- Chitinase 3-like 1 expression by human (MG63) osteoblasts in response to lysophosphatidic acid and 1,25-dihydroxyvitamin D3. [JOURNAL ARTICLE]
- Biochimie 2016 Aug 27.
Chitinase 3-like 1, otherwise known as YKL-40, is a secreted glycoprotein purported to have a role in extracellular matrix metabolism. The first mammalian cell type found to express YKL-40 was the human osteosarcoma-derived osteoblast, MG63. In that first study the active vitamin D3 metabolite, 1,25-dihydroxycholecalciferol (1,25D), stimulated YKL-40 expression, thereby indicating that a vital factor for skeletal health promoted YKL-40 synthesis by bone forming cells. However, when these MG63 cells were exposed to 1,25D they were also exposed to serum, a rich source of the pleiotropic lipid mediator, lysophosphatidic acid (LPA). Given that 1,25D is now known to co-operate with selected growth factors, including LPA, to influence human osteoblast differentiation we hypothesised that 1,25D and LPA may work together to stimulate osteoblast YKL-40 expression. Herein we report that 1,25D and LPA synergistically promote YKL-40 expression by MG63 cells. Inhibitors targeting AP1, MEK, Sp1 and STAT3 blunted the expression of both alkaline phosphatase and YKL-40 by MG63 cells in response to co-stimulation with 1,25D and LPA. Other ligands of the vitamin D receptor also co-operated with LPA in driving YKL-40 mobilisation. Collectively our findings highlight another important role of 1,25D and LPA in the regulation of human osteoblast function.
- [Not Available]. [English Abstract, Journal Article]
- Nutr Hosp 2016; 33(4):341.
El calcio (Ca) es el elemento mineral más abundante en nuestro organismo, ya que forma parte importante del esqueleto y los dientes. Supone alrededor del 2% del peso corporal. Las funciones del calcio son: a) funciones esqueléticas y b) funciones reguladoras. El hueso está formado por una matriz proteica que se mineraliza de forma mayoritaria con calcio (el más abundante), fosfato y magnesio; para ello es imprescindible un correcto aporte dietético de Ca, fósforo y vitamina D. El Ca iónico (Ca2+) es un componente celular imprescindible para mantener y/o realizar las diferentes funciones especializadas de prácticamente todas las células del organismo. Debido a sus importantes funciones, el Ca2+ debe estar estrechamente regulado, manteniéndose sus concentraciones plasmáticas dentro de unos rangos estrechos. Para ello existe una respuesta precisa frente a la hipocalcemia o la hipercalcemia, en la que intervienen la parathormona, el calcitriol, la calcitonina y la vitamina K. Las ingestas de Ca en la población española son bajas en un porcentaje significativo de la población, especialmente en adultos mayores, sobre todo en las mujeres. La principal fuente de Ca en la dieta son la leche y todos sus derivados. Las verduras de hoja verde, frutas y legumbres pueden tener importancia como fuentes de Ca en un patrón alimentario mediterráneo. La biodisponibilidad del Ca de la dieta depende de factores fisiológicos y dietéticos. Los fisiológicos incluyen la edad, situación fisiológica (gestación y lactación), el estatus de Ca y vitamina D y la enfermedad. Diversos estudios relacionan la ingesta de Ca en la dieta y distintas enfermedades, como osteoporosis, cáncer, enfermedades cardiovasculares y obesidad.
- Budget impact of secondary hyperparathyroidism treatment in chronic kidney disease in an Ecuadorian social security hospital. [JOURNAL ARTICLE]
- BMC Health Serv Res 2016; 16(1):443.
Chronic kidney disease (CKD) is a disorder with high morbidity and mortality worldwide whose complications generate multiple costs. In Ecuador, only a few healthcare institutions have implemented management protocols aimed to reduce costs and to improve the quality of life of patients. The aim of this study is to evaluate the short-term (1-year) and long-term (5-year) costs and savings in the management of secondary hyperparathyroidism (SHPT) of hemodialyzed CKD patients by comparing calcitriol and paricalcitol in a large social security hospital in Quito, Ecuador.The estimation model assessed the resources used in the management of SHPT by comparing prospectively the cost savings within 1-year and 5-year time horizon with calcitriol and paricalcitol. Hospitalization, erythropoietin (EPO), treatment doses, intravenous iron consumption, and medical supplies were estimated according international references, based on the initial parathormone level (iPTH) of patients. The Ecuadorian National Reference costs (2014-2015) and institutional costs were used to calculate treatment costs. A statistical sensitivity analysis was also performed.The study was based on data from 354 patients of whom 147 (41.4 %) had a value of iPTH in the range 300-600 pg/ml, 45 (12.8 %) in the range 601-800 pg/ml, and 162 (45.7 %) over 800 pg/ml. The 1-year estimated costs per patient for calcitriol and paricalcitol, respectively, were: medication, 63.88 USD and 1,123.44 USD; EPO, 19,522.95 USD and 16,478 USD; intravenous iron 143.21 USD and 187.76 USD. Yearly hospitalization costs per patient were 11,647.99 USD with calcitriol and 8,019.41 USD with paricalcitol. Total yearly costs per patient amounted to 31,378.02 USD with calcitriol and 25,809.50 USD with paricalcitol. Total savings using paricalcitol were 5,568.52 USD per patient compared with calcitriol. The 5-year cumulative medication costs were 319 USD for calcitriol and 2,403 USD for paricalcitol; EPO with calcitriol was 97,615 USD and with paricalcitol 82,394 USD; intravenous iron with calcitriol was 716 USD and paricalcitol 939 USD. Hospitalization costs for patients with calcitriol and paricalcitol were 43,095 USD and 62,595 USD, respectively. Total savings using paricalcitol amounted 32,414 USD per patient compared with calcitriol.Paricalcitol use generated more cost savings than calcitriol after 1 and 5 years.
- Autosomal dominant hypocalcemia due to a truncation in the C-tail of the calcium-sensing receptor. [JOURNAL ARTICLE]
- Mol Cell Endocrinol 2016 Aug 22.
Autosomal Dominant Hypocalcemia (ADH) is an endocrine disorder due to activating mutations of the calcium-sensing receptor (CASR) gene. We report on a young boy who presented low serum calcium with hypercalciuria, hyperphosphatemia and low serum concentration of parathyroid hormone, not accompanied by classic clinical signs of hypocalcemia. Treatment with calcitriol and calcium did not normalize serum calcium and renal calcium excretion. The use of thiazide diuretics slightly reduced calciuria. Despite high calcium excretion, no signs of nephrocalcinosis were detected. The patient had a prolonged Q-T interval at ECG, which did not normalize during treatment. PCR amplification of CASR coding sequence and direct sequencing of PCR products. showed a novel heterozygous deletion of a cytosine (c.2682delC), responsible for a frameshift (p.S895Pfs*44) and a premature stop codon resulting in a truncation of the CaSR's C-tail. Functional studies indicated increased activity of mutant receptor compared to the wild-type.
- Pancrelipase treatment in a patient with the history of Roux-en-Y gastric bypass operation that developed resistant hypocalcemia secondary to total thyroidectomy. [Journal Article]
- Endocr Regul 2016 Jan; 50(1):27-31.
Roux-en-Y gastric bypass (RYGB) is an independent risk factor for moderate hypocalcaemia and may lead to the development of resistant hypocalcaemia following thyroid surgery. Subject and Results. A 35-year old female patient was referred to our hospital by her family physician for treatment of resistant hypocalcaemia. The patient underwent RYGB three years ago and a total thyroidectomy for a benign thyroid nodule one year ago. Calcitriol, calcium carbonate, magnesium oxide, and ergocalciferol therapeutic dosages were incremented. Despite dosage increments, the desired calcium levels were not achieved. In the sixth month after admission to our hospital, pancrelipase was added to patient's treatment scheme. On the following visit, a good calcium increase had been achieved.This report presents a case history of RYGB and resistant hypocalcaemia, which developed after thyroid surgery and positively responded to pancrelipase treatment.
- Oral vitamin D supplementation at five times the recommended allowance marginally affects serum 25-hydroxyvitamin D concentrations in dogs. [Journal Article]
- J Nutr Sci 2016.:e31.
Little is known regarding optimal vitamin D status in adult dogs. To date no studies on vitamin D supplementation for improving vitamin D status have been reported for adult dogs. The aims of this study were to identify dogs with low vitamin D status and evaluate an oral dosage of cholecalciferol (D3) for effectiveness in increasing vitamin D status. For this, forty-six privately owned dogs were evaluated. Of the dogs, thirty-three (or 71·7 %) had serum 25-hydroxyvitamin D (25(OH)D) concentrations less than 100 ng/ml, a minimum previously suggested for vitamin D sufficiency in dogs. Subsequently, thirteen dogs were enrolled in a supplementation trial. Dogs were given either a D3 supplement (n 7; 2·3 µg/kg(0·75)) or olive oil placebo (n 6) daily with food. Serum concentrations of 25(OH)D were determined at weeks 1, 3 and 6, and at the trial end. Only at the trial end (weeks 9-10) was 25(OH)D significantly greater (P = 0·05) in supplemented v. placebo dogs. Serum concentrations of 24R,25-dihydroxycholecalciferol determined at the trial end were about 40 % of that of 25(OH)D3 and not significantly different between the groups. Concentrations of parathyroid hormone, ionised Ca, P and creatinine measured in initial and final serum samples indicated supplementation caused no toxicity. We conclude that vitamin D3 supplementation at a dosage near the National Research Council recommended safe-upper limit was not effective for rapidly raising serum 25(OH)D concentrations in healthy, adult dogs. Further work is needed in evaluating the metabolism of orally administered D3 in dogs before dosing recommendations can be made.
- Fibroblast Growth Factor 23 Regulation by Systemic and Local Osteoblast-Synthesized 1,25-Dihydroxyvitamin D. [JOURNAL ARTICLE]
- J Am Soc Nephrol 2016 Aug 17.
Circulating levels of fibroblast growth factor 23 (FGF23) increase during the early stages of kidney disease, but the underlying mechanism remains incompletely characterized. We investigated the role of vitamin D metabolites in regulating intact FGF23 production in genetically modified mice without and with adenine-induced uremia. Exogenous calcitriol (1,25-dihydroxyvitamin D) and high circulating levels of calcidiol (25-hydroxyvitamin D) each increased serum FGF23 levels in wild-type mice and in mice with global deficiency of the Cyp27b1 gene encoding 25-hydroxyvitamin D 1-α-hydroxylase, which produces 1,25-hydroxyvitamin D. Compared with wild-type mice, normal, or uremic mice lacking Cyp27b1 had lower levels of serum FGF23, despite having high concentrations of parathyroid hormone, but administration of exogenous 1,25-dihydroxyvitamin D increased FGF23 levels. Furthermore, raising serum calcium levels in Cyp27b1-depleted mice directly increased FGF23 levels and indirectly enhanced the action of ambient vitamin D metabolites via the vitamin D receptor. In chromatin immunoprecipitation assays, 25-hydroxyvitamin D promoted binding of the vitamin D receptor and retinoid X receptor to the promoters of osteoblastic target genes. Conditional osteoblastic deletion of Cyp27b1 caused lower serum FGF23 levels, despite normal circulating levels of vitamin D metabolites. In adenine-induced uremia, only a modest increase in serum FGF23 levels occurred in mice with osteoblastic deletion of Cyp27b1 (12-fold) compared with a large increase (58-fold) in wild-type mice. Therefore, in addition to the direct effect of high circulating concentrations of 25-hydroxyvitamin D, local osteoblastic conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D appears to be an important positive regulator of FGF23 production, particularly in uremia.
- 1,25 Dihydroxyvitamin d circulating levels, calcitriol administration, and incidence of acute rejection, CMV Infection, and polyoma virus infection in renal transplant recipients. [JOURNAL ARTICLE]
- Clin Transplant 2016 Aug 17.
The observation that 1,25-Dihydroxyvitamin-D3 has an immunomodulatory-effect on innate- and adaptive-immunity raises the possible effect on clinical graft outcome. Aim of this study was to evaluate the correlation of biopsy proven acute rejection, CMV-infection, BKV-infection, with 1,25-Dihydroxyvitamin-D3 deficiency and the benefit of calcitriol supplementation before and during the transplantation. Risk factors and kidney graft function were also evaluated. All RTRs received induction therapy with basiliximab, cyclosporine, mycophenolic acid, and steroids. During the first year, the incidence of BPAR (4% vs 11%, P=0.04), CMV-infection (3% vs 9%, P=0.04) and BKV-infection (6% vs 19%, P=0.04), were significantly lower in users compared to controls. By multivariate Cox regression analysis, 1,25-Dihydroxyvitamin-D3 deficiency and no calcitriol exposure were independent risk factors for BPAR (HR=4.30, P<0.005 and HR=3.25, P<0.05), for CMV-infection (HR=2.33, P<0.05 and HR=2.31, P=0.001), and for BKV-infection (HR= 2.41, P<0.05 and HR=2.45, P=0.001) . After one year, users had a better renal function: eGFR was 62.5±6.7 mL/min vs 51.4±7.6 mL/min (P<0.05). Only one user developed polyomavirus-associated nephropathy vs 15 controls. Two users lost their graft vs 11 controls. 1,25(OH)2-D3 deficiency circulating levels increased the risk of BPAR, CMV-infection, BKV-infection after kidney transplantation. Administration of calcitriol is a way to obtain adequate 1,25(OH)2-D3 circulating levels. This article is protected by copyright. All rights reserved.
- Vitamin D machinery and metabolism in porcine adipose-derived mesenchymal stem cells. [Journal Article]
- Stem Cell Res Ther 2016; 7(1):118.
Vitamin D, a hormone once thought to have a role limited to calcium homeostasis and bone mineralization, has pleiotropic effects on different types of cells. Vitamin D receptors are reported in vascular smooth muscle cells, endothelial cells, and cardiomyocytes. Adipose-derived MSCs (ADMSCs) are multipotent cells with the capacity to differentiate into cells of different lineages. To our knowledge, the presence of vitamin D machinery on porcine ADMSCs has not yet been examined. In this study, we investigated the presence of vitamin D machinery and metabolism in ADMSCs by analyzing the expression levels of vitamin D receptor (VDR), vitamin D metabolizing enzymes (CYP24A1 and CYP27B1) after in vitro stimulation with active vitamin D, calcitriol.ADMSCs isolated from porcine adipose tissue were characterized by positive staining for ADMSC markers, CD44, CD73, and CD90, and negative staining for macrophage marker CD11b and hematopoietic stem cell markers CD34 and CD45, and trilineage differentiation to osteocytes, chondrocytes, and adipocytes. No cytotoxicity was observed when MSCs were stimulated with 0.1-10 nM calcitriol. The ADMSCs were analyzed for mRNA and protein expression of CYP24A1, CYP27B1, and VDR by immunostaining, qPCR, and ELISA. A significant increase (p <0.01) in the mRNA expression of CYP24A1, CYP27B1, and VDR was observed after stimulation of ADMSCs with calcitriol (10 nM). The in vitro time-dependent effect of calcitriol (10 nM) on the components of vitamin D machinery in cultured MSCs was determined by qPCR. The VDR and CYP27B1 expression peaked at 3 h and CYP24A1 at 24 h, respectively. The in vitro biosynthesis of 1, 25(OH)2D3 by ADMSCs was analyzed by ELISA and Western blot. The levels of the active form of vitamin D were significantly decreased once the CYP enzymes were inhibited (p <0.01), demonstrating the ability of ADMSCs to convert inactive vitamin D into active vitamin D for cellular action.Porcine ADMSCs possess vitamin D hydrolases and VDR to metabolize and respond to vitamin D. Hence, in vivo circulating 25-hydroxy vitamin D levels may have a significant role in regulating the differentiation of ADMSCs into different lineages, which might assist in stem cell-based therapy.
- PTH(1-34) for the primary prevention of post-thyroidectomy hypocalcemia: the THYPOS trial. [JOURNAL ARTICLE]
- J Clin Endocrinol Metab 2016 Aug 15.:jc20162530.
There are no studies evaluating teriparatide for prevention of post-thyroidectomy hypocalcemia.To evaluate whether teriparatide can prevent post-surgical hypocalcemia and shorten the hospitalization in subjects at high risk of hypocalcemia following thyroid surgery.Prospective Phase II Randomized Open Label Trial.Surgical ward.26 subjects (6 males, 20 females) with iPTH<10 pg/ml, 4 hours after thyroidectomy.Subjects have been randomized (1:1) to receive subcutaneous administration of 20 mcg of teriparatide every 12 hours until the discharge (treatment group) or to follow standard clinical care (control group).Adjusted serum calcium, duration of hospitalization, calcium/calcitriol supplementation.Overall, the incidence of hypocalcemia was 3/13 in treatment group and 11/13 in the control group (P=0.006). Treated patients had a lower risk of hypocalcemia than controls [RR 0.26 (95% CI:0.09-0.723)]. The median duration of hospitalization was 3 days (IQR:1) in control subjects and 2 days (IQR:0) in treated subjects (P=0.012). One month after discharge, 10/13 subjects in the treatment group had stopped calcium carbonate supplements, while only 5/13 in the control group had discontinued calcium. The ANOVA for repeated measures showed a significant difference in calcium supplements between groups at one month visit (P=0.04) as well as a significant difference between discharge and one month visit in the treatment group (P for interaction time group =0.04) Conclusions: Teriparatide may prevent post-surgical hypocalcemia, shorten the duration of hospitalization and reduce the need for calcium and vitamin D supplementation after discharge in high risk subjects after thyroid surgery.