Direct Suppression of PTH Gene Expression by the Vitamin D Prohormones Doxercalciferol and Calcidiol Requires the Vitamin D Receptor

Ritter, Cynthia S.; Brown, Alex

doi:10.1677/jme-10-0128

Cited by 34 publications

(33 citation statements)

References 14 publications

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“…To investigate whether the parathyroid calcineurin-NFAT pathway acts independent of serum factors such as soluble Klotho, thyro-parathyroid explants from wild-type and PTH-KL −/− mice were treated with FGF23 with or without pre-treatment of CsA [20]. In explants without pretreatment of CsA, 2 h treatment with FGF23 (10 ng/mL) decreased PTH secretion similarly in wild-type and PTH-KL −/− mice (Figure 4E).…”

Section: Resultsmentioning

confidence: 96%

Parathyroid-Specific Deletion of Klotho Unravels a Novel Calcineurin-Dependent FGF23 Signaling Pathway That Regulates PTH Secretion

Olauson

Lindberg²,

Amin³

et al. 2013

PLoS Genet

149

120

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Klotho acts as a co-receptor for and dictates tissue specificity of circulating FGF23. FGF23 inhibits PTH secretion, and reduced Klotho abundance is considered a pathogenic factor in renal secondary hyperparathyroidism. To dissect the role of parathyroid gland resident Klotho in health and disease, we generated mice with a parathyroid-specific Klotho deletion (PTH-KL−/−). PTH-KL−/− mice had a normal gross phenotype and survival; normal serum PTH and calcium; unaltered expression of the PTH gene in parathyroid tissue; and preserved PTH response and sensitivity to acute changes in serum calcium. Their PTH response to intravenous FGF23 delivery or renal failure did not differ compared to their wild-type littermates despite disrupted FGF23-induced activation of the MAPK/ERK pathway. Importantly, calcineurin-NFAT signaling, defined by increased MCIP1 level and nuclear localization of NFATC2, was constitutively activated in PTH-KL−/− mice. Treatment with the calcineurin-inhibitor cyclosporine A abolished FGF23-mediated PTH suppression in PTH-KL−/− mice whereas wild-type mice remained responsive. Similar results were observed in thyro-parathyroid explants ex vivo. Collectively, we present genetic and functional evidence for a novel, Klotho-independent, calcineurin-mediated FGF23 signaling pathway in parathyroid glands that mediates suppression of PTH. The presence of Klotho-independent FGF23 effects in a Klotho-expressing target organ represents a paradigm shift in the conceptualization of FGF23 endocrine action.

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Section: Resultsmentioning

confidence: 96%

Parathyroid-Specific Deletion of Klotho Unravels a Novel Calcineurin-Dependent FGF23 Signaling Pathway That Regulates PTH Secretion

Olauson

Lindberg²,

Amin³

et al. 2013

PLoS Genet

149

120

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“…One functional definition of the optimal vitamin D status is the 25(OH)D levels that maximally suppress PTH [63, 64]; the reason for this is that the major stimulus for PTH secretion is a low level of serum calcium [7, 65]. It is generally agreed that the levels of PTH will start to rise significantly once the serum 25(OH)D levels drops below 75 nmol/L [50].…”

Section: Vitamin D Deficiencymentioning

confidence: 99%

Vitamin D Deficiency and Pain: Clinical Evidence of Low Levels of Vitamin D and Supplementation in Chronic Pain States

Shipton

2015

Pain Ther

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IntroductionA number of studies suggest a link between low levels of 25-hydroxy vitamin D and incidence of acute and chronic pain. Clinical studies of vitamin D supplementation in patients with known vitamin D deficiency have shown mixed results in improving pain scores.MethodsIn this article, vitamin D deficiency risk factors are observed and adequate levels of 25-hydroxy vitamin D defined. Clinical supplementation with vitamin D is explored, including the schedules used in published clinical trials. Evidence of the effectiveness of vitamin D supplementation for the treatment of chronic pain conditions from double-blind randomized controlled trials (RCTs) is examined.ResultsThe scientific evidence for vitamin D as a treatment option for chronic pain is limited due to lack of RCTs. It cannot be stated conclusively that vitamin D deficiency is directly linked to the etiology or maintenance of chronic pain states.ConclusionThere remains a growing body of both clinical and laboratory evidence pointing to a potential relationship between low levels of 25-hydroxy vitamin D and a variety of chronic pain states. More focused research involving large RCTs is necessary.Electronic supplementary materialThe online version of this article (doi:10.1007/s40122-015-0036-8) contains supplementary material, which is available to authorized users.

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“…L Bergadà et al and also in various cell types using either specific inhibition of the 1-hydroxylation of 25(OH)D, 33,35 or VD metabolites that cannot be 1-hydroxylated. 36 However, the potency of 25(OH)D-bound VDR is at least 100-fold lower than that of 1,25D-bound VDR.…”

Section: Local Vitamin D Actions In Endometrial Cancermentioning

confidence: 99%

Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma

Bergadà

Pallarés

Arcidiacono

et al. 2014

Laboratory Investigation

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Vitamin D (VD) deficiency has been suggested as a risk factor for cancer. One recognized mechanism is that the low-serum 25-hydroxyvitamin D (25(OH)D) of VD deficiency reduces intratumoral 25(OH)D conversion to 1a,25-dihydroxyvitamin D (1,25D, the hormonal form of VD), compromising 1,25D-VD receptor (VDR) antitumoral actions. Reduced tumoral VDR and increased CYP24A1, the enzyme that degrades 1,25D and 25(OH)D, further worsen cancer progression. Importantly, in cells expressing CYP27A1 and/or CYP2R1, which convert inert VD into 25(OH)D, low-serum VD may reduce intratumoral 25(OH)D synthesis thereby compromising VDR antitumoral actions because 25(OH)D can activate the VDR directly and enhance 1,25D-VDR action. Therefore, this study examined whether abnormal endometrial expression of CYP27A1 and/or CYP2R1 may impair VDR-antiproliferative properties in endometrial carcinoma (EC). Immunohistochemical analysis of tissue microarrays of normal human endometrium (NE; n ¼ 60) and EC (n ¼ 157) showed the expected lower VDR expression in EC (P ¼ 0.0002). Instead, CYP24A1 expression was lower in EC compared with NE, while CYP27A1 and CYP2R1 expressions were higher (P ¼ 0.0002; P ¼ 0.03). Furthermore, in NE and EC, CYP2R1 and CYP27A1 expression correlated directly with nuclear VDR levels, an indicator of ligand-induced VDR activation, and inversely with the proliferation marker Ki67. Accordingly, in the endometrioid carcinoma cell lines IK, RL95/2 and HEC1-A, which express VDR, CYP27A1, and CYP2R1, VD efficaciously reduced cell viability and colony number, with a time course that paralleled actual increases in both intracellular 25(OH)D and nuclear VDR levels. Thus, VD may protect from EC progression in part through increased intratumoral 25(OH)D production by CYP27A1 and CYP2R1 for autocrine/paracrine enhancement of 1,25D-VDR-antiproliferative actions. Endometrial carcinoma (EC) results from neoplastic transformation of normal endometrium (NE) 1 leading to two main clinicopathological variants: endometrioid carcinoma (EEC) and non-endometrioid carcinomas (NEEC). EECs are estrogen-related tumors, frequently well differentiated, and developing mostly in peri-and postmenopausal women. Low grades (1 and 2) tumors are usually confined to the uterus (stage I) while grade 3 EECs are less frequent, with a higher tendency for extrauterine spread. NEEC, either serous or clear cell (CC) carcinomas, occur in older women, are estrogenunrelated tumors, with aggressive behavior and frequent extrauterine spread to the peritoneum or lymph nodes. 2,3 One risk factor for human cancer that can be safely modified is vitamin D (VD) deficiency/insufficiency.

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Direct Suppression of PTH Gene Expression by the Vitamin D Prohormones Doxercalciferol and Calcidiol Requires the Vitamin D Receptor

Cited by 34 publications

References 14 publications

Parathyroid-Specific Deletion of Klotho Unravels a Novel Calcineurin-Dependent FGF23 Signaling Pathway That Regulates PTH Secretion

Parathyroid-Specific Deletion of Klotho Unravels a Novel Calcineurin-Dependent FGF23 Signaling Pathway That Regulates PTH Secretion

Vitamin D Deficiency and Pain: Clinical Evidence of Low Levels of Vitamin D and Supplementation in Chronic Pain States

Role of local bioactivation of vitamin D by CYP27A1 and CYP2R1 in the control of cell growth in normal endometrium and endometrial carcinoma

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