osteitis deformans

..Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway...

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..Inclusions seen in the muscle, brain and heart in VCP disease contain ubiquitin, beta amyloid and TDP-43, also seen in other neurodegenerative disorders thus implicating common pathways in their pathogenesis...

..Most observations seem to fit best with the idea that Paget disease behaves as a multifocal benign neoplasm...

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..These data implicate VCP in autophagy and suggest that impaired autophagy explains the pathology seen in IBMPFD muscle, including TDP-43 accumulation...

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..We identified several differentially regulated genes, and we suggest that these changes could lead to the formation of the lesions...

..Neither management strategy had a significant beneficial impact on pain or quality of life (Clinical trial registration number ISRCTN12989577)...

..09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility...

..Elevated ATPase activities, thus, may be a hidden primary defect causing IBMPFD pathological phenotypes, which would be revealed when abnormal proteins are accumulated, as typically observed in aging...

..These results provide additional proof that CDV is present within pagetic bone and further support the hypothesis that paramyxoviruses are involved in the etiopathology of Paget's disease...

..These findings also have wider implications for other studies investigating viral expression...

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..The latter findings provide a novel link to VCP carbohydrate interactions in the complex pathology of IBMPFD...

..It is proposed that the 5q35-qter and 5q31 loci be named "PDB3" and "PDB4," respectively...

..In patients previously treated with pamidronate, alendronate is more effective...

..TAFII-17 can bind VDR at low concentrations of 1,25(OH)2D3. These results suggest that MVNP expression in Paget's OCL precursors increases expression of a component(s) of the VDR transcription complex that can increase OCL formation...

..Those with a family history of PD (20%) suffered earlier deformity and fracture, and tended to have grandparents born abroad. These findings suggest heritage is important in PD; the role of environment remains unclear...

..The lesser involvement at the axial sites in monostotic disease may lead to overestimation of the decline in PDB based on abdominal radiographs...

..This study demonstrated that serum ALP activity is a sensitive marker of PDB in men and women >55 years of age, but the majority of those affected have normal serum ALP activity...

..The document provides the most updated recommendations based primarily on the "evidence-based- medicine" but also on the Italian regulation for the diagnostic procedures and on the available medical treatments...

..Single neridronate and zoledronate infusion showed a similar efficacy in up to 90% of patients nonresponders to pamidronate...

..Genetic variation in VCP does not appear to be a common cause of familial or sporadic PDB in the absence of myopathy and dementia...

..7% to 2.4%, were higher in males than in females, and slightly differed between the two towns. Unlike previous studies in populations of British descent, no secular trend for a decreasing prevalence emerged...

..This peculiar pattern might be traced to genetic predisposition and/or to the abnormal impact of a still undefined environmental trigger...

..We studied the effects of CDV on osteoclastogenesis in vitro and showed that CDV had a dose-dependent effect on osteoclastogenesis, through a possible mechanism involving activation of NF-kappaB and sequestosome 1/p62...

..Familial aggregation was observed in 15% of cases...

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..Physicians should be aware of the potential for hypocalcemia when patients with polyostotic Paget's disease and markedly elevated indicators of bone remodeling are initiated on powerful anti-resorptive therapy...

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..Detection of a mutation allows evaluation of family members to ensure early diagnosis of the disease before complications develop...

..The P392L mutation was the most prevalent, embedded in two different haplotypes, possibly shared by other populations. We also examined the phenotype and penetrance of P392L...

..Paget's disease has become less prevalent and patients are presenting later, with less severe disease than previously. These data suggest that environmental factors are important in the etiology of Paget's disease...

..There is no clear evidence from this study that any of these newer markers are superior to total AP in assessing patients with this severity of Paget's disease...

..The Panel recommends treating PDB with bisphosphonates that have demonstrated superior efficacy and remission rates...

..The SQSTM1 mutation rate in unrelated American patients described in the present study was similar to that reported in European populations...

..We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes and that defect in this function may contribute to IBMPFD pathogenesis...

..Dkk-1 over-production is implicated in osteolytic disease where it inhibits bone formation and stimulates bone breakdown. Recently it was reported that osteoblastic cells from Paget's disease of bone (PDB) over-expressed Dkk-1...

..Mice coexpressing MVNP and p62(P394L) developed dramatic Paget's-like bone lesions. These results suggest that p62(P394L) and IL-6 induction by MVNP play key roles in PD...

..Future studies are needed to determine whether these drugs, if used in an early stage of the disease, can prevent complications in asymptomatic patients...

..71, at marker D18S70. Our data are consistent with genetic heterogeneity within the pedigree and indicate that 18q23 harbors a novel susceptibility gene for PDB...

..Data on biological variation are useful for assessing actual changes induced by treatment...

..They also suggest that the SQSTM1 P392L mutation plays a role in PDB pathogenesis, even at early preclinical stages in healthy carriers of the P392L mutation...

..These data indicate that TNFRSF11A mutations contribute neither to the vast majority of cases of sporadic or familial PDB, nor to the development of osteosarcoma...

..Alkaline phosphatase (ALP) is routinely used in the assessment of Paget's disease of bone (PDB); however, the individual bone ALP isoforms (B/I, B1, and B2) have not been investigated in this disorder...

..Risedronate treatment had no deleterious effect on osteolytic lesions in weight-bearing bones; indeed, the majority of lesions with osteolytic fronts were improved after 6 months of risedronate treatment...

..These studies suggest that both genetic and environmental factors contribute to PD...

..Cytokines, specially interleukin (IL)-6, play an important role in the differentiation and activation of osteoclasts and might be involved in osteoblast stimulation in Paget's disease of bone (PDB)...

..The calculated cumulative population attributable risk of these four loci turned out to be about 67% in our two populations, indicating that most of the genetic risk for PDB is coming from genetic variants close to these four genes...

..1-q22. Mapping a new locus for a gene involved in regulation of bone metabolism may also have implications in the study of Paget's disease of bone which is a common related bone dysplasia...

..Paget's disease of bone (PDB) is a focal disorder of bone metabolism with overgrowth of affected bone resulting in the skeletal complications of this disease...

..This is likely caused by the small sample size, but this is by far the greatest number of cases of PDB described in a single skeletal assemblage to date. The distribution of lesions within the skeleton is unchanged...

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..We examined morbidity and mortality associated with this condition in a large inception cohort of Olmsted County, MN, residents with a new diagnosis of Paget's disease from 1950 through 1994...

..Its therapeutic efficacy, its long-term effect on biologic activity and its good tolerance currently supports its use as a first-line therapeutic option in patients suffering from PDB...

..We found a significant overexpression of the genes of the IFN pathway along with a downregulation of tnf-alpha. Our result suggest that IFN-mediated signaling may play important roles in aberrant osteoclastogenesis of PD...

..These results indicate that this PDB-associated p62 mutation is not sufficient to induce PDB and suggest that additional factors acting together with p62 mutation are necessary for the development of PDB in vivo...

..A once-weekly alendronate 280 mg oral buffered solution was compared with an alendronate 40 mg/day tablet. While both were similarly effective, the tablet appeared to be better tolerated in this study...

..Elevated circulating levels of immunoreactive OPG and soluble RANKL accompany this genetic defect that truncates the OPG monomer, preventing formation of OPG homodimers...

..The objective of this review is to provide a comprehensive overview of current standards of treatment in Paget's disease...

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..Thus, the positive effect of amino bisphosphonates in the treatment of PDB may be due to either direct or indirect suppression of RANKL-induced bone resorption through decreased RANKL and increased OPG production...

..The article gives an overview of recent perspectives on epidemiology, diagnosis, and treatment of the disease according to the new German guidelines for the diagnosis and therapy of Paget's disease...

..In conclusion, pagetic patients with skull involvement showed a marked increase in bone turnover and a lower response to therapy...

..This effect is largely independent of pretreatment disease activity and prior bisphosphonate therapy...

..All three had elevated markers of bone metabolism in the serum and urine. With monthly intravenous pamidronate there was significant improvement in the bone markers and follow-up bone scans...

..To compare the effects of tiludronate and risedronate on Paget's disease activity assessed by biochemical markers of bone turnover and quantitative bone scintigraphy...

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..In conclusion, bisphosphonate treatment results in an increase in mandibular condylar dimensions and normalization of mandibular ramus growth...

..No firm evidence as yet exists to show that bisphosphonates can prevent the development of complications of Paget's disease of bone, and further work is needed to address the effects of treatment on long-term clinical outcome...

..The aim of this article is to put the risks of osteonecrosis of the jaw into context with the benefits of bisphosphonate treatment in these clinical scenarios...

..It is not known whether resistance to other bisphosphonates in Paget's disease occurs...

..Correctly manipulating these may improve clinical development of drugs for the treatment of patients with metabolic bone diseases such as osteoporosis and cancer metastatic to the bone...

..In conclusion, zoledronic acid, apart from being safe and effective in Paget's disease, also appears to be able to achieve significantly prolonged remissions...

..The lack of correlation between ALP and quality of life observed in this study emphasizes the importance of addressing quality-of-life issues when treating PDB and not just focussing on response of ALP levels...

..This may provide a new diagnostic and monitoring tool for diseases such as metastatic bone cancer and Paget's disease...

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..Both ALP and the bisphosphonate space have wide prediction intervals, and are therefore poor guides to dose requirement...

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..Their youngest affected sibling was treated intensively with intravenous bisphosphonates for 3 years. The treatment was well tolerated and prevented the development of deformity and disability...

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..In patients with resistant PDB, oral risedronate therapy has comparable efficacy to IV pamidronate with a lower incidence of treatment-related side effects...

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..Paget's disease provides an ideal model in which to investigate the efficacy of the new third-generation bisphosphonates in the treatment of bone metastases as well as nonmalignant bone disease...

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..When she died of colon cancer twelve months later, with no marked progress of the Paget's disease of bone observed clinically...

..Hearing loss has long been known to be a complication of Paget's disease of bone. The aim of this study was to investigate Paget's disease of the temporal bone with special attention to hearing loss...

..To describe the effects of two consecutive intravenous infusions of aminohexane bisphosphonate (Neridronate) in patients with active Paget's disease of bone...

..Complications were common including deformity (21%), fracture (17%) and deafness (8%). Bisphosphonate therapy induced a remission in 22 patients...

..In addition, our results extend the potential clinical use of BPs to patients with early prostate cancer...

DESCRIPTION (Adapted from the Applicant's Abstract): Paget's disease of bone, or osteitis deformans, is a bone disorder characterized by rapid bone remodeling, resulting in abnormal bone formation...

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..These studies will lend insight into the molecular and cellular mechanisms involved in IBM disease pathogenesis and are critical for identifying future therapeutic targets. ..

..We propose to explore the consequence of disease mutations in p97/VCP on UPS-mediated protein degradation in skeletal muscle and its relevance to aging related disorders such as inclusion body myositis and fronto-temporal dementia. ..

..We propose to explore the consequence of disease mutations in p97/VCP on UPS-mediated protein degradation in skeletal muscle and its relevance to aging related disorders such as inclusion body myositis and fronto-temporal dementia. ..

..We propose to explore the consequence of disease mutations in p97/VCP on UPS-mediated protein degradation in skeletal muscle and its relevance to aging related disorders such as inclusion body myositis and fronto-temporal dementia. ..

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..Delineation of the genetic component responsible for the LGMD/PDB phenotype should promise similar insight and facilitate in the design of novel treatment protocols for the two disorders. ..

..e. effect on ATPase activity, protein-protein interactions, and hexamer formation). Study the VCP specific pathways in C2C12 cell lines (stably transfected wt and R155H VCP) during differentiation and under stress conditions...

..Elucidation of the genetic defect will help us understand the pathogenesis of this multifaceted disorder and hopefully result in specific therapy. ..

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..The receptors for this cytokine on normal and OA chondrocytes will be quantitated. Further definition of these cartilage metabolic pathways are of primary importance in our understanding of osteoarthritis...

..The study will also pave the way for the future, for providing more acceptable, affordable and cost- effective therapies for the prevention of postmenopausalosteoporosis. ..

..We will attempt to find markers for bone resorption using in vitro models, which can then be used to assess resorption in vivo...

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..This proposal will also facilitate my transition from a trainee to a fully independent experimental neuropathologist. ..

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..We will analyze the skeletal and extraskeletal phenotype of mice with a null mutation in the "neutrophil" collagenase, MMP-8, another collagenase expressed in the skeleton, as well as mice with double null MMP-8/MMP-13. ..

..Specific Aim 3: Target mutations that encode collagenase resistance into the murine type II collagen (Col2a-1) gene. ..

..Our long-term goal will be to characterize the role of ADAM8/a9b1 in the bone destruction which accompanies collagen induced arthritis, which will be started in grant year 5. ..

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..to become aware of the effectiveness of the various drugs that can be used to treat the two disorders; 5.) to understand the role of surgery in managing the two disorders. ..

..As part of these experiments, we will treat normal human OCL precursors transfected with p62P392L with varying concentrations of IL-6 to determine if they form OCLs that express a complete pagetic phenotype...

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..The knowledge gained from this P01 grant will offer important insights for normal bone cell biology especially for understanding the paracrine regulation of osteoblasts by OCLs. ..

..Our long-term goal will be to characterize the role of ADAM8/a9b1 in the bone destruction which accompanies collagen induced arthritis, which will be started in grant year 5. ..