Iron lactate-induced osteopenia in male Sprague-Dawley rats.
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Osteopenia was induced in rats fed a diet containing 50,000 ppm (5%) iron lactate for 2 or 4 weeks. Blood chemistry, urinalysis, and bone histomorphometry of the proximal tibial metaphysis were performed. Urinary pyridinoline and deoxypyridinoline and the osteoclast number per bone surface were selected for the measurement of dynamic resorption. The osteoclast surface, eroded surface, and osteoblast surface increased at both ends of the exposure periods, and bone resorption and formation both increased. The bone volume, trabecular thickness, and trabecular number decreased, and the secondary spongiosa of proximal metaphysis showed a marked bone loss. However, no mineralization defect was observed. At the end of the 2-week exposure period, biomarkers of osteoclasts and osteoblasts had increased the most, and the osteoblast surface, osteoclast surface, and osteoclast number per bone surface increased with prolonged exposure. The pathological changes of the bone lesion in iron lactate-overloaded rats were similar to those in rats of the osteoporotic model, because they consisted of changes reflecting the increase of bone resorption and formation without an osteomalacic change. However, the decline of serum parathyroid hormone (PTH) levels was different from that of the osteoporosis model rat. We concluded iron-induced bone lesions probably differ from those of low turnover bone diseases. (+info)
Modeling human congenital disorder of glycosylation type IIa in the mouse: conservation of asparagine-linked glycan-dependent functions in mammalian physiology and insights into disease pathogenesis.
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The congenital disorders of glycosylation (CDGs) are recent additions to the repertoire of inherited human genetic diseases. Frequency of CDGs is unknown since most cases are believed to be misdiagnosed or unrecognized. With few patients identified and heterogeneity in disease signs noted, studies of animal models may provide increased understanding of pathogenic mechanisms. However, features of mammalian glycan biosynthesis and species-specific variations in glycan repertoires have cast doubt on whether animal models of human genetic defects in protein glycosylation will reproduce pathogenic events and disease signs. We have introduced a mutation into the mouse germline that recapitulates the glycan biosynthetic defect responsible for human CDG type IIa (CDG-IIa). Mice lacking the Mgat2 gene were deficient in GlcNAcT-II glycosyltransferase activity and complex N-glycans, resulting in severe gastrointestinal, hematologic, and osteogenic abnormalities. With use of a lectin-based diagnostic screen for CDG-IIa, we found that all Mgat2-null mice died in early postnatal development. However, crossing the Mgat2 mutation into a distinct genetic background resulted in a low frequency of survivors. Mice deficient in complex N-glycans exhibited most CDG-IIa disease signs; however, some signs were unique to the aged mouse or are prognostic in human CDG-IIa. Unexpectedly, analyses of N-glycan structures in Mgat2-null mice revealed a novel oligosaccharide branch on the "bisecting" N-acetylglucosamine. These genetic, biochemical, and physiologic studies indicate conserved functions for N-glycan branches produced in the Golgi apparatus among two mammalian species and suggest possible therapeutic approaches to GlcNAcT-II deficiency. Our findings indicate that human genetic disease due to aberrant protein glycosylation can be modeled in the mouse to gain insights into N-glycan-dependent physiology and the pathogenesis of CDG-IIa. (+info)
Skeletal development in premature infants: a review of bone physiology beyond nutritional aspects.
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Bone development is usually seen as a process of bone mineral accretion or increase in bone mass, and treatment of bone disorders usually consists of attempts to maximise bone mass accumulation by nutritional means only. However, from a functional perspective, bones should not be as heavy as possible, but rather as stable as necessary. It is therefore important to create conditions that stimulate bones to become more stable. (+info)
Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor.
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The low-density lipoprotein receptor-related protein (Lrp)-5 functions as a Wnt coreceptor. Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype. In vivo and in vitro analyses indicate that this phenotype becomes evident postnatally, and demonstrate that it is secondary to decreased osteoblast proliferation and function in a Cbfa1-independent manner. Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts. In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis. These results implicate Wnt proteins in the postnatal control of vascular regression and bone formation, two functions affected in many diseases. Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation. (+info)
Prevalence of rheumatic diseases in a rheumatological outpatient practice.
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OBJECTIVE: To assess the prevalence and distribution of rheumatic diseases in a community based rheumatological outpatient practice. METHODS: Rheumatological diagnoses of 3751 consecutive new and returning patients were recorded using a standard diagnosis form. RESULTS: 6264 rheumatological diagnoses were made in 3751 patients, of whom 1097 were newly referred; 69% of all patients were female. Inflammatory joint and spine diseases were diagnosed in 42% of all patients (including 5% with connective tissue diseases), soft tissue rheumatism in 37%, degenerative joint and spine diseases in 36%, and metabolic bone diseases in 17% of all patients. In new patients soft tissue rheumatism was most prevalent (51%), 45% had osteoarthritis, 24% had inflammatory joint and spine disease (including 2% with connective tissue disease), and 13% had metabolic bone disease. One of 10 new patients was diagnosed with definite rheumatoid arthritis. In returning patients the prevalence of inflammatory rheumatic diseases was higher (49%, including 6% with connective tissue diseases). 28% of the returning patients had rheumatoid arthritis. Osteoarthritis was present in 33% and metabolic bone disease in 19% of the returning patients. CONCLUSIONS: Soft tissue rheumatism and degenerative joint and spine diseases are the most common rheumatological diagnoses in newly referred patients visiting a community based rheumatological outpatient practice. Inflammatory rheumatic diseases were most prevalent in returning patients. (+info)
Bone mineral density is not diminished by mild to moderate chronic renal insufficiency.
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BACKGROUND: Persons with end-stage renal disease are at higher risk for osteopenia and hip fracture relative to the age-matched general population. Persons with mild to moderate chronic renal insufficiency (CRI) may have reduced bone mineral density (BMD) as a result of abnormalities in acid-base and vitamin D-parathyroid hormone homeostasis. METHODS: We analyzed data on 13,848 adults aged 20 and above from the Third National Health and Nutrition Examination Survey (NHANES III; 1988-1994). Regression models were used to determine the relationship between femoral BMD and renal function, the latter assessed using serum creatinine, blood urea nitrogen or Cockcroft-Gault creatinine clearance. To control for confounding, we fit sex-stratified models that adjusted for age, weight, height, race-ethnicity, menopausal status, estrogen use, activity level, family history of osteoporosis, diuretic use, and dietary intake of calcium and alcohol. RESULTS: Although subjects with reduced renal function had significantly lower femoral BMD in unadjusted analysis, the association between CRI and bone mineral density was extinguished after adjustment in the multivariate models. In fact, controlling for only sex, age and weight was sufficient to extinguish any negative association between decreased renal function and decreased bone mineral density. CONCLUSION: Although subjects with worse renal function have significantly lower femoral BMD, this association can be explained by confounding, principally by sex, age and weight. After taking into account the facts that women, older individuals and smaller individuals have less renal function and lower BMD, renal function itself is not independently associated with BMD. (+info)
Normal or low initial PTH levels are not a predictor of morbidity/mortality in patients undergoing chronic peritoneal dialysis.
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OBJECTIVE: During the past few decades, the pattern of bone disease in uremic patients has changed significantly. There has been an increase in the number of patients with normal or low initial parathyroid hormone (PTH) levels, particularly in patients on chronic peritoneal dialysis (CPD). Previous authors have described a higher prevalence of bone pain, microfractures, and fractures, and higher mortality among these patients. The aim of this study was to determine the incidence, morbidity, and mortality of patients who had a low or normal intact PTH (iPTH) level when they started CPD. DESIGN: We reviewed the records of 251 patients in our program that started CPD during the past 5 years (January 1996-December 2000). Clinical data, laboratory variables, medication, and dialysis parameters/dose were available at every clinic visit (approximately every 4 weeks). Intact PTH was used to express parathyroid function; values 3 times higher than the upper limit of normal (ULN) were assumed to be optimal. Variables predictive of the development of parathyroid dysfunction were calculated by univariate and multivariate logistic regression analysis. RESULTS: Of the patients who started CPD, 15.5% had iPTH values below the ULN (7.6 pmol/L), and an additional 29.5% had an iPTH of less than 3 times the ULN (i.e., between 7.6 and 22.8 pmol/L). We call these two groups of patients the normal/low initial iPTH group. During the follow-up period (3-63 months), we found a trend toward increasing iPTH levels. By the end of the study period, 61.2% of those with normal/low initial iPTH remained in the normal/low iPTH range, and 38.8% had converted to a group with an iPTH range higher than 22.8 pmol/L. The patients who converted their iPTH grouping were younger, fewer of them were diabetics (p = not significant), and they were more frequently on low calcium dialysate (p < 0.05). Hyperphosphatemia was an independent risk factor for subsequent iPTH changes during the course of continuous ambulatory PD treatment. All patients in the normal/low iPTH groups had a low prevalence of bone fractures (3.5%). Also, patients who remained in the normal/low iPTH group at the end of the follow-up period did not have more fractures than those who converted to the hyperparathyroid group (3.8% vs 3.1%). We found no differences in bone fractures between patients with iPTH levels below 22.8 and those with levels above 22.8 pmol/L (3.5% vs 5.4%), nor were there differences in patient and technique survival between these two groups. CONCLUSION: Normal/low initial iPTH is a frequent finding among patients starting CPD. Serum phosphorus was an independent risk factor for subsequent iPTH changes during the course of CPD treatment. Use of low calcium dialysate was significantly higher in patients who converted their iPTH into the high iPTH range. Very few patients with low/normal iPTH had bone-related symptoms (pain and fractures), and their morbidity and mortality did not differ from those patients with a high initial iPTH level. (+info)
Effects of tibolone on the development of osteopenia induced by ovariectomy in rats.
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Experimental osteopenia caused by ovariectomy in rats may reflect postmenopausal bone changes, which are the effect of osteogen deficiency. The aim of the present study was to investigate the effects of tibolone (0.25 mg/kg/day and 2.5 mg/kg po) administered for 4 weeks on the development of osteopenia caused by bilateral ovariectomy in 3-month-old female Wistar rats. The experiments were carried out on six groups of animals: I (C) - control sham operated rats, II (OVX) - ovariectomized rats, III (OVX + T-0.25) - ovariectomized rats which were administered tibolone at a dose of 0.25 mg/kg, IV (OVX + T-2.5) - ovariectomized rats which were administered tibolone at a dose of 2.5 mg/kg, V (T-0.25) - sham operated rats which were administered tibolone at a dose of 0.25 mg/kg, VI (T-2.5) - sham operated rats which were administered tibolone at a dose of 2.5 mg/kg. The following parameters were examined in all the groups: body weight gain, bone mass, length and diameter, mineral and calcium contents in the tibia and femur, endosteal and periosteal transverse growth, endosteal and periosteal osteoid width, transverse cross-section area of the cortical diaphysis and that of the marrow cavity in the tibia, epiphyseal cartilage width, trabeculae width in the epiphysis and metaphysis of the femur. Mechanical properties of the femur were also studied. Bilateral ovariectomy induced osteopenic skeletal changes in mature female rats. Tibolone (0.25 mg/kg/day and 2.5 mg/kg/day po) administered to ovariectomized rats for 28 days decreased the development of osteopenic skeletal changes induced by bilateral ovariectomy. (+info)