DOCSLIB.ORG

Progesterone Enhances Calcitriol Antitumor Activity by Upregulating Vitamin D Receptor Expression and Promoting Apoptosis in Endometrial Cancer Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Progesterone Enhances Calcitriol Antitumor Activity by Upregulating Vitamin D Receptor Expression and Promoting Apoptosis in Endometrial Cancer Cells Published OnlineFirst May 16, 2013; DOI: 10.1158/1940-6207.CAPR-12-0493 Cancer Prevention Research Article Research Progesterone Enhances Calcitriol Antitumor Activity by Upregulating Vitamin D Receptor Expression and Promoting Apoptosis in Endometrial Cancer Cells Laura R. Lee1, Pang-Ning Teng4, Huyen Nguyen1, Brian L. Hood4, Leyla Kavandi1, Guisong Wang4, Jane M. Turbov6, Larry G. Thaete6, Chad A. Hamilton3, George L. Maxwell5, Gustavo C. Rodriguez6, Thomas P. Conrads4, and Viqar Syed1,2 Abstract Human studies suggest that progesterone and calcitriol may prove beneficial in preventing or inhibiting oncogenesis, but the underlying mechanism is not fully understood. The current study investigates the effects of progesterone, calcitriol, and their combination on immortalized human endometrial epithelial cells and endometrial cancer cells and identifies their targets of action. Combination treatment with both agents enhanced vitamin D receptor expression and inhibited cell proliferation through caspase-3 activation and induction of G0–G1 cell-cycle arrest with associated downregulation of cyclins D1 and D3 and p27 induction. We used mass spectrometry–based proteomics to measure protein abundance differences between calcitriol-, progesterone-, or combination-exposed endometrial cells. A total of 117 proteins showed differential expression among these three treatments. Four proteins were then selected for validation studies: histone H1.4 (HIST1H1E), histidine triad nucleotide-binding protein 2 (HINT2), IFN-induced, double-stranded RNA-activated protein kinase (EIF2AK2), and Bcl-2–associated X protein (BAX). Abun- dance levels of selected candidates were low in endometrial cancer cell lines versus the immortalized endometrial epithelial cell line. All four proteins displayed elevated expression in cancer cells upon exposure to calcitriol, progesterone, or the combination. Further BAX analysis through gain- or loss-of-function experiments revealed that upregulation of BAX decreased cell proliferation by changing the BAX:BCL-2 ratio. Knockdown of BAX attenuated progesterone- and calcitriol-induced cell growth inhibition. Our results showed that progesterone and calcitriol upregulate the expression of BAX along with other apoptosis-related proteins, which induce inhibition of endometrial cancer cell growth by apoptosis and cell-cycle arrest. Cancer Prev Res; 6(7); 731–43. Ó2013 AACR. Introduction and adjuvant therapy is administered in selected cases based Endometrial cancer is the most common gynecologic on surgico-pathologic factors predictive of recurrence risk. malignancy in the United States. In 2012, 47,130 new cases For early-stage disease, outcomes are quite favorable with 5- are anticipated, resulting in 8,010 deaths (1). Endometrial year survival rates more than 90% (2). However, the num- cancer is usually treated with surgical removal of the uterus ber of women presenting with endometrial cancer in an advanced-stage or a high histologic grade, which is indic- ative of a poor prognosis, is increasing and mortality rates are rising (3, 4). Discovery of novel molecular targets for the Authors' Affiliations: Departments of 1Obstetrics and Gynecology and 2Molecular and Cell Biology, Uniformed Services University of the Health diagnosis, prognosis, and treatment of endometrial cancer Sciences; 3Division of Gynecologic Oncology, Walter Reed National Mil- is imperative to improve the management and outcome of 4 itary Medical Center, Bethesda, Maryland; Women's Health Integrated this disease. Research Center at Inova Health System, Department of Defense Gyne- cologic Cancer Center of Excellence, Annandale; 5Department of Obstet- A strong body of clinical and epidemiologic evidence rics and Gynecology, Inova Fairfax Hospital, Falls Church, Virginia; and suggests that progestins are highly effective endometrial 6Division of Gynecologic Oncology, North Shore University Health System, University of Chicago, Evanston, Illinois cancer preventive agents. Routine use of progestins lowers endometrial cancer risk and the protective effect increases Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/). with increasing progestin potency. In premenopausal women, use of progestin containing oral contraceptives Corresponding Author: Viqar Syed, Department of Obstetrics and Gyne- cology, Uniformed Services University of the Health Sciences, Room# confers a significant reduction in endometrial cancer risk A-3080, 4301 Jones Bridge Road, Bethesda, MD 20814. Phone: 301-295- (5–7). In addition, progestin-potent oral contraceptives 3128; Fax: 301-295-6774; E-mail: [email protected] have enhanced endometrial cancer protective effects doi: 10.1158/1940-6207.CAPR-12-0493 compared with oral contraceptives containing weak pro- Ó2013 American Association for Cancer Research. gestins (8, 9). In menopausal women, the addition of a www.aacrjournals.org 731 Downloaded from cancerpreventionresearch.aacrjournals.org on September 27, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst May 16, 2013; DOI: 10.1158/1940-6207.CAPR-12-0493 Lee et al. progestin to estrogen replacement therapy decreases the rationale for chemoprevention or treatment trials using this risk of precancerous endometrial hyperplasias, suggesting combination. chemopreventive effects of progestins on the endometri- um (10, 11). Currently, progestins are often used as Materials and Methods salvage therapy in patients with recurrent endometrial Cell lines and culture conditions cancer and in young patients to preserve childbearing The immortalized human endometrial epithelial cell capacity (12). Progesterone mediates its inhibitory effects line, EM-E6/E7-TERT, established and characterized by on the endometrium and endometrial cancer via the Dr. Satoru Kyo, (Kanazawa University, School of Medi- progesterone receptor (PR), an intracellular steroid cine, Kanazawa, Japan) was kindly provided to us in receptor with A and B isoforms. An increase in the 2008. This line was not authenticated by us once received response rates to progestin therapy and improved survival in our laboratory. Human endometrial cancer cell lines outcomes have been reported in tumors with a higher HEC-1B and RL-95 were obtained from the American percentage of PR (12, 13). Progestin potency can be Type Culture Collection (ATCC) and Ishikawa cell line enhanced by either increasing the dosage of progestin or was obtained from Sigma. These human-derived cell lines by selecting a pharmacologically potent progestin. How- were authenticated by DNA short-tandem repeat analysis ever, both of these approaches are likely to be associated by ATCC and Sigma. All 4 cell lines were initially expand- with an increase in side effects that would be undesirable ed and cryopreserved within 1 month of receipt. Cells for long-term chemoprevention in women. An alternative were typically used for 3 months, at which time a fresh strategy would be to combine a shorter course or lower vial of cryopreserved cells was used. The cells were rou- dose of progestin with a second preventive agent that has tinely tested for Mycoplasma. an excellent safety profile and enhances the potency of the Immortalized epithelial endometrial (EM-E6/E7-TERT) progestin. cells were established and characterized by Kyo and collea- There is a growing body of epidemiologic and laboratory gues (23). Primary endometrial epithelial cells were trans- evidence in support of vitamin D for the prevention of formed by the combination of human papillomavirus-16 a number of malignancies including endometrial cancer E6/E7 expression and telomerase activation by the intro- (14, 15). Vitamin D3, produced in the epidermis or duction of human telomerase reverse transcriptase obtained from the diet, is metabolized to the dihydroxy- (hTERT). The immortalized cells contained no chromo- lated form [calcitriol, 1,25-(OH)2D3] to be biologically somal abnormalities, retained responsiveness to sex-steroid active. Calcitriol is well known for its antiproliferative roles hormones, exhibited glandular structure on 3-dimensional through multiple mechanisms including the induction of culture, and lacked transformed phenotypes on soft agar or cell-cycle arrest, apoptosis, and differentiation in a variety of in nude mice. The cells were grown in Dulbecco’s modified cancer types, including prostate, breast cancer, colon, skin, Eagle medium (DMEM). Ishikawa cells were derived from a and leukemic cells (16–18). The inhibitory role of calcitriol well-differentiated adenocarcinoma of the human endome- in cellular growth and proliferation potentially provides trial epithelium from a 39-year-old woman, and express protection from various types of cancers, as indicated by functional steroid receptors for estrogen, progesterone, and several epidemiologic studies (19, 20). However, as calci- androgen. Cells were grown in DMEM:F12 supplemented triol has been found to be efficacious in several preclinical with insulin (Invitrogen). HEC-1-B cells derived from a and clinical studies, dose-limiting calcemic effects have moderately differentiated adenocarcinoma of endometrial proved a major obstacle for the use of this compound as epithelium from a 71-year-old patient were cultured in a chemotherapeutic or chemopreventive agent (14, 15). Eagle minimum essential medium (Invitrogen). RL95-2 One approach to limit the toxicity is to use lower concen- was derived from a grade 2 moderately differentiated ade- trations of calcitriol
Load more

Recommended publications
  • A Left/Right Comparison of Twice-Daily Calcipotriol Ointment and Calcitriol Ointment in Patients with Psoriasis: the Effect on Keratinocyte Subpopulations
    Acta Derm Venereol 2004; 84: 195–200 INVESTIGATIVE REPORT A Left/Right Comparison of Twice-Daily Calcipotriol Ointment and Calcitriol Ointment in Patients with Psoriasis: The Effect on Keratinocyte Subpopulations Mannon E.J. FRANSSEN, Gys J. DE JONGH, Piet E.J. VAN ERP and Peter C.M. VAN DE KERKHOF Department of Dermatology, University Medical Centre Nijmegen, The Netherlands Vitamin D3 analogues are a first-line treatment of Calcipotriol (Daivonex1,50mg/g ointment, Leo chronic plaque psoriasis, but so far, comparative clinical Pharmaceutical Products, Denmark) has been investi- studies on calcipotriol and calcitriol ointment are sparse, gated intensively during the last decade, and has proven and in particular no comparative studies are available on to be a valuable tool in the management of chronic cell biological effects of these compounds in vivo. Using plaque psoriasis. A review by Ashcroft et al. (1), based on flow cytometric assessment, we investigated whether these a large number of randomized controlled trials, showed compounds had different effects on the composition and that calcipotriol was at least as effective as potent DNA synthesis of epidermal cell populations responsible topical corticosteroids, 1a,-25-dihydroxycholecalciferol for the psoriatic phenotype. For 8 weeks, 20 patients with (calcitriol), short-contact dithranol, tacalcitol and coal psoriasis vulgaris were treated twice daily with calcipo- tar. Recently, Scott et al. (2) presented an overview of triol and calcitriol ointment in a left/right comparative studies on the use of calcipotriol ointment in the study. Before and after treatment, clinical assessment of management of psoriasis. They reconfirmed the super- target lesions was performed, together with flow cyto- ior efficacy of a twice-daily calcipotriol ointment metric analysis of epidermal subpopulations with respect regimen to the treatments as mentioned above, and to keratin (K) 10, K6, vimentin and DNA distribution.
    [Show full text]
  • Endocrine System WS19
    Endocrine System Human Physiology Unit 3 Endocrine System • Various glands located throughout the body • Some organs may also have endocrine functions • Endocrine glands/organs synthesize and release hormones • Hormones travel in plasma to target cells Functions of the Endocrine System • Differentiation of nervous and reproductive system during fetal development • Regulation of growth and development • Regulation of the reproductive system • Maintains homeostasis • Responds to changes from resting state Mechanisms of Hormone Regulation • Hormones have different rates and rhythms of secretion • Hormones are regulated by feedback systems to maintain homeostasis • Receptors for hormones are only on specific effector cells • Excretion of hormones vary for steroid hormones and peptide hormones Regulation of Hormone Secretion • Release of hormones occurs in response to • A change from resting conditions • Maintaining a regulated level of hormones or substances • Hormone release is regulated by • Chemical factors (glucose, calcium) • Endocrine factors (tropic hormones, HPA) HPA = Hypothalamic-Pituitary Axis • Neural controls (sympathetic activation) Hormone Feedback Systems Negative feedback maintains hormone concentrations within physiological ranges • Negative feedback • Feedback to one level Loss of • Long-loop Negative Feedback feedback • Feedback to two levels control often leads to • Hypothalamus-Pituitary-Gland Axis pathology Negative Feedback Short-Loop Negative Feedback Long-Loop Negative Feedback Hormone Transport Peptide/Protein Hormones
    [Show full text]
  • The Role of Reproductive Hormones in Epithelial Ovarian Carcinogenesis
    H Gharwan et al. Hormones and epithelial 22:6 R339–R363 Review ovarian cancer The role of reproductive hormones in epithelial ovarian carcinogenesis Helen Gharwan1, Kristen P Bunch2,3 and Christina M Annunziata2 1National Cancer Institute, National Institutes of Health, 10 Center Drive, Building 10, 12N226, Bethesda, Correspondence Maryland 20892-1906, USA should be addressed 2Women’s Malignancies Branch, National Cancer Institute, National Institutes of Health, Center for Cancer Research, to H Gharwan Bethesda, Maryland, USA Email 3Department of Gynecologic Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA [email protected] Abstract Epithelial ovarian cancer comprises w85% of all ovarian cancer cases. Despite acceptance Key Words regarding the influence of reproductive hormones on ovarian cancer risk and considerable " ovarian cancer advances in the understanding of epithelial ovarian carcinogenesis on a molecular level, " hormone action complete understanding of the biologic processes underlying malignant transformation of " reproductive ovarian surface epithelium is lacking. Various hypotheses have been proposed over the past " immune several decades to explain the etiology of the disease. The role of reproductive hormones in " endocrine epithelial ovarian carcinogenesis remains a key topic of research. Primary questions in the field of ovarian cancer biology center on its developmental cell of origin, the positive and negative effects of each class of hormones on ovarian cancer initiation and progression, and the role of the immune system in the ovarian cancer microenvironment. The development of the female reproductive tract is dictated by the hormonal milieu during embryogenesis. Endocrine-Related Cancer Intensive research efforts have revealed that ovarian cancer is a heterogenous disease that may develop from multiple extra-ovarian tissues, including both Mu¨ llerian (fallopian tubes, endometrium) and non-Mu¨ llerian structures (gastrointestinal tissue), contributing to its heterogeneity and distinct histologic subtypes.
    [Show full text]
  • A Clinical Update on Vitamin D Deficiency and Secondary
    References 1. Mehrotra R, Kermah D, Budoff M, et al. Hypovitaminosis D in chronic 17. Ennis JL, Worcester EM, Coe FL, Sprague SM. Current recommended 32. Thimachai P, Supasyndh O, Chaiprasert A, Satirapoj B. Efficacy of High 38. Kramer H, Berns JS, Choi MJ, et al. 25-Hydroxyvitamin D testing and kidney disease. Clin J Am Soc Nephrol. 2008;3:1144-1151. 25-hydroxyvitamin D targets for chronic kidney disease management vs. Conventional Ergocalciferol Dose for Increasing 25-Hydroxyvitamin supplementation in CKD: an NKF-KDOQI controversies report. Am J may be too low. J Nephrol. 2016;29:63-70. D and Suppressing Parathyroid Hormone Levels in Stage III-IV CKD Kidney Dis. 2014;64:499-509. 2. Hollick MF. Vitamin D: importance in the prevention of cancers, type 1 with Vitamin D Deficiency/Insufficiency: A Randomized Controlled Trial. diabetes, heart disease, and osteoporosis. Am J Clin Nutr 18. OPKO. OPKO diagnostics point-of-care system. Available at: http:// J Med Assoc Thai. 2015;98:643-648. 39. Jetter A, Egli A, Dawson-Hughes B, et al. Pharmacokinetics of oral 2004;79:362-371. www.opko.com/products/point-of-care-diagnostics/. Accessed vitamin D(3) and calcifediol. Bone. 2014;59:14-19. September 2 2015. 33. Kovesdy CP, Lu JL, Malakauskas SM, et al. Paricalcitol versus 3. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors ergocalciferol for secondary hyperparathyroidism in CKD stages 3 and 40. Petkovich M, Melnick J, White J, et al. Modified-release oral calcifediol of vitamin D status and cancer incidence and mortality in men.
    [Show full text]
  • Endocrine Paraneoplastic Syndromes: a Review
    Endocrinology & Metabolism International Journal Review Article Open Access Endocrine paraneoplastic syndromes: a review Abstract Volume 1 Issue 1 - 2015 Paraneoplastic endocrine syndromes result from ectopic production of hormones by Hala Ahmadieh,1 Asma Arabi2 different tumors. Hypercalcemia of malignancy is the most common, mostly caused by 1Division of Endocrinology, American University of Beirut, ectopic parathyroid hormone related peptide (PTHrP) production which increases bone Lebanon resorption. Other causes include the rare ectopic parathyroid hormone (PTH) production, 2Department of Internal Medicine, American University of ectopic production of 1, 25-(OH)2 vitamin D by the tumor and its adjacent macrophages and Beirut-Medical Center, Lebanon bone metastasis which by itself in addition to the local production of PTHrP at the level of the bone lead to bone resorption and thus hypercalcemia. Treatment includes extracellular Correspondence: Asma Arabi, Department of Internal fluid volume repletion, bisphosphonates or denosumab and calcitonin. Ectopic Cushing’s Medicine, Division of Endocrinology, American University of syndrome caused by ectopic ACTH production results in hypokalemia, proximal muscle Beirut-Medical Center, Po Box 11-0236, Riad El-Solh, Beirut, weakness, easy bruisability, hypertension, diabetes and psychiatric abnormalities including Lebanon, Email depression and mood disorders. Different diagnostic measures help to differentiate Cushing’s disease from ectopic Cushing’s syndrome. Treatment includes surgical resection Received: October 26, 2014 | Published: January 02, 2015 of tumor and medical therapy to suppress excess cortisol production. Ectopic secretion of ADH has been associated with different tumor types. The best treatment options include removal of the underlying tumor, chemotherapy, or radiotherapy in addition to free water restriction, demeclocycline and vaptans.
    [Show full text]
  • TGF-Β Signaling Proteins and CYP24A1 May Serve As Surrogate
    1437 Original Article TGF-β signaling proteins and CYP24A1 may serve as surrogate markers for progesterone calcitriol treatment in ovarian and endometrial cancers of different histological types Ana Paucarmayta1, Hannah Taitz1, Yovanni Casablanca1,2,3, Gustavo C. Rodriguez4, G. Larry Maxwell2,3,5, Kathleen M. Darcy2,3,6, Viqar Syed1,3,7 1Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA; 2Gynecologic Cancer Center of Excellence, 3John P. Murtha Cancer Center, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, Bethesda, MD, USA; 4Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Evanston, IL, USA; 5Department of Obstetrics and Gynecology, Inova Fairfax Hospital, Falls Church, VA, USA; 6Inova Schar Cancer Institute, Inova Center for Personalized Health, Falls Church, VA, USA; 7Department of Molecular and Cell Biology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA Contributions: (I) Conception and design: KM Darcy, GL Maxwell, V Syed; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: A Paucarmayta, H Taitz, V Syed; (V) Data analysis and interpretation: A Paucarmayta, H Taitz, KM Darcy, V Syed; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Viqar Syed. John P. Murtha Cancer Center, Department of Obstetrics and Gynecology, Department of Molecular and Cell Biology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Room# A-3080, Bethesda, MD, USA. Email: [email protected]. Background: Strategies are needed to coordinately block drivers and induce suppressors of cancer to reduce incidence and improve outcomes for individuals with inherited or acquired risk.
    [Show full text]
  • Vitamin D3 Constrains Estrogen's Effects and Influences Mammary
    www.nature.com/scientificreports OPEN Vitamin D3 constrains estrogen’s efects and infuences mammary epithelial organization in 3D Received: 16 January 2019 Accepted: 18 April 2019 cultures Published: xx xx xxxx Nafs Hasan 1, Carlos Sonnenschein1,2 & Ana M. Soto 1,2 Vitamin D3 (vitD3) and its active metabolite, calcitriol (1,25-(OH)2D3), afect multiple tissue types by interacting with the vitamin D receptor (VDR). Although vitD3 defciency has been correlated with increased incidence of breast cancer and less favorable outcomes, randomized clinical trials have yet to provide conclusive evidence on the efcacy of vitD3 in preventing or treating breast cancer. Additionally, experimental studies are needed to assess the biological plausibility of these outcomes. The mammary gland of VDR KO mice shows a forid phenotype revealing alterations of developmental processes that are largely regulated by mammotropic hormones. However, most research conducted on vitD3’s efects used 2D cell cultures and supra-physiological doses of vitD3, conditions that spare the microenvironment in which morphogenesis takes place. We investigated the role of vitD3 in mammary epithelial morphogenesis using two 3D culture models. VitD3 interfered with estrogen’s actions on T47D human breast cancer cells in 3D diferently at diferent doses, and recapitulated what is observed in vivo. Also, vitD3 can act autonomously and afected the organization of estrogen-insensitive MCF10A cells in 3D collagen matrix by infuencing collagen fber organization. Thus, vitD3 modulates mammary tissue organization independent of its efects on cell proliferation. Breast cancer remains a major cause of mortality among women worldwide. Epidemiological studies have shown that key stages during breast development are particularly susceptible to the efects of carcinogens.
    [Show full text]
  • Paclitaxel, Carboplatin and 1,25-D3 Inhibit Proliferation of Endometrial
    ANTICANCER RESEARCH 37 : 6575-6581 (2017) doi:10.21873/anticanres.12114 Paclitaxel, Carboplatin and 1,25-D3 Inhibit Proliferation of Endometrial Cancer Cells In Vitro TEA KUITTINEN 1, PÄIVI ROVIO 1, SYNNÖVE STAFF 1,2 , TIINA LUUKKAALA 3,4 , ANNE KALLIONIEMI 5,6 , SEIJA GRÉNMAN 7,8 , MARITA LAURILA 9 and JOHANNA MÄENPÄÄ 1,10 1Department of Obstetrics and Gynaecology, Tampere University Hospital, Tampere, Finland; 2Laboratory of Cancer Biology, BioMediTech Institute, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; 3Research and Innovation Centre, Tampere University Hospital, Tampere, Finland; 4Health Sciences, Faculty of Social Sciences, University of Tampere, Tampere, Finland; 5BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland; 6Fimlab Ltd, Tampere University Hospital, Tampere, Finland; 7Department of Obstetrics and Gynaecology, Turku University Hospital, Turku, Finland; 8University of Turku, Turku, Finland; 9Department of Pathology, Fimlab Ltd, Tampere University Hospital, Tampere, Finland; 10 Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland Abstract. Background/Aim: Endometrial cancer cells are combination of these compounds. The corresponding numbers known to be sensitive to carboplatin and paclitaxel. in UT-EC-3 were 70%, 33% and 65%, respectively. 1,25-D3 Further more , vitamin D (1,25-D3) has been reported to inhibit suppressed cell growth 88% with paclitaxel, 63% with endometrial cancer cell growth both as a single agent and carboplatin and 87% with their combination in the UT-EC-1 combined with carboplatin. However, there are no studies cell line. Conclusion: In both cell lines, single-agent paclitaxel comparing the effect of paclitaxel and carboplatin as single was as effective as the combination of the compounds and agents vs.
    [Show full text]
  • Calcitriol, Parathyroid Hormone, and Accumulation of Aluminum in Bone in Dogs with Renal Failure
    Calcitriol, parathyroid hormone, and accumulation of aluminum in bone in dogs with renal failure. H H Malluche, … , C Matthews, P Fanti J Clin Invest. 1987;79(3):754-761. https://doi.org/10.1172/JCI112881. Research Article Accumulation of aluminum in bone is a frequent finding in patients requiring chronic dialysis and is associated with considerable morbidity and/or mortality. Until now, evidence seemed to point to relatively low circulating levels of parathyroid hormone as a contributing factor, but because levels of parathyroid hormone and calcitriol are interrelated, calcitriol might be also involved. In this study we employed an animal model to evaluate the single and combined effects of parathyroid hormone and calcitriol on bone aluminum accumulation. The results show significantly less aluminum accumulation in calcitriol-replete dogs independent of the presence or absence of parathyroid hormone. These results indicate that low levels of calcitriol may play a role in the development of aluminum related bone disease. Further studies are needed to demonstrate whether administration of calcitriol in patients with renal insufficiency will prevent development of aluminum-related bone disease. Find the latest version: https://jci.me/112881/pdf Calcitriol, Parathyroid Hormone, and Accumulation of Aluminum in Bone in Dogs with Renal Failure Hartmut H. Malluche, Marie-Claude Faugere, Robert M. Friedler, Clifford Matthews, and Paolo Fanti Division ofNephrology, Bone and Mineral Metabolism, Department ofMedicine, University ofKentucky, Lexington, Kentucky 40536-0084 Abstract We found patients with predominant hyperparathyroid bone disease to have less stainable bone aluminum than those with Accumulation of aluminum in bone is a frequent finding in pa- mixed uremic osteodystrophy or low turnover osteomalacia (8) tients requiring chronic dialysis and is associated with consid- whereas Alfrey et al.
    [Show full text]
  • The Interfaces Between Vitamin D, Sleep and Pain
    234 1 D L DE OLIVEIRA and others Sleep and pain: the role of 234:1 R23–R36 Review vitamin D The interfaces between vitamin D, sleep and pain Correspondence Daniela Leite de Oliveira, Camila Hirotsu, Sergio Tufik and Monica Levy Andersen should be addressed to C Hirotsu Department of Psychobiology, Universidade Federal de São Paulo, São Paulo, Brazil Email [email protected] Abstract The role of vitamin D in osteomineral metabolism is well known. Several studies have Key Words suggested its action on different biological mechanisms, such as nociceptive sensitivity f sleep and sleep–wake cycle modulation. Sleep is an important biological process regulated f vitamin D by different regions of the central nervous system, mainly the hypothalamus, in f pain combination with several neurotransmitters. Pain, which can be classified as nociceptive, f hyperalgesia neuropathic and psychological, is regulated by both the central and peripheral nervous systems. In the peripheral nervous system, the immune system participates in the inflammatory process that contributes to hyperalgesia. Sleep deprivation is an important condition related to hyperalgesia, and recently it has also been associated with vitamin D. Poor sleep efficiency and sleep disorders have been shown to have an important role Endocrinology in hyperalgesia, and be associated with different vitamin D values. Vitamin D has been of inversely correlated with painful manifestations, such as fibromyalgia and rheumatic diseases. Studies have demonstrated a possible action of vitamin D in the regulatory Journal mechanisms of both sleep and pain. The supplementation of vitamin D associated with good sleep hygiene may have a therapeutic role, not only in sleep disorders but also in Journal of Endocrinology the prevention and treatment of chronic pain conditions.
    [Show full text]
  • Anti-Proliferative and Apoptotic Activities of Müllerian Inhibiting Substance Combined with Calcitriol in Ovarian Cancer Cell Lines
    Original Article Yonsei Med J 2016 Jan;57(1):33-40 http://dx.doi.org/10.3349/ymj.2016.57.1.33 pISSN: 0513-5796 · eISSN: 1976-2437 Anti-Proliferative and Apoptotic Activities of Müllerian Inhibiting Substance Combined with Calcitriol in Ovarian Cancer Cell Lines Yeon Soo Jung1,2, Hee Jung Kim2, Seok Kyo Seo2,3, Young Sik Choi2,3, Eun Ji Nam2,3, Sunghoon Kim2,3, Sang Wun Kim2,3, Hyuck Dong Han1, Jae Wook Kim2,3, and Young Tae Kim2,3 1Department of Obstetrics and Gynecology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju; 2Institute of Women’s Life Medical Science, Yonsei University College of Medicine, Seoul; 3Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. Purpose: This study aimed to investigate whether Müllerian inhibiting substance (MIS) in combination with calcitriol modulates proliferation and apoptosis of human ovarian cancer (OCa) cell lines (SKOV3, OVCAR3, and OVCA433) and identify the signaling pathway by which MIS mediates apoptosis. Materials and Methods: OCa cell lines were treated with MIS in the absence or presence of calcitriol. Cell viability and prolifera- tion were evaluated using the Cell Counting Kit-8 assay and apoptosis was evaluated by DNA fragmentation assay. Western blot and enzyme-linked immunosorbent assay were used to determine the signaling pathway. Results: The cells showed specific staining for the MIS type II receptor. Treatment of OCa cells with MIS and calcitriol led to dose- and time-dependent inhibition of cell growth and survival. The combination treatment significantly suppressed cell growth, down- regulated the expression of B-cell lymphoma 2 (Bcl-2), and up-regulated the expressions of Bcl-2 associated X protein, caspase-3, and caspase-9 through the extracellular signal-regulated kinase signaling pathway.
    [Show full text]
  • Hypoparathyroidism and Digeorge Syndrome
    Endocrinology and Diabetes Clinic Disorders of Calcium 4480 Oak Street, Vancouver, BC V6H 3V4 604-875-2117 1-888-300-3088 x2117 and Phosphorus http://endodiab.bcchildrens.ca Hypoparathyroidism the parathyroid cells. The body has developed cells that destroy some of its Hypoparathyroidism occurs when the body own tissue. This may include other does not produce enough parathyroid organs and endocrine glands, causing hormone (PTH). This hormone is made in 4 type 1 diabetes, Addison disease or or 5 parathyroid glands, located behind the other autoimmune diseases. thyroid tissue in the neck area. They are 2. Surgery or radiation to the thyroid gland very small—the size of peas. Their only job which damages the parathyroid glands. is to produce PTH, which keeps the calcium levels in the blood in the right range. 3. Iron deposits in the parathyroid glands, a side-effect of repeated transfusions to The name “hypo-parathyroid-ism”, means a treat thalassemia or other blood condition of low parathyroid hormone. diseases What does PTH do? How is hypoparathyroidism diagnosed? PTH balances the calcium level in the blood, keeping it in the right range. When the Something will have happened to make your calcium level is low, PTH is produced and it doctor request special blood tests. Perhaps raises the calcium level by: a heart problem is discovered during a routine pregnancy ultrasound or at birth, or 1. Moving calcium from the bones into the perhaps your baby or child became very sick blood. with symptoms of low blood calcium (see 2. Decreasing how much calcium is handout Disorders of Calcium and eliminated from the blood into the urine Phosphorus).
    [Show full text]