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1.
Medicine (Baltimore) ; 98(42): e17458, 2019 Oct.
Article En | MEDLINE | ID: mdl-31626101

RATIONALE: Asymptomatic Paget disease of bone (PDB) is mostly diagnosed by accidental finding of osteolytic lesion on the plain film. However, in elderly patient with chronic renal insufficiency and weight loss, it is crucial to differentiate PDB from metabolic and metastatic bone diseases for further treatment and better outcome. PATIENT CONCERNS: An 80-year-old man with chronic kidney disease presented to our emergency department due to fever with chillness for a day, while the abdominal fullness, anorexia, and weight loss had been noted for 3 months. Mixed osteoblastic and lytic changes in the pelvic bone were accidentally found on the abdominal plain film. DIAGNOSIS: The patient was diagnosed as asymptomatic PDB and urinary tract infection of Pseudomonas aeruginosa. INTERVENTIONS AND OUTCOME: The patient received 7 days intravenous and followed by 7 days oral antibiotic treatment, which lead to clinical improvement of his urinary tract infection. No pharmacological treatment was initiated for the asymptomatic and localized PDB. The patient was discharged under stable condition afterward. LESSONS: In patients with mixed osteolytic and blastic lesions, the differential diagnoses include metabolic and metastatic bone disease. Thorough understanding of the morphology of the bone lesions in high risk patient, not only helps to make differential diagnosis, but it also leads to precise treatment and better outcome.


Osteitis Deformans/diagnosis , Renal Insufficiency, Chronic/complications , Aged, 80 and over , Diagnosis, Differential , Humans , Male , Osteitis Deformans/etiology , Weight Loss
2.
Joint Bone Spine ; 86(3): 373-380, 2019 05.
Article En | MEDLINE | ID: mdl-30594595

OBJECTIVES: This study explored the role of outdoor and indoor air pollutants in Paget's disease of bone (PDB). METHODS: We performed a survey in 140 French-Canadian patients with PDB, including 39 carriers of p.Pro392Leu mutation (SQSTM1 gene) and 113 healthy not mutated controls. The survey covered outdoor air pollution near the residence and indoor air pollutants by focusing on heating fuels and exposure to tobacco smoke. In a subgroup of patients, urinary concentrations of 17 heavy metals and 11 polycyclic aromatic hydrocarbons were measured by mass spectrometry. In light of what we learned from the survey and urinary assays, we explored the in vitro effects of certain toxics on osteoclasts in PDB. We conducted in vitro monocytes differentiation from peripheral blood of more than 40 participants, whose osteoclasts were treated with or without the toxic. The morphology of osteoclasts, their bone resorption abilities, gene and protein expression levels, and cellular oxidative stress levels were assayed. RESULTS: An inhibitory effect of cigarette smoke condensate and heavy metals was observed on morphology and bone resorption activity of patients' osteoclasts. SQSTM1 gene expression was upregulated in osteoclasts from patients with PDB versus healthy controls in presence of cadmium, and SQSTM1 protein expression was upregulated in presence of bismuth and tobacco smoke condensates, in particular in osteoclasts from carriers of the SQSTM1 mutation. Furthermore, high levels of oxidative stress in patients' osteoclasts were observed. CONCLUSIONS: Our in vitro experiments suggest an interaction between SQSTM1 gene and exposure to cadmium and tobacco smoke condensates.


Adaptor Proteins, Signal Transducing/genetics , Air Pollutants/adverse effects , Genetic Predisposition to Disease/epidemiology , Osteitis Deformans/epidemiology , Osteitis Deformans/genetics , Sequestosome-1 Protein/genetics , Adult , Age Factors , Cadmium/adverse effects , Cross-Sectional Studies , Environmental Exposure/adverse effects , Female , Gene Expression Regulation , Gene-Environment Interaction , Humans , Incidence , Logistic Models , Male , Middle Aged , Multivariate Analysis , Mutation , Osteitis Deformans/etiology , Osteoclasts/drug effects , Quebec , RANK Ligand/metabolism , Reference Values , Risk Assessment , Sex Factors , Tobacco Smoke Pollution/adverse effects
3.
Best Pract Res Clin Endocrinol Metab ; 32(5): 657-668, 2018 10.
Article En | MEDLINE | ID: mdl-30449547

Paget's disease of bone is a focal disorder of bone remodelling that progresses slowly and leads to changes in the shape and size of affected bones and to skeletal, articular and vascular complications. In some parts of the world it is the second most common bone disorder after osteoporosis though in recent years its prevalence and severity appear to decrease. The disease is easily diagnosed and effectively treated but its pathogenesis remains incompletely understood.


Osteitis Deformans , Bone and Bones/pathology , Bone and Bones/physiology , Humans , Osteitis Deformans/epidemiology , Osteitis Deformans/etiology , Osteitis Deformans/pathology , Osteoporosis/epidemiology , Osteoporosis/etiology , Osteoporosis/pathology , Prevalence
4.
PLoS One ; 13(5): e0197543, 2018.
Article En | MEDLINE | ID: mdl-29782529

Paget's disease of bone (PDB) is a chronic bone disorder and although genetic factors appear to play an important role in its pathogenesis, to date PDB causing mutations were identified only in the Sequestosome 1 (SQSTM1) gene at the PDB3 locus. PDB6 locus, also previously linked to PDB, contains several candidate genes for metabolic bone diseases. We focused our analysis in the most significantly associated variant with PDB, within the Optineurin (OPTN) gene, i.e. the common variant rs1561570. Although it was previously shown to be strongly associated with PDB in several populations, its contribution to PDB pathogenesis remains unclear. In this study we have shown that rs1561570 may contribute to PDB since its T allele results in the loss of a methylation site in patients' DNA, leading to higher levels of OPTN gene expression and a corresponding increase in protein levels in patients' osteoclasts. This increase in OPTN expression leads to higher levels of NF-κB translocation into the nucleus and increasing expression of its target genes, which may contribute to the overactivity of osteoclasts observed in PDB. We also reported a tendency for a more severe clinical phenotype in the presence of a haplotype containing the rs1561570 T allele, which appear to be re-enforced with the presence of the SQSTM1/P392L mutation. In conclusion, our work provides novel insight towards understanding the functional effects of this variant, located in OPTN intron 7, and its implication in the contribution to PDB pathogenesis.


Osteitis Deformans/genetics , Transcription Factor TFIIIA/genetics , Active Transport, Cell Nucleus/genetics , Alleles , Autophagy/genetics , Bone Resorption/genetics , Cell Cycle Proteins , Cell Differentiation/genetics , Cell Line , DNA Methylation/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Variation , Haplotypes , Humans , Introns , Membrane Transport Proteins , Mutation , NF-kappa B/metabolism , Osteitis Deformans/etiology , Osteitis Deformans/metabolism , Osteoclasts/metabolism , Osteoclasts/pathology , Polymorphism, Single Nucleotide , Sequestosome-1 Protein/genetics , Up-Regulation
5.
Proc Natl Acad Sci U S A ; 114(22): E4380-E4388, 2017 05 30.
Article En | MEDLINE | ID: mdl-28512218

p97 is a "segregase" that plays a key role in numerous ubiquitin (Ub)-dependent pathways such as ER-associated degradation. It has been hypothesized that p97 extracts proteins from membranes or macromolecular complexes to enable their proteasomal degradation; however, the complex nature of p97 substrates has made it difficult to directly observe the fundamental basis for this activity. To address this issue, we developed a soluble p97 substrate-Ub-GFP modified with K48-linked ubiquitin chains-for in vitro p97 activity assays. We demonstrate that WT p97 can unfold proteins and that this activity is dependent on the p97 adaptor NPLOC4-UFD1L, ATP hydrolysis, and substrate ubiquitination, with branched chains providing maximal stimulation. Furthermore, we show that a p97 mutant that causes inclusion body myopathy, Paget's disease of bone, and frontotemporal dementia in humans unfolds substrate faster, suggesting that excess activity may underlie pathogenesis. This work overcomes a significant barrier in the study of p97 and will allow the future dissection of p97 mechanism at a level of detail previously unattainable.


Frontotemporal Dementia/genetics , Frontotemporal Dementia/metabolism , Muscular Dystrophies, Limb-Girdle/genetics , Muscular Dystrophies, Limb-Girdle/metabolism , Myositis, Inclusion Body/genetics , Myositis, Inclusion Body/metabolism , Nuclear Proteins/metabolism , Osteitis Deformans/genetics , Osteitis Deformans/metabolism , Proteins/metabolism , Valosin Containing Protein/genetics , Valosin Containing Protein/metabolism , Adaptor Proteins, Vesicular Transport , Adenosine Triphosphate/metabolism , Frontotemporal Dementia/etiology , Humans , Hydrolysis , Intracellular Signaling Peptides and Proteins , Kinetics , Muscular Dystrophies, Limb-Girdle/etiology , Mutation , Myositis, Inclusion Body/etiology , Osteitis Deformans/etiology , Protein Unfolding , Proteolysis , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Substrate Specificity , Ubiquitin/metabolism , Valosin Containing Protein/chemistry
6.
Joint Bone Spine ; 84(6): 719-723, 2017 Dec.
Article En | MEDLINE | ID: mdl-27932202

OBJECTIVES: The most frequent mutation linked to Paget's disease of bone (PDB), p.Pro392Leu within SQSTM1 gene, leads to phenotypic characteristics of PDB, but this mutation is seemingly insufficient to result in complete pagetic osteoclast phenotype, suggesting that possible environmental factors play a role in PDB pathogenesis. We performed an exploratory study to identify environmental factors potentially associated with familial or non-familial form of PDB in the French-Canadian population. METHODS: We investigated environmental factors through a questionnaire in 176 pagetic patients, including 86 patients with a familial form, and 147 healthy controls. All participants lived in the same geographic area, within a 120km radius of Quebec City. Associations between environmental factors and familial and non-familial forms of PDB were searched. RESULTS: In the multivariate model adjusted for intra-familial correlation, PDB was associated with wood fired heating in childhood and/or adolescence (OR=2.10; 95% CI 1.13-3.90, P=0.02). In the multivariate model without considering correlation for family relatedness, familial form of PDB was associated with residency near a mine (OR=11.70; 95% CI 2.92-46.80, P<0.01) and hunting (OR=2.92; 95% CI 1.14-7.47, P=0.03). Wood fired heating during childhood and/or adolescence (P=0.02) was associated with both familial and non-familial forms. CONCLUSIONS: In conclusion, PDB was significantly associated with wood fired heating in childhood and/or adolescence, regardless of the form of PDB, familial or not.


Genetic Predisposition to Disease/epidemiology , Osteitis Deformans/epidemiology , Osteitis Deformans/etiology , Surveys and Questionnaires , Adult , Age Distribution , Aged , Canada/epidemiology , Cross-Sectional Studies , DNA Mutational Analysis , Environment , Female , Humans , Incidence , Male , Middle Aged , Osteitis Deformans/genetics , Reference Values , Risk Assessment , Severity of Illness Index , Sex Distribution , Young Adult
7.
J Cell Biochem ; 117(2): 289-99, 2016 Feb.
Article En | MEDLINE | ID: mdl-26212817

Paget's disease of bone (PDB) is a common skeletal disorder characterized by increased and disorganized bone remodeling affecting one or more skeletal sites. Although some patients are asymptomatic others develop complications such as bone pain, deformity, nerve compression syndromes, and fragility fractures. Genetic factors play an important role in the pathogenesis of PDB and there is strong evidence that susceptibility is determined by variants within or close to genes that regulate osteoclast function. Environmental factors also play a key role but the nature of the environmental triggers is less clear. Bisphosphonates are a highly effective treatment for the elevations in bone turnover that are characteristic of PDB but it is unclear at present if they alter the natural history of the disease. Here, we review the epidemiology, clinical, cellular, and molecular abnormalities in PDB as well as environmental and genetic triggers, and current available treatment options.


Osteitis Deformans/pathology , Animals , Bone Remodeling , Humans , Mutation , Osteitis Deformans/epidemiology , Osteitis Deformans/etiology , Osteitis Deformans/therapy
8.
Orthop Clin North Am ; 46(4): 577-85, 2015 Oct.
Article En | MEDLINE | ID: mdl-26410646

The current understanding of Paget disease of bone (PDB) has vastly changed since Paget described the first case in 1877. Medical management of this condition remains the mainstay of treatment. Surgical intervention is usually only used in fractures through pagetic bone, need for realignment to correct deformity in major long bones, prophylactic treatment of impending fractures, joint arthroplasty in severe arthritis, or spinal decompression in cases of bony compression of neural elements. Advances in surgical technique have allowed early return to function and mobilization. Despite medical and surgical intervention, a small subset of patients with PDB develops Paget sarcoma.


Osteitis Deformans , Humans , Osteitis Deformans/diagnosis , Osteitis Deformans/etiology , Osteitis Deformans/physiopathology , Osteitis Deformans/therapy
10.
PLoS One ; 10(6): e0128984, 2015.
Article En | MEDLINE | ID: mdl-26030385

Paget disease of bone (PDB) is a focal bone disorder affecting the skeleton segmentally. The main alteration resides in osteoclasts that increase in size, number and activity. Many osteoclasts have cytoplasmic inclusions that have been associated with protein aggregates, increasing the evidences of a possible deregulation of autophagy in the development of the PDB. Autophagy starts with encapsulation of the target into a double-membrane-bound structure called an "autophagosome." It has been reported that at least 18 ATG genes (autophagy-related genes) are involved in autophagosome formation. We have studied the distribution of genotypes of the ATG2B rs3759601, ATG16L1 rs2241880, ATG10 rs1864183 and ATG5 rs2245214 polymorphisms in a Spanish cohort of subjects with PDB and compared with healthy subjects. Our results show that being a carrier of the C allele of the ATG16L1 rs2241880 and the G allele of ATG5 rs2245214 polymorphisms were associated with an increased risk of developing PDB, whereas being a carrier of the T allele of ATG10 rs1864183 polymorphism decreased the risk of suffering the disease in our series. This is the first report that shows an association between autophagy and Paget Disease of Bone and requires further confirmation in other series.


Autophagy/genetics , Genetic Predisposition to Disease/etiology , Osteitis Deformans/genetics , Polymorphism, Genetic/genetics , Alleles , Case-Control Studies , Female , Gene Frequency/genetics , Genotype , Humans , Male , Middle Aged , Osteitis Deformans/etiology , Osteoclasts/metabolism , Risk
11.
Ir Med J ; 108(10): 316-7, 2015.
Article En | MEDLINE | ID: mdl-26817293

Paget's disease of bone is a focal disorder of bone remodelling leading to areas of enlarged weakened bone manifesting with chronic pain, bone deformity, and fracture. Predominantly a disease of older adults, its prevalence is strongly linked to European ancestry. Pre-disposing factors include exposure to viruses such as measles and mutations in the SQSTM1 gene. PDB is diagnosed on plain radiograph, the extent of disease is delineated by radionuclide bone imaging, the degree of activity is quantified biochemically, and it is treated with a nitrogen-containing bisphosphonate, most effectively by a single intravenous infusion of zoledronate 5mg. Lifelong specialist follow-up is advocated because some patients require repeated infusions. Current clinical research is focusing on genetic factors in order to identify patients suitable for prevention.


Osteitis Deformans/etiology , Osteitis Deformans/therapy , Humans , Osteitis Deformans/diagnosis , Remission Induction
12.
Arq Bras Endocrinol Metabol ; 58(6): 587-99, 2014 Aug.
Article En | MEDLINE | ID: mdl-25211441

OBJECTIVE: To conduct a literature review on the diagnosis and management of Paget's disease of bone. MATERIALS AND METHODS: This scientific statement was generated by a request from the Brazilian Medical Association (AMB) to the Brazilian Society of Endocrinology and Metabolism (SBEM) as part of its Clinical Practice Guidelines program. Articles were identified by searching in PubMed and Cochrane databases as well as abstracts presented at the Endocrine Society, Brazilian Society for Endocrinology Annual Meetings and the American Society for Bone and Mineral Research Annual Meeting during the last 5 years. Grading quality of evidence and strength of recommendation were adapted from the first report of the Oxford Centre for Evidence-based Medicine. All grades of recommendation, including "D", are based on scientific evidence. The differences between A, B, C and D, are due exclusively to the methods employed in generating evidence. CONCLUSION: We present a scientific statement on Paget's disease of bone providing the level of evidence and the degree of recommendation regarding causes, clinical presentation as well as surgical and medical treatment.


Alkaline Phosphatase/blood , Bone Density Conservation Agents/therapeutic use , Evidence-Based Medicine/standards , Osteitis Deformans/diagnosis , Osteitis Deformans/prevention & control , Biomarkers/analysis , Brazil/epidemiology , Diphosphonates/therapeutic use , Humans , Osteitis Deformans/epidemiology , Osteitis Deformans/etiology
13.
Arq. bras. endocrinol. metab ; 58(6): 587-599, 08/2014. tab, graf
Article En | LILACS | ID: lil-721389

Objective: To conduct a literature review on the diagnosis and management of Paget’s disease of bone. Materials and methods: This scientific statement was generated by a request from the Brazilian Medical Association (AMB) to the Brazilian Society of Endocrinology and Metabolism (SBEM) as part of its Clinical Practice Guidelines program. Articles were identified by searching in PubMed and Cochrane databases as well as abstracts presented at the Endocrine Society, Brazilian Society for Endocrinology Annual Meetings and the American Society for Bone and Mineral Research Annual Meeting during the last 5 years. Grading quality of evidence and strength of recommendation were adapted from the first report of the Oxford Centre for Evidence-based Medicine. All grades of recommendation, including “D”, are based on scientific evidence. The differences between A, B, C and D, are due exclusively to the methods employed in generating evidence. Conclusion: We present a scientific statement on Paget’s disease of bone providing the level of evidence and the degree of recommendation regarding causes, clinical presentation as well as surgical and medical treatment. Arq Bras Endocrinol Metab. 2014;58(6):587-99 .


Objetivo: Conduzir uma atualização das últimas evidências científicas a respeito da apresentação, diagnóstico e manejo clínico da doença de Paget óssea. Materiais e métodos: Este documento foi concebido pelo Departamento de Metabolismo Ósseo da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) a partir daquele oriundo do Programa de Diretrizes da Associação Médica Brasileira (AMB). Realizamos uma revisão dos artigos mais relevantes obtidos nos bancos de dados PubMed e Cochrane, além de abstracts apresentados nos encontros anuais da Endocrine Society, Sociedade Brasileira de Endocrinologia e da American Society for Bone and Mineral Research dos últimos cinco anos e classificamos as evidências em níveis de recomendações de acordo com a força científica por tipo de estudo, adaptando o primeiro relato do “Oxford Centre for Evidence-based Medicine”. Todos os graus de recomendação, incluindo-se o “D”, foram baseados em evidência científica, sendo as diferenças entre o A, B, C e D devidas exclusivamente ao desenho empregado na geração da evidência. Conclusão: Apresentamos uma atualização científica a respeito da doença de Paget óssea, classificando e graduando em níveis de recomendações as principais evidências científicas sobre as suas causas, as variadas formas de apresentação, seu diagnóstico e tratamento. .


Humans , Alkaline Phosphatase/blood , Bone Density Conservation Agents/therapeutic use , Evidence-Based Medicine/standards , Osteitis Deformans/diagnosis , Osteitis Deformans/prevention & control , Biomarkers/analysis , Brazil/epidemiology , Diphosphonates/therapeutic use , Osteitis Deformans/epidemiology , Osteitis Deformans/etiology
14.
Reumatismo ; 66(2): 171-83, 2014 Jul 28.
Article En | MEDLINE | ID: mdl-25069498

Paget's disease of bone is the most common metabolic bone disease after osteoporosis and affects 2-4% of adults over 55 years of age. Its etiology is only partly understood and includes both genetic and environmental factors. The disease may be asymptomatic and can be uncovered incidentally on x-ray or in biochemical tests performed for another condition. It can also manifest itself with bone pain, deformity, fracture or other complications. Paget's disease is diagnosed by x-rays and in general has very typical radiological features, but occasionally the clinical picture may be unusual and a differential diagnosis of sclerotic or lytic metastases needs to be considered. Plasma total alkaline phosphatase activity is the most clinically useful indicator of disease activity. It is elevated in most untreated patients, but may be within the normal range in patients with monostotic or limited disease. Bisphosphonate therapy is indicated for patients with symptoms and should also be considered in patients with disease sites that suggest a risk of complications, such as long bones, vertebrae or base of the skull. Orthopedic surgery in Paget's disease patients includes almost exclusively the correction of fractures and arthroplasty.


Osteitis Deformans , Humans , Osteitis Deformans/complications , Osteitis Deformans/diagnosis , Osteitis Deformans/epidemiology , Osteitis Deformans/etiology , Osteitis Deformans/therapy
15.
QJM ; 107(11): 865-9, 2014 Nov.
Article En | MEDLINE | ID: mdl-24757095

Paget's disease of bone is a common disorder characterized by increased but disorganized bone remodelling. Some patients are asymptomatic but others present with bone pain or other complications such as fracture and deformity. Major advances have been made in understanding the pathophysiology of Paget's disease in recent years and highly effective agents are now available with which to suppress the abnormal bone turnover that causes the disease. Here we review recent advances in the epidemiology, pathogenesis, clinical features and management of Paget's disease. We also reflect upon the future challenges that remain to be overcome to explain the unusual distribution of the disease and to favourably alter the natural history and prevent the development of complications.


Osteitis Deformans , Adaptor Proteins, Signal Transducing/genetics , Bone Density Conservation Agents/therapeutic use , Bone Remodeling/physiology , Environmental Exposure/adverse effects , Forecasting , Fractures, Spontaneous/etiology , Genetic Predisposition to Disease/genetics , Humans , Musculoskeletal Pain/etiology , Mutation/genetics , Osteitis Deformans/diagnosis , Osteitis Deformans/etiology , Osteitis Deformans/therapy , Osteoprotegerin/genetics , Practice Guidelines as Topic , Receptor Activator of Nuclear Factor-kappa B/genetics , Sequestosome-1 Protein
16.
Gac. méd. Caracas ; 122(1): 29-33, ene.-mar. 2014. ilus, tab
Article Es | LILACS | ID: lil-772735

Las estrias angioides de la retina se aprecian como líneas dentelladas rosadas u oscuras radiando irregularmente en todas direcciones desde el área peripapilar hacia la periferia de la retina. Corresponden a roturas del componente elástico de la membrana de Bruch. Su presencia indica una enfermedad sistémica siendo las más importantes el pseudoxantoma elástico, la enfermedad de Paget ósea y la drepanocitosis, Los tumores hipofisiarios raramente se han asociado a está condición existiendo apenas tres descriptores en la literatura. A estas adicionamos tres pacientes más, no obstante, aun no puede asegurarse si se trata de una asociación o de un simple hallazgo incidental.


Retinal angioid streaks can be seen as rough lines pink or dark, irregularly radiating in all directions from the peripapilar area to the periphery of the retina. They correspond of breaks in the elastic component of the Bruch membrane. Its presence indicates a systemic disease being the most important pseudoxanthoma elasticum, bone Paget's disease and sickle cell disease. Pituitary tumors have rarely been associated with this condition and exist just three descriptions in the literature. To these we add three more patients, however, still not be tightened if it's an association or a simple incidental finding.


Humans , Male , Adult , Middle Aged , Headache/diagnosis , Angioid Streaks/complications , Bruch Membrane/anatomy & histology , Nausea/diagnosis , Osteitis Deformans/etiology , Diplopia/physiopathology , Hemianopsia/physiopathology , Ophthalmology , Visual Acuity
17.
Clin Transl Sci ; 7(1): 29-32, 2014 Feb.
Article En | MEDLINE | ID: mdl-24119107

Valosin containing protein (VCP) disease (also known as Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia [IBMPFD] syndrome) is caused by mutations in the gene encoding VCP classically affecting the muscle, bone and brain. Although the genetic cause has been identified, details regarding the pathogenesis of IBMPFD have not been fully determined. Muscle wasting observed in VCP disease is suggestive of cytokine imbalance. We hypothesized that dysfunctional protein homeostasis caused by VCP mutations leads to cytokine imbalances thereby contributing to the muscle wasting phenotype. Circulating levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF a) and epidermal growth factor (EGF) were measured in plasma of patients with VCP disease or controls. TNF a and EGF were significantly altered in VCP disease as compared to control. TNF a was up-regulated, consistent with a cachexia phenotype and EGF levels were increased. No significant differences were observed in IL-4 and IL-6. Cytokine imbalances may be associated with VCP disease and may play a contributory role in VCP myopathy. Further understanding of how VCP dysfunction leads to aberrant protein homeostasis and subsequent cytokine imbalances may also aid in the understanding of other proteinopathies and in the development of novel treatments.


Cytokines/blood , Epidermal Growth Factor/blood , Frontotemporal Dementia/blood , Interleukin-4/blood , Interleukin-6/blood , Muscular Dystrophies, Limb-Girdle/blood , Myositis, Inclusion Body/blood , Osteitis Deformans/blood , Tumor Necrosis Factor-alpha/blood , Adenosine Triphosphatases/genetics , Case-Control Studies , Cell Cycle Proteins/genetics , Frontotemporal Dementia/etiology , Frontotemporal Dementia/genetics , Humans , Muscle Development/genetics , Muscle Development/physiology , Muscular Atrophy/blood , Muscular Atrophy/etiology , Muscular Atrophy/genetics , Muscular Dystrophies, Limb-Girdle/etiology , Muscular Dystrophies, Limb-Girdle/genetics , Mutation , Myositis, Inclusion Body/etiology , Myositis, Inclusion Body/genetics , Osteitis Deformans/etiology , Osteitis Deformans/genetics , Signal Transduction , Syndrome , Valosin Containing Protein
18.
Rinsho Shinkeigaku ; 53(11): 947-50, 2013.
Article Ja | MEDLINE | ID: mdl-24291843

Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disease caused by mutations in the VCP gene. VCP encodes a well-conserved multifunctional protein, valosin containing protein (VCP), which has important roles in protein quality control via proteasome and autophagy, protein aggregation, quality control of mitochondria, cell proliferation, and so on. Clinically, muscle weakness is the most common symptom of which disease onset is around 40 years. Affected muscles are variable, and the patients are sometimes diagnosed as limb girdle muscular dystrophy or GNE myopathy. Muscle pathology shows characteristic features including cytoplasmic/nuclear inclusions, rimmed vacuoles, and disorganized myofibrills, together with neurogenic changes. Paget's disease of bone is reported to be observed in a half of the patients around the age of 40 years, but less common in Japanese patients. Frontotemporal dementia is seen around one third of the patients which appears nearly 10 years later than muscle or bone disease. In addition to cognitive dysfunctions, motor neuron involvement and cerebellar signs were also seen in our series. IBMPFD is not so rare disease as previously thought, but complicate clinical findings may make its diagnosis difficult.


Frontotemporal Dementia , Muscular Dystrophies, Limb-Girdle , Myositis, Inclusion Body , Osteitis Deformans , Adenosine Triphosphatases/genetics , Adenosine Triphosphatases/physiology , Cell Cycle Proteins/genetics , Cell Cycle Proteins/physiology , Cognition Disorders/etiology , Diagnosis, Differential , Frontotemporal Dementia/complications , Frontotemporal Dementia/diagnosis , Frontotemporal Dementia/etiology , Frontotemporal Dementia/genetics , Frontotemporal Dementia/pathology , Muscle, Skeletal/pathology , Muscular Diseases , Muscular Dystrophies, Limb-Girdle/complications , Muscular Dystrophies, Limb-Girdle/diagnosis , Muscular Dystrophies, Limb-Girdle/genetics , Muscular Dystrophies, Limb-Girdle/pathology , Mutation , Myositis, Inclusion Body/complications , Myositis, Inclusion Body/diagnosis , Myositis, Inclusion Body/genetics , Myositis, Inclusion Body/pathology , Osteitis Deformans/complications , Osteitis Deformans/diagnosis , Osteitis Deformans/etiology , Osteitis Deformans/genetics , Osteitis Deformans/pathology , Valosin Containing Protein
19.
Cleve Clin J Med ; 80(7): 452-62, 2013 Jul.
Article En | MEDLINE | ID: mdl-23821690

Paget disease of bone is a focal disorder of aging bone that may be asymptomatic or may present with pain, bowing deformity, fracture, or a nonspecific rheumatic complaint. It is the second most common disease of bone in the elderly after osteoporosis, and the loss of structural integrity in affected bone conveys a risk of fracture. It may occur sporadically or in geographic or familial clusters. This article discusses the prevalence, pathology, workup, and treatment of Paget disease of bone.


Osteitis Deformans , Bone Density Conservation Agents/therapeutic use , Diphosphonates/therapeutic use , Genetic Predisposition to Disease , Global Health , Humans , Osteitis Deformans/diagnosis , Osteitis Deformans/drug therapy , Osteitis Deformans/epidemiology , Osteitis Deformans/etiology , Risk Factors
20.
Recenti Prog Med ; 104(3): 89-92, 2013 Mar.
Article It | MEDLINE | ID: mdl-23548950

Paget's disease of bone is a chronic disorder of unknown etiology that can result in enlarged and misshapen bones. The excessive breakdown and formation of bone tissue cause affected bones to weaken, resulting in pain, misshapen bones, fractures, and arthritis in the joints. In most cases the diagnosis is achieved casually, as only 5% of patients develop burning pain at the level of affected bones. As regards therapy, the use of anti-reabsorbing drugs, such as bisphosphonates and calcitonin, appears reasonable. Given the disease pathogenesis, the administration of denosumab and tocilizumab may be a valuable alternative to inhibit RANK expression, and thus osteoclast formation, and interleukin-6 production.


Osteitis Deformans/drug therapy , Adaptor Proteins, Signal Transducing/genetics , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Bone Density Conservation Agents/therapeutic use , Bone Neoplasms/diagnosis , Calcitonin/therapeutic use , Denosumab , Diagnosis, Differential , Diphosphonates/therapeutic use , Drug Evaluation, Preclinical , Genetic Heterogeneity , Genetic Predisposition to Disease , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/physiology , Osteitis Deformans/diagnosis , Osteitis Deformans/etiology , Osteitis Deformans/genetics , Osteitis Deformans/physiopathology , Osteoclasts/pathology , Osteomyelitis/diagnosis , Osteoporosis/diagnosis , Paramyxoviridae Infections/complications , RANK Ligand/physiology , Receptor Activator of Nuclear Factor-kappa B/genetics , Receptor Activator of Nuclear Factor-kappa B/physiology , Sequestosome-1 Protein
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