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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A sensitive and accurate method for determining the ratios of RNA and DNA templates by polymerase chain reaction (PCR) is presented. A common competitor containing tandemly arranged internal standards differing from the target template by the presence of different restriction enzyme sites is coamplified with the target templates under identical conditions. Products from each template and internal standard are identified by the band pattern after digestion with the restriction enzyme. As the amount of the common competitor is kept constant for all target templates, the ratio of PCR products from the templates reflects their ratio in the reaction mix before amplification. The method was used to study the relative abundance of mRNA for the pro-alpha1 and pro-alpha2 chains of type I collagen and for estimating disturbances of normal ratio in the inherited bone disorder, osteogenesis imperfecta.
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PMID:Tandem competitive polymerase chain reaction (TC-PCR): a method for determining ratios of RNA and DNA templates. 128 4

Peptides of low molecular weight that contain pyridinoline cross-links were isolated from adolescent human urine. A fraction was selected that was enriched in the N-telopeptide-to-helix intermolecular cross-linking domain of bone type I collagen. Mouse monoclonal antibodies were generated against these urinary peptides conjugated to a carrier protein as immunogen. A high-affinity antibody was identified that specifically bound to the trivalent peptides derived from the N-telopeptide-to-helix pyridinoline cross-linking site in type I collagen of human bone. This was confirmed by the direct isolation from human bone collagen of similar fragments recognized selectively by the antibody. A sensitive inhibition ELISA was established on microtiter plates that could quantify the bone-derived peptides in human urine. The assay, which can be run directly on untreated urine, was thoroughly tested against samples from normal subjects and from patients with metabolic bone disease. For example, strong correlations with urinary hydroxyproline and total pyridinoline cross-links were found in patients with Paget's disease of bone. The method shows considerable promise as a rapid and specific index of human bone resorption rates, with greatly improved specificity and convenience over total pyridinoline analysis. Potential applications include the study of normal metabolism, the diagnosis and monitoring of bone disease, and evaluating the effectiveness of antiresorption therapies.
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PMID:A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen cross-linked N-telopeptides in urine. 146 51

A structural defect in the alpha 2(I) chain of type I collagen was characterized in a new case of the Ehlers-Danlos syndrome type VII. The patient's skin, fascia, and bone collagens all showed an abnormal additional chain, pN-alpha 2(I)s, running slower than the alpha 2(I) chain on electrophoresis. The extension was shown to be on the amino-terminal fragment of pN-alpha (I)s by cleavage with human collagenase, but pepsin was unable to convert pN-alpha 2(I)s to alpha 2(I). Skin collagen was 4-fold more extractable and contained fewer beta-dimers and a lower concentration of cross-linking amino acids than control skin collagen. Electron micrographs of both dermis and bone showed markedly irregular ragged outlines of the collagen fibrils in cross-section, although the patient had no clinical signs of bone disease. Procollagen secreted by her skin fibroblasts in culture showed equal amounts of the normal and abnormal alpha 2(I) chains on pepsin digestion. Before pepsin, the pN-alpha 2(I) component ran as a doublet on electrophoresis; pepsin removed only the normal slower chain. The suspected deletion in pN-alpha 2(I)s was traced by CNBr peptide analysis to the N-propeptide fragment, which behaved on electrophoresis about 15-20 residues smaller than that from the normal pN-alpha 2(I) chain. The simplest genetic explanation is a spontaneous heterozygote in which one normal and one abnormal allele for the pro-alpha 2(I) gene are expressed, the protein defect being a deletion of the junction domain that spans the N-propeptidase cleavage site and the N-telopeptide cross-linking sequence.
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PMID:A heterozygous collagen defect in a variant of the Ehlers-Danlos syndrome type VII. Evidence for a deleted amino-telopeptide domain in the pro-alpha 2(I) chain. 299 7

Using molecular sieve chromatography on Bio-Gel P-2 and then on Bio-Gel P-30, hydroxyproline-containing urinary polypeptides (molecular weight greater than 1500 daltons) were separated into eight fractions. The three main fractions were separated further on phosphocellulose giving seven, nineteen and twelve peaks, respectively, each containing 4-hydroxyproline. Hypotheses about the origin of certain polypeptides are proposed, which take into account the sequence of type I collagen. Among these 38 polypeptides only one shows a quantitative variation in Paget's bone disease and was thus purified. It consists of equal amounts of glycine, proline and 4-hydroxyproline. This particular polypeptide may originate from the N-terminal propeptide of type I collagen.
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PMID:Polymorphism of urinary 4-hydroxyproline-containing polypeptides. 729 59

We have measured the free and peptide-bound type I collagen cross-link excretions in normal women and in patients with metabolic bone disease using the HPLC technique and immunoassays recognizing specifically the free or peptide-bound forms of pyridinoline (Pyr). After menopause, free deoxypyridinoline (free D-Pyr) excretion measured by HPLC without urine hydrolysis and expressed as a fraction of the total excretion was lower than in premenopausal women (45 +/- 15% vs. 59 +/- 12%, p < 0.005), whereas the fraction of free Pyr was not changed. In normal pre- and postmenopausal women (n = 43), the fraction of free D-Pyr was negatively correlated with bone turnover rate as assessed by the total urinary excretion of Pyr (r = -0.64, p < 0.001). In patients with a variety of metabolic bone diseases characterized by increased bone turnover (osteoporosis, Paget's disease, and hyperthyroidism), the fractions of free Pyr and free D-Pyr were significantly lower than in premenopausal controls (p < 0.001 for all diseases). After 3 days of intravenous (iv) treatment with the bisphosphonate pamidronate in patients with Paget's disease and osteoporosis, the urinary excretion of cross-linked peptides measured by high performance liquid chromatography (HPLC) or enzyme-linked immunoassay (ELISA) (NTX and CrossLaps) was markedly decreased (-52% and -85% for NTX, -71% and -93% for CrossLaps in Paget's disease and osteoporosis, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Different effects of bisphosphonate and estrogen therapy on free and peptide-bound bone cross-links excretion. 761 Sep 36

Although osteosclerotic bone metastases are characteristic of prostate cancer, mixed metastases with a lytic component are not uncommon. Type I collagen is synthesised by osteoblasts and accounts for about 90% of the organic matrix of bone. We have used new specific immunoassays for PICP (carboxy-terminal propeptide of type I procollagen) and ICTP (cross-linked carboxy-terminal telopeptide of type I collagen) which allow simultaneous assessment of the synthesis and degradation of type I collagen respectively. Forty patients with bone metastases due to prostate cancer at the time of diagnosis were investigated with these methods. Twenty-three of them had sclerotic (S) and 17 had mixed metastases with sclerotic and lytic components (S + L) as assessed by radiographs. The concentrations of PICP and ICTP in serum as well as the activity of alkaline phosphatase (AP) were increased in all patients of the S + L group, who had more aggressive bone disease and a shorter survival than the S group (P < 0.017). The ICTP level was above the reference range in half of the patients in the S group, whereas the PICP and AP levels were elevated in 35%. Of the bone markers, only ICTP was of prognostic significance (P < .05). We conclude that ICTP and PICP give information about the type and activity of the skeletal metastases. In addition, ICTP predicts prognosis.
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PMID:Type I collagen degradation product (ICTP) gives information about the nature of bone metastases and has prognostic value in prostate cancer. 773

Osteogenesis imperfecta (OI) type I is the mildest form of inherited brittle-bone disease. Dermal fibroblasts from most affected individuals produce about half the usual amount of type I procollagen, as a result of a COL1A1 "null" allele. Using PCR amplification of genomic DNA from affected individuals, followed by denaturing gradient gel electrophoresis (DGGE) and SSCP, we identified seven different COL1A1 gene mutations in eight unrelated families with OI type I. Three families have single nucleotide substitutions that alter 5' donor splice sites; two of these unrelated families have the same mutation. One family has a point mutation, in an exon, that creates a premature termination codon, and four have small deletions or insertions, within exons, that create translational frameshifts and new termination codons downstream of the mutation sites. Each mutation leads to both marked reduction in steady-state levels of mRNA from the mutant allele and a quantitative decrease in type I procollagen production. Our data demonstrate that different molecular mechanisms that have the same effect on type I collagen production result in the same clinical phenotype.
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PMID:Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen. 794 41

Clodronate and alendronate were compared in 27 patients with active Paget's bone disease. Carboxyterminal crosslinked telopeptide of type I collagen (ICTP) was evaluated as a marker of bone turnover in Paget's bone disease. Group 1. Nineteen patients received clodronate infusions (300 mg/daily) on 5 consecutive days. After 1 year, 12 patients (63%) were still in remission; urinary hydroxyproline (64.8%) and serum alkaline phosphatase (59.4%) were significantly reduced and had returned to normal in 30%. Patients in remission had significantly higher basal values of urinary hydroxyproline. No adverse side effects were observed. Group 2. One year after clodronate, seven relapsing patients retrospectively underwent five consecutive infusions of alendronate (5 mg/daily). Within 12 months, urinary hydroxyproline fell by 74.7%, alkaline phosphatase dropped by 75.2%, osteocalcin by 47.3%, and ICTP by 56.4%. In all patients, urinary hydroxyproline and alkaline phosphatase returned to normal within 3 months and remained within the normal range during the 12-month follow-up. Most patients had mild, short course fever and arthromyalgia. Group 3. Eight newly diagnosed pagetics, received alendronate alone (5 mg/daily for 5 days). All patients responded well to alendronate within the first month. None suffered a relapse during the follow-up. At month 12, urinary hydroxyproline was down by 71.4%, alkaline phosphatase by 75.3%, osteocalcin by 58.1%, and ICTP by 67.4%. In all patients, markers of bone remodeling were in the normal range at the end of the follow-up. Moderate, transitory arthromyalgia, and fever (high and lasting for 7 days in only one case) were observed in half of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of two different bisphosphonates on Paget's disease of bone: ICTP assessed. 806 46

We have used a new enzyme-linked immunoassay (ELISA) to measure the urinary excretion of type I collagen peptides (CrossLaps) released during bone matrix degradation in a sample of healthy adults comprising 146 women and 60 men, aged 31-89 yr, and in patients with metabolic bone disease. The intra- and interassay coefficients of variation were less than 10% and 13%, respectively. The recovery of CrossLaps antigen from urine samples ranged from 92-115%, and the ELISA was linear for serial sample dilutions. The CrossLaps assay does not cross-react with either free pyridinoline (Pyr) or free deoxypyridinoline (D-Pyr). CrossLaps measured by ELISA and the total excretion of Pyr measured by high performance liquid chromatography were highly correlated in normal women (n = 91; r = 0.73; P < 0.001). Urinary CrossLaps excretion increased with age in women, but not in men. In women, the menopause was reflected by a mean 141% increase in CrossLaps excretion [from an average 217 to 524 micrograms/mmol creatinine (Cr)] that was higher than the mean increase in total D-Pyr (+91%) and total Pyr (+47%) measured by HPLC and the mean increase in bone alkaline phophatase (+48%) and osteocalcin (+41%). Urinary CrossLaps excretion was increased from control values in Paget's disease (n = 32; mean, 1810 +/- 2300 micrograms/mmol Cr; P < 0.001), in patients with primary hyperparathyroidism (n = 10; mean, 780 +/- 380 micrograms/mmol Cr; P < 0.001), and in patients with hyperthyroidism (n = 27; mean, 1280 +/- 970 micrograms/mmol Cr; P < 0.001), with Z-scores (number of SD from the mean of sex- and age-matched controls) of 4.4 +/- 6.6, 1.5 +/- 1.2, and 6.7 +/- 6.5, respectively. In patients with Paget's disease, CrossLaps values were highly correlated with urinary hydroxyproline levels (r = 0.91; P < 0.001), and the decrease in urinary CrossLaps excretion was greater than that in urinary hydroxyproline (-71% vs. -17%; P < 0.001) after 3 days of i.v. treatment with the bisphosphonate pamidronate. In patients with hyperthyroidism, CrossLaps excretion was elevated above the normal range in most patients (78%) and returned to normal within 1 month of treatment for hyperthyroidism. It is concluded that this new convenient assay represents a sensitive and specific index of the bone resorption rate, and that it should be useful for the clinical investigation and therapeutic monitoring of patients with osteoporosis and other metabolic bone diseases.
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PMID:Assessment of bone resorption with a new marker of collagen degradation in patients with metabolic bone disease. 807 61

Mutations in one of the two genes encoding type I procollagen (COL1A1 and COL1A2) are frequently the cause of osteogenesis imperfecta (OI), a disorder characterized by brittle bones. Here we tested whether patients with low bone density also have mutations in these genes. The 26 patients studied had no apparent metabolic bone disease, but most had a positive family history of osteopenia or osteoporosis. Although a diagnosis of OI was considered by the clinician in some cases, the clinical criteria for OI were not satisfied. Our strategy for mutation analysis consisted of PCR amplification of cDNA made to fibroblast mRNA using primers specific for the coding regions of COL1A1 and COL1A2. The PCR products were then sequenced directly with primers located within each PCR product. We found that 3 of 26 patients had mutations that altered the encoded amino acid. One mutation, at position alpha 2(I)-661 has been reported (Spotila et al. 1991 Proc Natl Acad Sci USA PNAS 88:5423). The other 2 patients, who were not related to each other, had a mutation that altered the proline codon at alpha 1(I)-27 to alanine. This mutation was not found in 81 normal individuals or in 37 additional osteopenic individuals. However, its effect on the biologic function of type I collagen, as well as its role in osteopenia, is uncertain. In addition to the two mutations, we found a polymorphism in codon alpha 2(I)-459. Although this polymorphism involved an amino acid substitution, it was present with equal frequency in the patient and the normal population. By analyzing this and previously reported neutral sequence variants in the COL1A2 gene, we determined that all patients expressed both alleles of the COL1A2 gene. The 12 patients who were heterozygous for a COL1A1 neutral sequence variant also expressed both alleles. Here we present all PCR primer and sequencing primer information. The results suggest that surveying a larger group of similarly selected individuals may reveal additional mutations in the COL1A1 or COL1A2 genes.
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PMID:Mutation analysis of coding sequences for type I procollagen in individuals with low bone density. 807 66


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