Gene/Protein Disease Symptom Drug Enzyme Compound
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Together, osteoporosis and osteopetrosis comprise a substantial proportion of the bone diseases that severely affect humans. In order to understand and effectively treat these disorders, an understanding of the mechanisms controlling bone remodelling is essential. While numerous animal models of bone disease have been generated, the lack of correlation between these animal models and human disease has limited their utility in terms of defining therapeutic strategies. The generation and analysis of cathepsin K knockout mice has resulted in a model for pycnodysostosis, a rare human osteopetrotic disease, and is now providing considerable insights into both osteoclast function and potential therapeutic strategies for the treatment of bone disease. This review highlights the importance of genes such as cathepsin K in understanding bone remodelling and illustrates a new trend towards understanding bone disease as a complete entity rather than as a series of unrelated disorders.
Hum Mol Genet 1999
PMID:Osteopetrosis and osteoporosis: two sides of the same coin. 1046 35

The aim of this study was to characterize the spectrum of 13-glucocerebrosidase gene mutations in Czech and Slovak Gaucher patients and to study genotype/phenotype associations. We have analyzed fifty-eight chromosomes from twenty-six type I, two type 2, and one type 3 13-glucocerebrosidase deficient subjects by direct sequencing of PCR products. Fifty-eight mutant alleles were identified. Seventy-eight percent of mutant alleles carried common mutations (N370S 28/58, L444P 11/58, recNciI 5/58, and IVS2(+1)A 1/58), the remaining twenty-two percent carried rare and private mutations (1263del55, l326insT, S196P, rec(g4889-6506), 2O3delC, G202E, F216Y, R257X, R12OW, R359Q, S1O7L, L444P + V460V, and D409H + T369M). Six of these alleles have not been previously described (rec(g4889-6506), 1326insT, SI96P. G202E, D409H + T369M, and L444P + V460V). The most common genotypes were N370S/L444P (8/29). N370S/recNciI (5/29), and N370S/N370S (2/29). The spectrum of the mutations is characteristic for a Caucasian (non-Jewish) population, with N370S, L444P and recNciI being the most prevalent mutations. The absence of the mutation 84insG that is frequently associated with severe bone disease may have contributed to the low incidence of severe bone disease in Czech and Slovak Gaucher subjects.
Blood Cells Mol Dis
PMID:Analysis of the beta-glucocerebrosidase gene in Czech and Slovak Gaucher patients: mutation profile and description of six novel mutant alleles. 1074 24

The Runt domain family of transcription factors play key roles in transcriptional regulation of definitive hematopoiesis and osteogenesis. This transcription factor family is characterized by a DNA-binding alpha-subunit harboring the Runt domain and a secondary subunit, beta, which binds to the Runt domain and enhances its interaction with DNA. Missense mutations in the Runt domain from either the blood or bone-related gene product are associated with the onset of acute human leukemia as well as a disease of skeletal patterning known as cleidocranial dysplasia. NMR "footprinting" analysis of Runt domain/beta/DNA ternary complexes in solution previously identified the likely residues that form the heterodimerization and DNA-binding surfaces of the Runt domain. Functional mutagenesis at 37 positions in the Runt domain or beta confirms the original identification of these interaction surfaces and reveals that the heterodimerization and DNA-binding surfaces of the Runt domain occur at distinct, non-overlapping sites within the domain. The analysis of an additional 21 disease-related missense mutations identified from patients with either blood or bone disease demonstrates that the primary defect in these patients is a failure in DNA-recognition by the Runt domain. The molecular basis for the DNA-binding defect is analyzed in the context of the three-dimensional structure of the Runt domain in binary and ternary protein/DNA complexes.
J Mol Biol 2001 Apr 27
PMID:Functional mutagenesis of AML1/RUNX1 and PEBP2 beta/CBF beta define distinct, non-overlapping sites for DNA recognition and heterodimerization by the Runt domain. 1132 61

Type 1 Gaucher disease can be effectively treated with enzyme supplementation therapy. Bone disease is a debilitating feature of the disorder and results from infiltration of the bone marrow by Gaucher cells. The effect of treatment on bone marrow infiltration is difficult to measure, necessitating the development of sensitive techniques to allow adequate dosing. Dixon quantitative chemical shift imaging (Dixon-QCSI) is a MRI technique to measure displacement of fatty marrow by Gaucher cells. Low bone marrow fat fractions have been found in Gaucher disease. We studied the effect of individualized low doses of enzyme therapy on the fat fractions of the lumbar spine in 12 adult Gaucher disease patients before and during treatment and in 9 untreated Gaucher controls. Fat fractions were decreased in 9/12 patients (median 0.20, range 0.08-0.40) and equally low in the untreated Gaucher controls compared to age-matched healthy volunteers (normal values 0.27-0.43, P < 0.01). During treatment, fat fractions increased significantly already after 1 year in 11/12 patients (P = 0.007). After 4 to 5 years, fat fractions normalized in 11/12 patients. Fat fractions remained low in the untreated Gaucher controls (P = 0.5 and 0.6 at 1 and 2 years, respectively). Six of 11 patients had a dose increase, which did not clearly affect fat fractions. Dixon-QCSI is a sensitive tool for the measurement of the response of bone marrow to enzyme therapy.
Blood Cells Mol Dis
PMID:Dixon quantitative chemical shift imaging is a sensitive tool for the evaluation of bone marrow responses to individualized doses of enzyme supplementation therapy in type 1 Gaucher disease. 1183 67

The subject of this article is the state of a benign bone disease. The principle aim of this study is the construction of a statistical model for estimating the otherwise unobservable variable for the state of the disease. The distribution of intensity of X-ray images of the affected part and the healthy part of the bone are evaluated. Quantiles of both distributions are used in the estimation of a multinomial logit model by which the variable for the state of the disease is quantified.
Cell Mol Biol Lett 2002
PMID:Modelling the state of bone cysts by statistical analysis of intensities of x-ray images. 1209 82

Previously, we identified a parathyroid hormone-related high-turnover bone disease after gastrectomy in mini pigs. Dynamic [(18)F]fluoride ion positron emission tomography (PET) revealed that bone metabolism was significantly increased, but that bone blood flow derived from permeability-surface area product (PS product)-corrected K(1) values was not. Since bone blood flow and metabolism are coupled in normal bone tissues, we hypothesised that the capillary permeability and/or surface area might be altered in high-turnover bone disease. The "true" bone blood flow ( f(H2O)) was measured in vertebral bodies by dynamic [(15)O]H(2)O PET, followed by a 120-min dynamic [(18)F]fluoride ion PET study, 6 months after total gastrectomy (n=5) and compared with results in sham-operated animals (n=5). Estimates for bone blood flow based on PS-corrected K(1) values (f) and the net uptake of fluoride in bone tissue (K(i)), representing the bone metabolic activity, were calculated using standard compartmental modelling and non-linear fitting. Gastrectomy was followed by a significant elevation of K(i) and k(3) ( P<0.05), which was mainly caused by an increase of the fraction of bound tracer in tissue (P<0.01). In contrast, f(H2O), f, the single-pass extraction fraction of [(18)F]fluoride (E) and the volume of distribution (DV) of [(18)F]fluoride were not significantly different between groups. In both groups, a coupling of the mean f(H2O) and K(i) values was found, but the intercept with the y-axis was higher in high-turnover bone disease. It is concluded that in high-turnover bone disease following gastrectomy, the PS product for [(18)F]fluoride remains unchanged. Therefore, even in high-turnover bone diseases, [(18)F]fluoride ion PET can provide reliable blood flow estimates (f), as long as a proper PS product correction is applied. The increased bone metabolism in high-turnover bone disease after gastrectomy is mainly related to an up-regulation of the amount of ionic exchange of [(18)F]fluoride with the bone matrix, while tracer delivery remains unchanged.
Eur J Nucl Med Mol Imaging 2002 Jul
PMID:Coupling of porcine bone blood flow and metabolism in high-turnover bone disease measured by [(15)O]H(2)O and [(18)F]fluoride ion positron emission tomography. 1211 Nov 31

Idiopathic hyperphosphatasia is an autosomal recessive bone disease characterized by deformities of long bones, kyphosis and acetabular protrusion, increasing in severity as affected children pass through adolescence. Biochemical and histological evidence indicate that there is extremely rapid bone turnover, with indices of both bone resorption and formation greatly increased. A genome-wide search, in a family with three children affected by idiopathic hyperphosphatasia, suggested linkage to a locus on the long arm of chromosome 8 (8q24). The gene TNFRSF11B encoding osteoprotegerin (OPG), which lies within this locus, was an obvious candidate, given the critical role of OPG in regulating osteoclast development. All three affected siblings were homozygous for a 3 bp inframe deletion in exon 3 of the TNFRSF11B gene, resulting in the loss of an aspartate residue. Their parents (who were first cousins) were heterozygous for the mutation. Recombinant wild-type and mutant OPG cDNAs were expressed in human epithelial kidney cells, and secreted OPG was collected from the conditioned medium. In vitro measurements of bone resorption showed that wild-type OPG suppressed bone resorption, whereas the mutant form did not, confirming this to be an inactivating mutation. This description of abnormal OPG function in humans expands the spectrum of genetic bone diseases arising from perturbations of the OPG/RANK-L/RANK system that regulates osteoclastogenesis.
Hum Mol Genet 2002 Sep 01
PMID:A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. 1218 64

Legg-Calve-Perthes disease (LCPD) is an avascular necrosis of the femoral head with an annual incidence of 5-15/100,000. The estimated incidence of Gaucher disease, a lysosomal recessive storage disease, is 1:850, with a carrier rate of 1:17.5 for the 1226G (N370S) mutation among Ashkenazi Jews in whom there is a predilection. Since clinical and radiological findings of avascular hip necrosis due to either Gaucher disease or LCPD may be indistinguishable, misdiagnosis may occur. The purpose of this study was to evaluate the incidence of 1226G Gaucher mutation in a cohort of radiologically confirmed LCPD patients (diagnosed 1986-2000) in Israel. Enzyme assay was performed for confirmation of affected versus carrier status in patients with the 1226G mutation. In all, 78 LCPD patients, 86% males, 51% with severe bone disease, were studied. Family history was negative for Gaucher disease. Ethnic origin was 39% Ashkenazi Jewish, 6% Arab, and 55% other ethnicities. One Ashkenazi Jewish LCPD patient was homozygous for the 1226G mutation, and 4 LCPD patients were carriers: 3 Ashkenazi Jewish and 1 Arab patient. The frequency of the 1226G mutation among the LCPD patients was increased relative to historical Ashkenazi Jewish Israeli controls (P = 0.01). Since Gaucher disease may be misdiagnosed as LCPD, glucocerebrosidase enzyme testing is recommended among Ashkenazi Jewish children diagnosed with LCPD.
Blood Cells Mol Dis
PMID:The 1226G (N370S) Gaucher mutation among patients with Legg-Calve-Perthes disease. 1285 Apr 87

Myeloma bone disease is characterized by osteolytic bone destruction that is not followed by reactive new bone formation. This results in a purely lytic process, which differs from other cancers that metastasize to bone where bone destruction is followed by new bone formation. The bone destructive process in myeloma is mediated by the osteoclast (OCL), the normal bone resorbing cell. Factors that increase OCL formation and activity are produced by both myeloma cells themselves, as well as by marrow stromal cells when myeloma cells bind to marrow stromal cells. The bone destructive process releases factors that further increase the growth and survival of myeloma cells. Thus, there is a symbiotic relationship between the bone destructive process and increased growth of myeloma cells. Several studies have shown that blocking bone destruction can result in decreased tumor burden in animal models of myeloma. This overview will focus on the factors recently identified that appear to play an important role in the bone destructive process in myeloma.
Blood Cells Mol Dis
PMID:Pathogenesis of myeloma bone disease. 1500 20

Breast cancer represents a major health problem, with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade, in spite of an increasing incidence, breast cancer mortality has been declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments. Better knowledge of breast cancer biology now allows the cosmetic, physical and psychological consequences of radical mastectomy to be spared in the majority of breast cancer patients. Use of the sentinel node technique is rapidly expanding and this will further reduce the extent and the consequences of surgery. Several clinico-pathological factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse. Nodal status, tumour size, tumour grade and age are accepted universally as important factors to define risk categories. Newer factors such as uPA/PAI-1, HERer2-neu, proliferative indices and gene expression profile are promising and will allow better discrimination between patients at different risk. Endocrine manipulation with tamoxifen, ovarian ablation or both is the preferred option in the case of endocrine-responsive tumours. Tamoxifen administered for 5 years is the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen, with a different safety profile. At present, anastrozole can be used in the adjuvant setting in cases of tamoxifen intolerance or toxicity. Chemotherapy is the treatment of choice for steroid receptor-negative tumours. Polychemotherapy is superior to single agents and anthracycline-containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four of CMF are the recommended regimens. New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. The taxanes have been approved for adjuvant therapy in the USA, while European approval is pending. Combined endocrine-chemotherapy is the standard adjuvant treatment in high-risk patients with endocrine-responsive tumours. Endocrine manipulation is usually administered after completion of the chemotherapy programme. For HER2-neu overexpressing tumours, several rapidly accruing trials are exploring the potential additive effect of trastuzumab, a monoclonal antibody directed against the extramembrane portion of the HER2 receptor. Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer, with increased rates of breast-conserving surgery. A proportion of patients achieve a pathological complete response and these patients have significantly better long-term outcomes. Twenty-five to forty percent of breast cancer patients develop distant metastases. At this stage the disease is incurable; however, treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In the case of hormone receptor positivity and in the absence of visceral, life-threatening disease, endocrine manipulation is the treatment of choice. Active treatments include tamoxifen, ovarian ablation, aromatase inhibitors, pure anti-oestrogens and progestins. Aromatase inhibitors are the most active agents, but the choice and the sequence of endocrine therapies are also dictated by prior adjuvant treatment. Chemotherapy has to be preferred in cases of receptor-negative tumours, acquired resistance to hormones and aggressive visceral disease. Combination regimens are usually associated with higher response rates and sometimes survival prolongation, and this approach should be recommended in young patients with good performance status and visceral disease. On the other hand, single agents have a better tolerability profile and should be tand should be the treatment of choice when a careful balance between activity and tolerability is needed. For HER2-neu positive tumours, the combination of trastuzumab and chemotherapy is significantly superior to chemotherapy alone in terms of both response rates and survival. Other useful palliative treatments include bisphosphonates for the control of metastatic bone disease and radiotherapy for painful bone lesions or local relapses.
Eur J Nucl Med Mol Imaging 2004 Jun
PMID:The curability of breast cancer and the treatment of advanced disease. 1510 48


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