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J Gonzalez-Macias

Publications and source records attributed to J Gonzalez-Macias.

16 recordsLinked to original sources
PubMed2007

Klotho gene polymorphism and male bone mass.

The Klotho gene codes for a protein that is thought to influence the homeostasis of several tissues, including bone, as well as the aging process. Although the mechanism of action has not been fully elucidated, some studies in women have associated Klotho allelic variants to bone mineral density (BMD). The objective of this study was to determine the relationship of a common T/G polymorphism, resulting in a phenylalanine (F) to valine (V) substitution, with male bone mass. BMD was measured by dual-energy X-ray absorptiometry in 362 Spanish men aged 19-83 years. Klotho alleles were determined by a Taqman assay. Allele frequencies were 85% and 15% for the F and V alleles, respectively. In comparison with the most common FF genotype, young and middle-aged men (age less than 53 years) with FV/VV genotypes had higher age- and body mass index-adjusted BMD at the lumbar spine (1.059 +/- 0.017 vs. 1.016 +/- 0.011 g/cm(2), P = 0.036), the hip (1.077 +/- 0.017 vs. 1.033 +/- 0.011 g/cm(2), P = 0.028), and the calcaneus (0.599 +/- 0.125 vs. 0.547 +/- 0.108 g/cm(2), P = 0.012). Klotho alleles explained about 2-4% of BMD variance. However, Klotho genotype was not associated to BMD in older men. There were no Klotho-related differences in height, body weight, calcium intake, tobacco or alcohol consumption, or serum testosterone levels. In conclusion, these results suggest that allelic variants of Klotho constitute one of the genetic factors influencing BMD in male adults.

Adult↗
PubMed1995

Mechanisms controlling nitric oxide synthesis in osteoblasts.

Nitric oxide (NO) modulates the activity of a number of cell types, but little is known about its possible role in bone metabolism. In the present study we demonstrate that freshly isolated murine osteoblasts and an osteoblastic cell line express NO-synthase mRNA and release NO when stimulated with IL-1 or LPS, thus confirming the results of some recent reports using human and rat osteoblast-like cells. Synergistic effects were found between IL-1 and LPS or TNF. Enzyme induction was blocked by dexamethasone and IL-4. 1,25-dihydroxyvitamin D3 did not modify basal NO synthesis, but it markedly increased the cytokine-induced NO release. M-CSF, GM-CSF, IL-3, LIF, PTH, estradiol and calcitonin did not show significant effects on NO synthesis. NOS induction was blocked by various tyrosine-kinase inhibitors, geldanamycin and herbimycin A being the most potent. These results suggest that endogenous NO might participate in the regulation of bone remodeling at the local level, and may mediate some effects of vitamin D on bone. NO has recently been reported to inhibit osteoclastic bone resorption. The release of NO induced by bone-stimulating factors such as IL-1 may represent a protective mechanism helping to avoid excess resorption and preserve bone integrity in inflammatory conditions.

Amino Acid Oxidoreductases↗
PubMed1993

Interleukin-4 modulates osteoclast differentiation and inhibits the formation of resorption pits in mouse osteoclast cultures.

Interleukin-4 (IL-4) is a well known lymphocyte growth factor, but it may also modulate the activity of other cell types. In the present study we show that IL-4 exerts a potent dose-dependent inhibitory effect on the resorptive activity of mouse bone cells, measured as the number of resorption pits (decreased down to 14% of control, p < 0.001) or the total resorbed area (down to 20% of control, p < 0.001). The results obtained in bone marrow and unfractionated bone cell cultures indicate that such an effect is mainly due to an inhibition of osteoclast precursors differentiation, rather than to a reduced activity of mature osteoclasts, and is not mediated by the IL-4-induced release of other soluble inhibitory factors. Likewise, although IL-4 may stimulate M-CSF expression, its inhibitory effect on osteoclast recruitment was not prevented by anti-M-CSF antibodies, suggesting that it was not mediated by M-CSF. These results point out IL-4 as an potentially important regulatory factor of osteoclast differentiation.

Animals↗
PubMed1993

Effects of interleukin-4 on human osteoblast-like cells.

Interleukin-4 (IL-4) modulates the activity of a variety of lymphoid, hemopoietic and mesenchymal cells, but little is known about its influence on bone cells. We have studied the effects of IL-4 on the human osteoblast-like cell line MG63. IL-4 (0.1-50 ng/ml) inhibited cell proliferation. The effect did not depend on cell density, but it was more marked in serum-free cultures than in the presence of serum. IL-4 also induced a dose-dependent increase in the expression of alkaline phosphatase stimulated by 1,25-dihydroxyvitamin D3, a marker of differentiated osteoblast activity. However, IL-4 did not modify the secretion of interleukin-6 or tumor necrosis factor. These results suggest that interleukin-4 may play a role as a modulator of osteoblast activity.

Alkaline Phosphatase↗
PubMed1993

Vitamin D therapy modulates cytokine secretion in patients with renal failure.

In studies in vitro calcitriol (1,25-dihydroxyvitamin D3) inhibits lymphocyte proliferation and modulates several monocyte functions, including the secretion of prostaglandins and monokines. However its effects on monokine production in vivo are not known. Therefore we studied the secretion of interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) by peripheral blood mononuclear cells (PBMC) from 7 patients on periodic hemodialysis, before and after oral treatment with calcitriol (0.5 microgram daily) for 1 month. Calcitriol therapy resulted in significant increases in the phorbol myristate acetate (PMA)-induced secretion of IL-1 and IL-6 (p = 0.04 and 0.03, respectively). This was a transient effect, observable by day 7 of therapy, but no longer evident by day 30. However, calcitriol induced a progressive reduction of TNF secretion (down to 53% of control values by day 30, p = 0.02). There were no correlations between the individual changes in calcium/PTH and cytokine release. These results show that doses of calcitriol within the therapeutic range induce marked changes in cytokine secretion by PBMC from uremic patients.

Adult↗
PubMed1992

Effect of calcitriol on the secretion of prostaglandin E2, interleukin 1, and tumor necrosis factor alpha by human monocytes.

Cells of the monocyte/macrophage lineage express specific receptors for calcitriol (1,25-dihydroxyvitamin D3) and secrete prostaglandins and several cytokines with potent effects on bone metabolism. The aim of this study was to determine the effect of calcitriol on the secretion of prostaglandin E2 (PGE2), interleukin-1 (IL-1), and tumor necrosis factor (TNF alpha). Monocyte-enriched peripheral blood mononuclear cells (PBMC) from healthy subjects were cultured in the presence or absence of calcitriol (10(-11)-10(-7) M) and several stimulating agents. After 24 h, PGE2, IL-1, and TNF alpha were measured in the culture supernatants or lysates with specific immunoassays. Calcitriol induced a biphasic effect on PGE2 production by unstimulated cells and increased PGE2 synthesis by cells stimulated with either endotoxin or tau-interferon (IFN-tau). On the other hand, calcitriol inhibited the production of TNF alpha by monocytes stimulated with either IFN-tau or phorbol esters. This effect was not prevented by the addition of indomethacin, IL-1, or IL-2. Under the conditions used, we observed no effect of calcitriol on IL-1 alpha or IL-1 beta production. These results indicate that calcitriol induces in vitro marked changes in the secretion of monocyte products with known activity on bone cells. Further studies are needed to elucidate whether some effects of calcitriol on bone metabolism are mediated by the interaction of the sterol with cells of the immune system.

Calcitriol↗
PubMed1991

Cytokine production by peripheral blood cells in postmenopausal osteoporosis.

It has been suggested that the release of cytokines with bone-resorbing activity from cells of the immune system might have a role in the pathogenesis of osteoporosis. We measured the secretion of the bone-resorbing products tumor necrosis factor, interleukin 1 beta and PGE2 by peripheral blood mononuclear cells from seven healthy postmenopausal women and 12 patients with postmenopausal osteoporosis. No differences were observed between both groups either in unstimulated cultures or in cultures activated with calcitriol, endotoxin or phorbol esters. These results give no support for a role of peripheral blood immune cells in postmenopausal bone loss.

Aged↗
PubMed1991

Erythromycin and the treatment of Coxiella burnetii pneumonia.

Erythromycin is commonly used for the empirical treatment of community-acquired pneumonia, but there is some concern about its usefulness when Q fever is suspected because of in-vitro studies showing a lack of efficacy against Coxiella burnetii. This study was undertaken to assess the clinical value of the antibiotic in this setting. Nineteen patients with Q fever pneumonia treated with a variety of antibiotics considered ineffective against C. burnetii, were reviewed. Eleven patients who received erythromycin had a rapid clinical improvement and each became afebrile by the fourth day of treatment. However, only two of eight patients who received other antibiotics improved (both of them had been treated with beta-lactams). Both groups were comparable regarding to age and previous duration and severity of disease. Those patients who did not respond to other antibiotics improved promptly after erythromycin was started. This study suggests that erythromycin is an adequate treatment for Q fever pneumonia.

Adolescent↗
PubMed1988

Serum levels of 1,25-dihydroxyvitamin D after renal transplantation.

Serum levels of vitamin D metabolites have been studied in 68 patients 1-131 months (mean 23 +/- 23) after kidney transplantation. They were separated into two groups according to the duration of the graft. Patients with a graft duration longer than 6 months had a mean GFR of 73 +/- 36 ml/min. Their serum levels of 25-hydroxyvitamin D (25-OHD) were normal (15.9 +/- 8.4 ng/ml), while serum levels of 1,25-dihydroxyvitamin D (1,25-OHD) were reduced (28 +/- 11 pg/ml). A highly significant correlation between GFR and 1,25-OHD was observed (r = 0.58; p less than 0.001). Most patients with normal renal function had levels of 1,25-OHD in the normal range, but they frequently remained slightly lower than those of healthy controls (33 +/- 9 vs. 38 +/- 10 pg/ml; p = 0.05), albeit the presence of elevated PTH and/or hypophosphatemia. In some patients, a low supply of 25-OHD could impair the normalization of 1,25-OHD levels. No clear differences in vitamin D metabolites were observed between patients transplanted 1-6 months ago and those with a longer duration of the graft. Nevertheless, serum 25-OHD showed a tendency to increase with time. These results indicate that, although 1,25-OHD levels may not be fully normalized, successful kidney transplantation restores the ability to effectively metabolize vitamin D.

Adolescent↗
PubMed1987

Role of monocytes in the inhibitory effect of calcitriol on PHA-stimulated lymphocytes.

The possible role played by monocytes in the inhibitory effect of calcitriol on phytohemagglutinin (PHA)-stimulated lymphocyte proliferation was assessed by testing the effect of this sterol under different cell culture conditions. Calcitriol had a dose-dependent inhibitory effect on lymphocyte proliferation in concentrations ranging from 10(-10) up to 10(-8) M. The effect of 10(-9) M calcitriol was almost completely abolished by: a) monocyte depletion, b) inhibition of prostaglandin (PG) synthesis by indomethacin, and c) addition of exogenous interleukin-2 (IL-2). These results suggested that the inhibitory effect of calcitriol was mediated through monocytes. This possibility was substantiated by the following observations: a) the calcitriol inhibitory effect was restored when autologous adherent cells were added to monocyte-depleted PBM cells; b) the supernatant of adherent cells cultured for 24 hours in the presence of calcitriol exerted a marked inhibitory effect on lymphocyte proliferation; and c) this effect was not longer evident when adherent cells were cultured in the presence of calcitriol plus indomethacin. These data support the hypothesis that calcitriol acts, at least partially, through the monocytes, inducing an increased release of PG, with subsequent inhibition of IL-2 synthesis, then resulting in a decreased lymphocyte proliferation.

Calcitriol↗
PubMed1987

Calcium and calcitonin responses to calcium infusion in type I diabetes mellitus.

We studied calcium and calcium and calcitonin responses to intravenous calcium infusion (3 mg of elemental calcium/kg of body weight in 10 minutes) in 21 type I diabetic males and 17 age-matched normal males. Baseline total calcium, parathyroid hormone and calcitonin levels were normal in the diabetic group, but ionized calcium was lowered. Cortical bone status and osteocalcin levels were normal, suggesting a normal osteoblastic function. Total calcium and ionized calcium responses to calcium infusion were lowered in the diabetic group. Despite these lowered calcaemic responses, calcitonin secretion was normal.

Adult↗
PubMed1978

Normocalcaemic pseudohypoparathyroidism with unusual phenotype.

We describe a boy who presented at 4 years of age with radiological hyperparathyroidism, osteosclerosis, and necrosis of the femoral heads. Plasma biochemistry was normal but the parathyroid hormone (PTH) level was very high. He was deaf and had an unusual facies but did not have the phenotype of Albright's hereditary osteodystrophy. Plasma and urine cyclic AMP reponses to bovine PTH were markedly subnormal. Vitamin D produced sustained hypercalcaemia and a fall in plasma phosphorus. After four hyperplastic parathyroid glands were removed he became hypocalcaemic and plasma phosphorus rose. After operation he remained unresponsive to exogenous PTH; We suggest that he had a form of pseudohypoparathyroidism without the phenotype of Albright's hereditary osteodystrophy and with some residual skeletal and renal responsiveness to PTH.

Bone and Bones↗
PubMedDate not supplied

Comparison of the efficacy and bioequivalence of two oral formulations of tiludronate in the treatment of Paget's disease of bone.

Tiludronate, an oral bisphosphonate used to treat Paget's disease of bone, is currently being studied as a treatment for osteoporosis. A multicenter, open-label, parallel-group study was performed to compare the efficacy of two tablet formulations of tiludronate in the treatment of Paget's disease. Eighty-eight patients with active Paget's disease were recruited. The diagnosis was based on radiologic evidence of bone lesions, and all patients included in the study had serum alkaline phosphatase (SAP) levels equal to or more than twice the upper normal value of the local laboratory that assayed the sample. Each patient received treatment with oral tiludronate 400 mg/d for 84 +/- 2 days; 39 patients received the previously tested tablet formulation 3C1, and 49 patients received formulation 9O1, which is prepared using an improved manufacturing technique. The objective of this study was to determine whether the two formulations have an equivalent therapeutic effect, the primary end point being SAP levels in both groups after 3 months of treatment. This equivalence is commonly assessed by comparing pharmacokinetic data; however, in previous studies of tiludronate, large intra-individual variability prevented statistically valid comparisons of the data. Therefore, in addition to pharmacokinetic data, biochemical and clinical response data were collected during the trial. The secondary objectives of the trial were to measure the plasma levels and to assess the efficacy and safety of the two tiludronate formulations. The relative pharmacologic activities of the two formulations were assessed by comparison of the confidence intervals of levels of SAP at monthly intervals. After 3 months of treatment, the 90% confidence interval of the difference between the formulations was included in the reference confidence interval. These findings suggest that the 9O1 and 3C1 formulations did not show a significant difference in therapeutic activity. Furthermore, after 3 months of treatment, the frequency of normalization of SAP levels was 30.6% in the 9O1 treatment group and 28.2% in the 3C1 treatment group. The percentage of patients responding to treatment (defined as a decrease in SAP levels of at least 50% from baseline) was 67.3% in the 9O1 treatment group and 69.2% in the 3C1 treatment group. Statistical analyses performed on the maximum and minimum plasma concentrations of tiludronate showed no significant differences between the two formulations. In this trial, the two tablet formulations of tiludronate demonstrated therapeutic and pharmacokinetic equivalence.

Administration, Oral↗