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36 records · Page 2Linked to original sources
PubMed2006

Shear stress stabilizes NF-E2-related factor 2 and induces antioxidant genes in endothelial cells: role of reactive oxygen/nitrogen species.

We have previously reported that antioxidant response element (ARE)-regulated genes, such as heme oxygenase 1 (HO-1), sequestosome 1 (SQSTM1), and NAD(P)H quinone oxidoreductase 1 (NQO1), are induced in human umbilical vein endothelial cells (HUVEC) upon exposure to laminar shear stress. In the present study, we have confirmed a critical role for NF-E2-related factor 2 (Nrf2) in the induction of gene expression in HUVEC exposed to laminar shear stress. Although the mRNA levels of Nrf2 were unchanged during exposure to shear stress, the protein levels of Nrf2 were markedly increased. Small interfering RNA (SiRNA) against Nrf2 significantly attenuated the expression of Nrf2-regulated genes such as HO-1, SQSTM1, NQO1, glutamate-cysteine ligase modifier subunit (GCLM), and ferritin heavy chain. Nrf2 was rapidly degraded in cells treated with cycloheximide under static conditions, but shear stress decreased the rate of Nrf2 degradation. Incubation with the thiol antioxidant N-acetylcysteine strongly inhibited both the Nrf2 accumulation and the expression of Nrf2-regulated genes such as HO-1, GCLM, and SQSTM1. Nitric oxide (NO) production was increased with the strength of shear stress but neither the inhibitor of endothelial NO synthase (eNOS) nor the siRNA against eNOS affected the expression of Nrf2-regulated genes. A xanthine oxidase inhibitor oxypurinol and the flavoprotein inhibitor diphenyleneiodonium, which inhibits NAD(P)H oxidase and mitochondrial respiratory chain, markedly suppressed the expression of these genes. Moreover, diphenylpyrenlphosphine, a reducing compound of lipid hydroperoxides, also significantly suppressed Nrf2-regulated gene expression. Taken together, these findings suggest that shear stress stabilizes Nrf2 protein via the lipid peroxidation elicited by xanthine oxidase and flavoprotein mediated generation of superoxide, resulting in gene induction by the Nrf2-ARE signaling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Genetics of Paget's disease of bone.

Paget's disease of bone is a chronic bone disease that affects up to 3% of Caucasians older than 55 years. The cause of Paget's disease is unknown but involves genetic factors. Familial cases display an autosomal dominant pattern of inheritance with incomplete penetrance. Genetic heterogeneity has been demonstrated and eight potential susceptibility loci identified. There is sound evidence incriminating Sequestosome 1 (SQSTM1) on the long arm of chromosome 5 (5q35-qter), of which nine mutations have been described in Paget's disease of bone. These mutations are located in exons 7 and 8, which encode a highly conserved ubiquitin-binding domain. The prevalence of SQSTM1 mutations is about 10% in France. Tests for SQSTM1 mutations should be done in patients with Paget's disease of bone, even where the family history is negative. Detection of a mutation allows evaluation of family members to ensure early diagnosis of the disease before complications develop.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Genetics of Paget's disease of bone.

PDB (Paget's disease of bone) is a common condition characterized by focal increases in bone turnover affecting one or more sites throughout the skeleton. Genetic factors are important in the pathogenesis of PDB and many families have been described where PDB is inherited in an autosomal-dominant fashion. Several candidate loci for susceptibility to PDB and related syndromes have been identified by genome-wide scans and recent evidence suggests that mutations in genes that encode components of the RANK [receptor activator of NF-kappaB (nuclear factor-kappaB)]/NF-kappaB signalling pathway play an important role in the pathogenesis of this group of diseases. Insertion mutations in the TNFRSF11A gene encoding RANK have been identified as the cause of familial expansile osteolysis, some cases of early onset PDB and expansile skeletal hyperphosphatasia. Inactivating mutations in the TNFRSF11B gene that encodes OPG (osteoprotegerin) have been found to cause the syndrome of juvenile PDB. Polymorphisms in OPG also appear to increase the risk of developing PDB. The most important causal gene for classical PDB is Sequestosome 1 (SQSTM1), which is a scaffold protein in the NF-kappaB signalling pathway, and mutations affecting the UBA (ubiquitin-associated) domain of this protein occur in between 20-50% of familial and 10-20% of sporadic PDB cases. The rare syndrome of IBMPFD (inclusion body myopathy, PDB and fronto-temporal dementia) is due to mutations in the VCP gene and these also cluster in the domain of VCP that interacts with ubiquitin, suggesting a common disease mechanism with SQSTM1-mediated PDB.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Susceptibility to Paget's disease of bone is influenced by a common polymorphic variant of osteoprotegerin.

UNLABELLED: To clarify the role of the TNFRSF11B gene encoding osteoprotegerin (OPG), in Paget's disease of bone (PDB) we studied TNFRSF11B polymorphisms in an association study of 690 UK subjects and in a worldwide familial study of 66 kindreds. We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB. INTRODUCTION: Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone turnover. Genetic factors are important in the pathogenesis of PDB, and studies have shown that inactivating mutations of the TNFRSF11B gene, encoding osteoprotegerin (OPG), cause the rare syndrome of juvenile Paget's disease. In this study, we sought to determine whether polymorphisms of the TNFRSF11B gene contribute to the pathogenesis of classical PDB. MATERIALS AND METHODS: We screened for polymorphisms of the TNFRSF11B gene by DNA sequencing of the proximal promoter, coding exons, and intron-exon boundaries in 20 PDB patients and 10 controls. Informative single nucleotide polymorphisms (SNPs), including a G1181C SNP, which predicts a lysine-asparagine substitution at codon 3 of the OPG signal peptide and haplotypes, were related to the presence of PDB in 312 cases compared with 378 controls and to transmission of PDB in 140 affected offspring from 66 kindreds with familial PDB. RESULTS AND CONCLUSIONS: The G1181 allele was significantly over-represented in PDB patients (chi(2) = 5.7, df = 1, p = 0.017, adjusted alpha = 0.024), equivalent to an odds ratio for PDB of 1.55 (95% CI: 1.11-2.16). The distribution of TNFRSF11B haplotypes significantly differed in sporadic PDB cases and controls (chi(2) = 30.2, df = 9, p < 0.001) because of over-representation of haplotypes containing the G1181 allele in cases. The family study showed that the most common haplotype containing the G1181 allele was transmitted more frequently than expected to 140 individuals with familial PDB (chi(2) = 7.35, df = 1, p < 0.01), and the transmission disequilibrium was even more pronounced in a subgroup of 78 familial PDB patients who did not carry mutations of the SQSTM1 gene (chi(2) = 8.44, df = 1, p < 0.005). We conclude that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to the development of sporadic PDB and familial PDB that is not caused by SQSTM1 mutations.

Aged↗
PubMed2007

Multisystem Proteinopathy

CLINICAL CHARACTERISTICS: Multisystem proteinopathy (MSP) is a genetically heterogeneous, multisystem degenerative disorder characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset Paget disease of bone (PDB), and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, and paraphasic errors, with minimal impairment of episodic memory; later stages are characterized by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease is 43 years, PDB is 41 years, and FTD is 56 years. Dilated cardiomyopathy, amyotrophic lateral sclerosis, and Parkinson disease are now known to be part of the spectrum of findings associated with MSP. DIAGNOSIS/TESTING: The diagnosis of MSP is established in a proband with typical clinical findings and a heterozygous pathogenic variant in VCP, HNRNPA1, HNRNPA2B1, or SQSTM1 identified by molecular genetic testing. MANAGEMENT: Treatment of manifestations: Weight control to avoid obesity; physical therapy and stretching exercises to promote mobility and prevent contractures; occupational therapy and mechanical aids (canes, walkers, orthotics, wheelchairs) as needed for ambulation/mobility; surgical intervention for foot deformity and scoliosis as needed; respiratory aids when indicated; assisted living arrangements for muscle weakness and/or dementia; bisphosphonates to relieve pain and disability from PDB; social and emotional support; education regarding safety precautions. Surveillance: Echocardiogram and electrocardiogram with repeat cardiac evaluation every two to three years or earlier if symptomatic; annual pulmonary function studies; sleep studies as clinically indicated; annual alkaline phosphatase measurement; skeletal imaging as indicated for evaluation of PDB; neurologic and neuropsychological assessment every two to three years or more frequently as needed; multidisciplinary monitoring for respiratory, cardiac, musculoskeletal, and cognitive decline. GENETIC COUNSELING: MSP is inherited in an autosomal dominant manner. Most individuals diagnosed with MSP have an affected parent. Estimates based largely on VCP-MSP suggest that approximately 5% of individuals have a de novo pathogenic variant. Each child of an individual with MSP has a 50% chance of inheriting the MSP-related pathogenic variant. Marked intrafamilial variability may be observed among heterozygous family members, including differences in age at onset, severity, rate of progression, and the specific combination of manifestations. Once the MSP-related pathogenic variant has been identified in an affected family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing are possible.

Inclusion Body Myopathy with Early-Onset Paget Dis↗
PubMed2006

Etiologic factors in Paget's disease of bone.

Paget's disease of bone is a chronic focal skeletal disorder characterized by increased bone resorption by the osteoclasts. Paramyxoviral gene products have been detected in pagetic osteoclasts. Paget's disease is an autosomal dominant trait with genetic heterogeneity. Several mutations in the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1/p62) have been identified in patients with Paget's disease. Similarly, mutations in the valosin-containing protein (VCP) gene have been shown to cause inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, gene polymorphisms and enhanced levels of cytokine/growth factors associated with Paget's disease have been identified. However, the etiologic factors in Paget's disease remain elusive. A cause and effect relationship for the paramyxoviral infection and SQSTM1/ p62 gene mutations responsible for pagetic osteoclast development and disease severity are unclear. This article will highlight the etiologic factors involved in the pathogenesis of Paget's disease.

Adaptor Proteins, Signal Transducing↗
PubMed2026

Activation of pro-survival autophagy by a small molecule promoting p62 oligomerization.

Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterize SQ-1, a small-molecule activator of autophagy that engages the prototypical SAR protein p62/sequestosome-1 (SQSTM1). We show that SQ-1 sensitizes p62 to oxidation and promotes its disulfide-mediated oligomerization in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterized by defective autophagy.

Niemann-Pick type C1 disease↗
PubMed2004

Surface plasmon resonance-based sensors to identify cis-regulatory elements.

In eukaryotes, transcription is regulated by multiprotein complexes binding to specific regions of genomic DNA, called cis-regulatory elements. Comprehensive identification of these elements is an important goal of functional genomics. Hence, it is of practical interest to develop a high-throughput assay to identify cis-regulatory elements. Toward that goal, we demonstrate that a surface plasmon resonance-based assay can identify whether a specific region of DNA binds to proteins present in raw nuclear lysate. Specifically, we immobilized a 16-basepair double-stranded DNA region of the SQSTM1 promoter to the Texas Instruments Spreeta, a surface plasmon resonance sensor. As a control, in a separate experiment, we immobilized a similar piece of DNA that differed by only a single base pair. We observed a significant difference in surface plasmon resonance signal when these two probes were exposed to raw nuclear lysate from NIH/3T3 cells. Using a luciferase-reporter vector transfected into live NIH/3T3 cells, we measured a significant difference in transcriptional activity between the two pieces of DNA. We conclude that a surface plasmon resonance-based sensor is capable of identifying physiologically significant cis-regulatory elements.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Mechanisms of disease: genetics of Paget's disease of bone and related disorders.

Paget's disease of bone (PDB) is a common disorder in which focal abnormalities of increased bone turnover lead to complications such as bone pain, deformity, pathological fractures, and deafness. PDB has a strong genetic component and several susceptibility loci for the disease have been identified by genome-wide scans. Mutations that predispose individuals to PDB and related disorders have been identified in four genes. The rare PDB-like syndromes of familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia are caused by insertion mutations in TNFRSF11A, which encodes receptor activator of nuclear factor (NF)kappaB (RANK)-a critical regulator of osteoclast function. Inactivating mutations in TNFRSF11B, which encodes osteoprotegerin (a decoy receptor for RANK ligand) cause idiopathic hyperphosphatasia, and polymorphisms in this gene seem to increase the risk for classical PDB. Mutations of the sequestosome 1 gene (SQSTM1), which encodes an important scaffold protein in the NFkappaB pathway, are a common cause of classical PDB. The rare syndrome of hereditary inclusion body myopathy, PDB, and fronto-temporal dementia is caused by mutations in the valosin-containing protein (VCP) gene. This gene encodes VCP, which has a role in targeting the inhibitor of NFkappaB for degradation by the proteasome. Several additional genes for PDB remain to be discovered, and it seems likely that they will also involve the RANK-NFkappaB signaling pathway or components of the proteasomal processing of this pathway, underscoring the critical importance of this signaling pathway in bone metabolism and bone disease.

Adaptor Proteins, Signal Transducing↗
PubMed2006

p62 mutations, ubiquitin recognition and Paget's disease of bone.

Functional analyses of PDB (Paget's disease of bone)-associated mutants of the p62 [also known as SQSTM1 (sequestosome 1)] signalling adaptor protein represent an interesting paradigm for understanding not only the disease mechanism in this skeletal disorder, but also the critical determinants of ubiquitin recognition by an ubiquitin-binding protein. The 11 separate PDB mutations identified to date all affect the C-terminal region of p62 containing the UBA domain (ubiquitin-associated domain), a ubiquitin-binding element. All of these mutations have deleterious effects on ubiquitin binding by p62 in vitro, and there is evidence of an inverse relationship between ubiquitin-binding function and disease severity. The effects on ubiquitin-binding function of most of the mutations can be attributed to either reduced UBA domain stability, and/or the mutations affecting the presumed ubiquitin-binding interface of the UBA domain. However, a subset of the mutations are more difficult to rationalize; several of these affect sequences of p62 outside of the minimal ubiquitin-binding region, providing insights into non-UBA domain sequences within the host protein which mediate ubiquitin-binding affinity. The p62 mutations are presumed to result in activation of (osteoclast) NF-kappaB (nuclear factor kappaB) signalling. Understanding how loss of ubiquitin-binding function of p62 impacts on signal transduction events in osteoclasts will undoubtedly further our understanding of the disease mechanism in PDB at the molecular level.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Microarray expression profiling identifies early signaling transcripts associated with 6-OHDA-induced dopaminergic cell death.

The parkinsonian mimetic 6-hydroxydopamine (6-OHDA) has been shown to cause transcriptional changes associated with cellular stress and the unfolded protein response. As these cellular sequelae depend on upstream signaling events, the present study used functional genomics and proteomic approaches to aid in deciphering toxin-mediated regulatory pathways. Microarray analysis of RNA collected from multiple time points following 6-OHDA treatment was combined with data mining and clustering techniques to identify distinct functional subgroups of genes. Notably, stress-induced transcription factors such as ATF3, ATF4, CHOP, and C/EBP beta were robustly up-regulated, yet exhibited unique kinetic patterns. Genes involved in the synthesis and modification of proteins (various tRNA synthetases), protein degradation (e.g., ubiquitin, Herpud1, Sqstm1), and oxidative stress (Hmox1, Por) could be subgrouped into distinct kinetic profiles as well. Realtime PCR and/or two-dimensional electrophoresis combined with western blotting validated data derived from microarray analyses. Taken together, these data support the notion that oxidative stress and protein dysfunction play a role in Parkinson's disease, as well as provide a time course for many of the molecular events associated with 6-OHDA neurotoxicity.

Animals↗
PubMed2002

Identification and confirmation of a module of coexpressed genes.

We synthesize a large gene expression data set using dbEST and UniGene. We use guilt-by-association (GBA) to analyze this data set and identify coexpressed genes. One module, or group of genes, was found to be coexpressed mainly in tissue extracted from breast and ovarian cancers, but also found in tissue from lung cancers, brain cancers, and bone marrow. This module contains at least six members that are believed to be involved in either transcritional regulation (PDEF, H2AFO, NUCKS) or the ubiquitin proteasome pathway (PSMD7, SQSTM1, FLJ10111). We confirm these observations of coexpression by real-time RT-PCR analysis of mRNA extracted from four model breast epithelial cell lines.

Adult↗
PubMed2006

Cytosolic overexpression of p62 sequestosome 1 in neoplastic prostate tissue.

AIMS: To investigate the expression of p62 in various prostatic tissues, and to demonstrate different immunohistochemical patterns of p62 expression in distinct pathological entities of the prostate. The p62 sequestosome 1 (SQSTM1) gene product is a multifunctional protein with ubiquitous expression in normal adult tissue. METHODS AND RESULTS: Overexpression of p62 was detected in prostate cancer cell lines and tissues by reverse transcriptase-polymerase chain reaction. Immunohistochemical staining for p62 was performed on 73 cases of paraffin-embedded prostatic tissue. p62 was negative or weakly positive only in the nucleus (pattern N) of prostatic gland epithelium in nine normal and hyperplastic prostate specimens, whilst most cancerous tissue showed intense, uniform staining for p62 in the cytoplasm (pattern C). Of the prostate cancer specimens, 91% showed positive pattern C immunoreactivity. Of the cases with high-grade prostatic intraepithelial neoplasia (PIN) around cancer, 77% showed pattern C. However, in specimens from the patients without prostate cancer PIN displayed pattern C in only 32% of cases. Western blot analysis showed that all cancer cell lines expressed p62 in the cytoplasm but there was little nuclear expression. CONCLUSION: Cytosolic overexpression of p62 is a novel immunohistochemical characteristic in prostatic adenocarcinoma and high-grade PIN, suggesting that p62 might be a novel marker for prostatic malignancy.

Adaptor Proteins, Signal Transducing↗
PubMed2026

Phenotyping of post-fertilization sperm mitophagy determinants discovered in a mammalian gamete-based cell-free system.

The targeted, substrate-specific degradation of paternal mitochondria inside the zygote, known as post-fertilization sperm mitophagy, is a crucial and evolutionarily conserved early embryonic event. It ensures the exclusive maternal inheritance of the mitochondrial genome. Post-fertilization sperm mitophagy was initially thought to only be achieved via the ubiquitin-proteasome system. Until pro-autophagic receptor proteins such as SQSTM1, GABARAP, as well as the proteasome-interacting ubiquitinated protein dislocase VCP, were identified as contributors to the degradation of the sperm mitochondria early after mammalian fertilization. This synergy of proteasomal and autophagic pathways ensures a timely degradation of sperm mitochondria shortly after fertilization. The discovery of these autophagic receptors lead researchers to believe there might be other autophagic receptors and determinants necessary for proper post-fertilization sperm mitophagy. Based on the established inventory of proteins from mass spectrometry trials of boar spermatozoa exposed to porcine oocyte extracts in an intra-specific porcine cell-free system (CFS), five candidate mitophagy determinants were further investigated in this study, namely LACTB, PRDX3, PSMA8, TOMM34, and FUNDC1. These proteins of interest were studied and validated by using in vitro fertilization (IVF) protocols, cell imaging of spermatids, spermatozoa, oocytes and zygotes, protein interactome analysis, and the porcine CFS. The proteins PSMA8 and TOMM34 behaved in accordance with our proteomic study predictions. The PSMA8 labeling increased after exposure to CFS; in agreement with the classification PSMA8 was given from the mass spectrometry findings. TOMM34 underwent a visible decrease in labeling after exposure to CFS, which also agreed with its proteomic classification; this labeling persisted in IVF zygotes. Except for LACTB, the examined proteins showed mutual interactions as well as interactions with previously identified sperm mitophagy factors in the STRING interactome analysis. Results from this study validate the novel porcine CFS as a valuable tool for the exploration of early fertilization events at a molecular level. Future phenotyping and functional studies using porcine CFS will advance the understanding of mitochondrial inheritance and zygotic development and potentially shed light on the origins of certain mitochondrial diseases arising from the failure of post-fertilization sperm mitophagy.

Animals↗
PubMed2006

Paget's disease of bone in Italy.

Epidemiological studies of Paget's disease of bone (PDB) suggest a pronounced geographical variation in the prevalence of the disease and a decrease in prevalence and clinical severity over time. To analyze epidemiological and clinical features of PDB in Italy, we recently established a registry of Italian PDB cases and performed radiological, biochemical, and bone scan surveys in the towns of Siena and Turin. The overall prevalence of PDB in Italy varied between 0.7% and 2.4%. Prevalence rates increased with age and were higher in men than in women. We observed clinically confirmed familial aggregation in 15-26% of cases. Pedigree analysis indicated an autosomal dominant pattern of inheritance with variable penetrance. SQSTM1 gene analysis in two Italian studies revealed the presence of at least three different mutations accounting for both familial and sporadic cases. Interestingly, no decrease in the prevalence of PDB over time was observed, the opposite of what is described in populations of British descent. However, clinical severity of PDB cases included in the Registry in 2002-2004 seemed reduced with respect to that of PDB patients from the previous epidemiological studies, including a 1950-1956 Italian study. Of interest, a consistent association between PDB and animal-related factors and a significantly higher prevalence of the disease in rural than in urban districts were observed. These findings are in keeping with an important role of the environment in the pathogenesis of PDB, perhaps facilitating the expression of the disease in genetically susceptible subjects. Finally, there was also preliminary evidence indicating regional clustering of PDB in Italy, with a concentration of cases in rural districts of Campania and Tuscany. These districts may represent high prevalence areas of PDB in Italy, similar to what has been observed in other countries. Extrapolation estimates suggest that approximately 150,000-300,000 subjects may be affected with PDB in our country. These results confirm PDB to be the most common bone remodeling disorder in elderly people in Italy, excluding osteoporosis.

Cluster Analysis↗
PubMed2006

Osteosarcoma in Paget's disease of bone.

Paget's disease of bone (PDB) is a focal disorder of bone metabolism first described by Sir James Paget in 1876. It is presumed benign in nature and mediated by abnormal osteoclast function. The incidence of osteosarcomas complicating PDB is estimated at <1%. These cancers occur mostly in persons with long-standing, polyostotic disease and affect patients in their seventh decade or when osteosarcoma is remarkably rare in the general population. Epidemiological studies suggest that this late peak of osteosarcomas is absent in regions where Paget's is infrequently reported. Whereas PDB has a predilection for the axial skeleton, skull, femurs, and tibias, pagetic osteosarcoma tend to spare the spine, and are reported more commonly in the pelvis, femur, humerus, and skull. A molecular basis for the association of osteosarcoma with Paget's disease is unclear. These osteosarcomas are osteogenic in origin, consistently arise in sites of pagetic bone, and may present as metachronous, multifocal lesions. On histopathology, the lesions are usually osteoblastic, and the tumor phenotype is sometimes characterized as an exaggerated, chaotic form of the accelerated bone remodeling that characterizes PDB. New insights from the biology of adolescent osteosarcomas, VCP and SQSTM1 mutations now defined in patients with Paget's disease, and emerging evidence that stromal lesions are present in patients with Paget's disease are changing the way we think about the pathogenesis of PDB and the rare complication of pagetic osteosarcomas.

Bone Remodeling↗
PubMed2006

p62 ubiquitin binding-associated domain mediated the receptor activator of nuclear factor-kappaB ligand-induced osteoclast formation: a new insight into the pathogenesis of Paget's disease of bone.

Paget's disease of bone (PDB) is a debilitating bone disorder characterized by giant osteoclasts, enhanced bone destruction, and irregular bone formation. Recently, mutations in SQSTM1 (also known as p62) have been detected in PDB sufferers, with all mutations resulting in either loss of function or truncation/deletion of the ubiquitin binding-associated (UBA) domain. We hypothesized that mutation in the p62 gene resulting in either deletion or premature termination of the UBA domain accounts for the elevated osteoclastic formation and bone resorption associated with PDB. Remarkably, overexpression of the p62 UBA domain deletion mutant (p62DeltaUBA) significantly enhanced osteoclastogenesis in vitro compared to cells expressing either wild-type p62 (p62WT) or a control vector in a RAW264.7 osteoclastogenic system. Overexpression of p62DeltaUBA potentiated the formation of abnormally large multinucleated osteoclasts and resorption of bone, reminiscent of PDB. Consistent with the enhancement of osteoclastogenesis, overexpression of p62DeltaUBA potentiated receptor activator of nuclear factor-kappaB ligand-induced activation of nuclear factor-kappaB, NFAT, and ERK phosphorylation. Furthermore, as determined by confocal microscopy, deletion of the p62 UBA domain impaired the association of p62 with TRAF6 in the proteasomal compartment. These results suggest that the UBA domain encodes essential regulatory elements required for receptor activator of nuclear factor-kappaB ligand-induced osteoclast formation and bone resorption that may be directly associated with the progression of PDB.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Gene expression profiling of bovine skeletal muscle in response to and during recovery from chronic and severe undernutrition.

Gene expression profiles of LM from beef cattle that underwent significant postweaning undernutrition were studied using complementary DNA (cDNA) microarrays. After 114 d of undernutrition, the RNA from LM showed 2- to 6-fold less expression of many genes from the classes of muscle structural proteins, muscle metabolic enzymes, and extracellular matrix compared with animals on a rapid growth diet. The expression levels of these genes had mostly returned to pretreatment levels after 84 d of realimentation. The gene expression changes associated with undernutrition and BW loss showed an emphasis on downregulation of gene expression specific to fast-twitch fibers, typical of starving mammals, with a preferential atrophy of glycolytic fast-twitch fibers. We also identified a small group of genes that showed 2- to 5-fold elevated expression in LM after 114 d of undernutrition. Putative roles for these genes in atrophying skeletal muscle are regulation of myogenic differentiation (CSRP3), maintenance of mesenchymal stem cells (CYR61), modulation of membrane function (TM4SF2), prevention of oxidative damage (SESN1), and regulation of muscle protein degradation (SQSTM1). A significant increase in stearoyl-CoA desaturase (SCD) gene expression was observed in atrophying muscle, suggesting either that increased fatty acid synthesis is part of the tissue response to caloric restriction, or that SCD plays another role in energy metabolism in the mixed cellular environment of bovine skeletal muscle.

Animal Feed↗