans and 9-cis RAs in vivo, but their respective roles in different tissues are still poorly characterized. We have previously characterized and cloned from kidney tissues the rat retinal dehydrogenase type 1 (RALDH1), which oxidizes all-trans and 9-cis retinal with high efficiency but is inactive with 13-cis retinal. Here we have characterized the retinal-oxidizing activity in monkey JTC12 cells, which are derived from kidney proximal tubules. In vitro assay of cell lysates revealed the presence of a NAD ؉ -dependent dehydrogenase that catalyzed the oxidation of all-trans , 9-cis, and 13-cis retinal. Northern blot analysis of JTC12 RNAs and cloning by reverse transcriptionpolymerase chain reaction demonstrated expression of a monkey homolog of RALDH1. Bacterially expressed JTC12 RALDH1 catalyzed conversion of all three retinal isomers, with a higher catalytic efficiency for 9-cis retinal than for alltrans and 13-cis retinal. Accordingly, live JTC12 produced 9-cis retinoic acid more efficiently than all-trans retinoic acid from their respective retinal precursors.Only metabolites corresponding to the same steric conformation were formed from 9-cis or all-trans retinal, indicating a lack of detectable isomerizing activity in JTC12 cells. Retinoids are important regulators of cell growth, differentiation, and embryonic development (1-3). They are also needed for normal vision, reproduction, and immunity (4-6). The biological actions of retinoids are mediated through binding and modulation of retinoic acid receptors (RARs) or retinoid X receptors (RXRs), which function as ligand-dependent transcription factors (7). All-trans retinoic acid (RA) is a natural ligand for RARs, and 9-cis RA binds to both RARs and RXRs (8). The influence of vitamin A (retinol) in the control of gene expression is made possible by enzymes regulating RA synthesis. RA is formed from retinol via a 2-step metabolic pathway that involves oxidation of retinol to retinal and then of retinal to RA (9, 10). Although the metabolic pathways leading to the formation of all-trans and 9-cis RAs are beginning to be elucidated, the enzymes controlling production of these compounds within specific cells and tissues are still poorly characterized. In particular, it is not firmly established whether both all-trans and 9-cis RAs can be produced from the precursor all-trans retinol. Several studies have shown that externally supplied all-trans, 9-cis , and 13-cis RAs are isomerized into cis or trans RAs in cells and tissues and appear to reach equilibrium (11-16). Since no isomerase(s) involved in these processes have been identified, it is generally believed that the interconversion of cis -trans RA occurs in cells through nonenzymatic mechanism(s), alth...

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Biosynthesis and Function of All-trans- and 9-cis-Retinoic Acid in Parathyroid Cells

Cited by 13 publications

References 0 publications

Differentiation of human parathyroid cells in culture

Differentiation of human parathyroid cells in culture

Retinoic acid receptor gamma 2 interactions with vitamin D response elements

Cloning of monkey RALDH1 and characterization of retinoid metabolism in monkey kidney proximal tubule cells

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