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PubMedDate not supplied

Syndecan-1 expression is upregulated in degenerating articular cartilage in a transgenic mouse model for osteoarthritis.

OBJECTIVE: Mice heterozygous for the Del1 transgene locus with a short deletion mutation in the type II collagen gene develop early-onset degenerative changes in the knee joints that progress to end-stage osteoarthritis by the age of 12-15 months. This study focuses on the expression and distribution of syndecan-1, a cell-surface heparan sulfate proteoglycan, during the development of osteoarthritic cartilage degeneration, to better understand its role in this disease. METHODS: Northern analyses of total RNA extracted from knee joints of transgenic Del1 mice and their nontransgenic controls were used to monitor changes in syndecan-1 mRNA levels during development, growth, ageing, and cartilage degeneration. Immunohistochemistry was used to study the distribution of syndecan-1 in the knee joints at different stages of cartilage degeneration. RESULTS: Syndecan-1 mRNA was present in knee joints throughout life, with the highest mRNA levels in ageing knee joints. In Del1 mice, a transient upregulation of syndecan-1 mRNA synthesis was observed at the age of 6 months coinciding with early stages of cartilage degeneration and a period of attempted repair. Immunostaining for syndecan-1 was most intense in chondrocytes of superficial and intermediate zones of articular cartilage adjacent to defect areas. Chondrocyte clusters also stained strongly for syndecan-1. CONCLUSION: The present temporospatial expression data on upregulation of syndecan-1 in articular cartilage during early stages of cartilage degeneration suggest that this molecule is involved in the attempted repair of cartilage fibrillations. Combined with the known role of syndecan-1 during skeletal development and wound healing, this interesting finding warrants further validation.

Animals↗
PubMed2001

Analysis of cerebral amyloid angiopathy in a transgenic mouse model of Alzheimer disease using in vivo multiphoton microscopy.

Transgenic mice overexpressing the human amyloid precursor protein (APPV717F) develop cerebral amyloid angiopathy (CAA) as they age. We have examined the effect of CAA on blood vessels in vivo using multiphoton laser scanning microscopy. We are able to simultaneously detect, in an alive but anesthetized animal, fluorescent angiography of microvessels as well as the presence of amyloid angiopathy in 3-dimensional volumes near the surface of the brain. Analysis revealed dilation of the portions of vessels that were associated with amyloid deposition, even when that amyloid deposition was quite mild. In addition, analysis of the 3-dimensional reconstruction of the relationship between the vasculature and CAA suggest that CAA is initiated close to branch points of vessels. Taken together, these data suggest that CAA has a substantial effect on the physiology of the microvasculature in vivo.

Alzheimer Disease↗
PubMed2000

Multiorgan nuclear factor kappa B activation in a transgenic mouse model of systemic inflammation.

We utilized a line of transgenic mice expressing Photinus luciferase complementary DNA (cDNA) under the control of a nuclear factor kappa B (NF-kappaB)-dependent promoter (from the 5' human immunodeficiency virus-1 [HIV-1] long terminal repeat) to examine the role of NF-kappaB activation in the pathogenesis of systemic inflammation induced by bacterial endotoxin (lipopolysaccharide [LPS]). After intraperitoneal injection of E. coli LPS, these mice displayed a time- and dose-dependent, organ-specific pattern of luciferase expression, showing that NF-kappaB-dependent gene transcription is transiently activated in multiple organs by systemic LPS administration. Luciferase expression in liver could be specifically blocked by intravenous administration of replication-deficient adenoviral vectors expressing a dominant inhibitor of NF-kappaB (IkappaB-alphaDN), confirming that luciferase gene expression is a surrogate marker for NF-kappaB activation in this line of mice. After treatment with intraperitoneal LPS, the mice were found to have increased lung tissue messenger RNA (mRNA) expression of a variety of cytokines that are thought to be NF-kappaB-dependent, as well as elevated serum concentrations of presumed NF-kappaB-dependent cytokines. In lung tissue homogenates, a close correlation was identified between luciferase activity and KC levels. These studies show that systemic treatment with LPS orchestrates a multiorgan NF-kappaB-dependent response that likely regulates the pathobiology of systemic inflammation.

Animals↗
PubMed1995

A simple test to monitor the motor dysfunction in a transgenic mouse model of amyotrophic lateral sclerosis.

We reported recently that transgenic mice overexpressing human neurofilament heavy (NF-H) proteins develop a progressive neurological disorder with pathological features resembling those found in amyotrophic lateral sclerosis (ALS) (Côté et al 1993). A simple behavioral test, the grasping ability, has been used here for evaluating the motor dysfunction during aging of NF-H transgenic mice. Transgenic mice overexpressing NF-H proteins are normal at birth but they progressively fail to uphold their weight when tested for their grasping ability. The deficits in motor function during aging correlate with a progressive disruption of peripheral nerve function as evidenced by the atrophy and degeneration of distal axons.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Transgenic mouse model for estrogen-regulated lipoprotein metabolism: studies on apoVLDL-II expression in transgenic mice.

We have produced transgenic mice that express an estrogen-responsive avian apolipoprotein, apoVLDL-II. An apoVLDL-II natural gene construct containing 4.7 kb of 5' flanking and 19 bp of 3' flanking sequences together with the 4 exon/3 intron structural gene was expressed in a liver-specific manner in transgenic mice. A single injection of estrogen caused a 5.9- to 7.5-fold stimulation of apoVLDL-II mRNA in the liver. The transgene mRNA had the same initiation sites of transcription as the native mRNA isolated from laying hen liver, and the same sites were used before and after estrogen treatment. The number of hepatocytes that stain positive for immunoreactive apoVLDL-II increased from < 1% to 40-60% in 24 h after estrogen treatment. Thus, in trangenic mice as in the cockerel, hepatocytes are biochemically heterogeneous and induction of apoVLDL-II synthesis occurs by recruitment of hepatocytes. In the plamsa compartment, compared to controls, transgenic mice have a 3- to 5-fold higher basal total plasma triglyceride which was accounted for by a 5.4-fold high basal VLDL triglyceride. Estrogen treatment results in a approximately 2-fold increase in the VLDL triglycerides over basal levels and 8.5-fold increase over nontransgenic mice, which did not show any change in VLDL in response to estrogen. Transgenic mice with the integrated apoVLDL-II gene provide a useful model for the study of the regulation of lipoprotein metabolism by estrogen.

Animals↗
PubMed2002

Effect of the intestinal flora on amyloid deposition in a transgenic mouse model of familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy (FAP) is a hereditary disease characterized by the systemic accumulation of amyloid fibrils. A mutant transthyretin (TTR) gene is mainly responsible for the disease. However, the variable age of onset and low penetrance might be due to environmental factors, one of which is the intestinal flora. Three types of intestinal flora were introduced into a transgenic (Tg) mouse FAP model, 6.0-hMet30. The CV1 and CV2 group transgenic mice were transferred with the intestinal flora from two different mouse facilities housed under conventional conditions, and the SPF group transgenic mice were kept under specific pathogen free conditions in our facility. All the mice were maintained under controlled temperature, humidity and bacterial conditions. Over a period of 28 months, amyloid was not deposited in the SPF and CV1 groups. In contrast, amyloid was deposited in the esophagus and small intestine of two of the three CV2 mice at 18 months. Many neutrophils infiltrated the lesions. The numbers of tissue neutrophils were higher in the CV2 group than in the SPF and CV1 groups at 18 months. The CV2 flora included fewer gram-positive anaerobic cocci as well as higher proportions of yeasts, staphylococci and enterobacteriaceae compared with the SPF and CV1 flora. These findings suggest that the intestinal flora plays an important role in amyloid deposition.

Amyloid↗
PubMed2001

A human immunodeficiency virus-transgenic mouse model for assessing interventions that block microbial-induced proviral expression.

A human immunodeficiency virus (HIV) type 1-transgenic mouse line (166) that previously showed up-regulated expression of viral proteins and infectious particles after infection with pathogenic agents was tested as a model for screening the in vitro and in vivo efficacy of inhibitors of HIV-1 immune activation. Two types of interventions were assessed: use of either the immunosuppressive drug prednisolone or an HIV-1 envelope-targeted toxin (sCD4-PE40). Both agents inhibited lipopolysaccharide-induced p24 expression by splenocytes in vitro and, when administered to transgenic mice, suppressed the induction of plasma p24, as well as the ex vivo production of p24 and infectious virus stimulated by in vivo infection with Mycobacterium avium. Moreover, HIV-1 mRNA levels in the spleen were greatly reduced in mice treated with either agent. Because HIV-1 expression cannot be induced in T lymphocytes from line 166 mice, this model may be of particular advantage for testing interventions that target virus production by non-T cell virus reservoirs.

Animals↗
PubMed2005

Quantifying in vivo somatic mutations using transgenic mouse model systems.

This chapter describes the use of the bacteriophage cII positive selection assay with the MutaMouse transgenic model system. The assay is similar to others involving a transgenic target, including the cII and lacI assays in the Big Blue(R) Mouse, lacZ in the MutaMouse, and the gpt delta assay. Briefly, high-molecular-weight DNA is purified from the tissue of interest and used as substrate during in vitro packaging reactions, in which the lambda transgenes are excised from the genome and assembled into viable phage. Phage containing the mutational targets are then adsorbed into an appropriate bacterial host, and mutations sustained in vivo are evidenced by either standard recombinant screening or selection assays. Mutant frequencies are reported as the ratio of mutant phage to total phage units analyzed. The lambda-based transgenic mouse assays are used to study and characterize in vivo mutagenesis, as well as for mutagenicity assessment. The models permit the enumeration of mutations sustained in virtually any tissue of the mouse and are sensitive and robust. Application of the assays is simple, not requiring resources beyond those commonly found in most academic laboratories.

Animals↗
PubMed1996

A poliovirus-susceptible transgenic mouse model as a possible replacement for the monkey neurovirulence test of oral poliovirus vaccine.

Two poliovirus-susceptible transgenic mouse (Tg PVR) strains, Tg1 and Tg21, were compared with the monkey test for their sensitivity to neurovirulence of live oral poliovirus vaccine (OPV). Intracerebral (i.c.) and intraspinal (i.s.) routes of inoculation were investigated to determine the most suitable combination of mouse strain and route. Evaluation of the mouse tests was performed using several indicators; clinical score and failure time were selected as the most efficient. Tg1 and Tg21 mice inoculated i.s. with type 2, and Tg21 mice inoculated i.s. with type 3 OPV were determined to be the most appropriate systems, whereas they are shown not to be suitable for type 1 OPV. The sensitivity of each of the two mouse models was at least equal to that of the monkey test, suggesting that these mouse systems might be considered as a potential replacement for the monkey test of OPV. However, more data are needed to establish regulatory criteria of acceptability for vaccine lots tested in Tg PVR mice. This is the first study conducted with Tg PVR mice with all three types of poliovirus vaccine preparations.

Animals↗
PubMed2006

Early vascular and neuronal changes in a VEGF transgenic mouse model of retinal neovascularization.

PURPOSE: To investigate early retinal changes in a vascular endothelial growth factor (VEGF) transgenic mouse (tr029VEGF; rhodopsin promoter) with long-term damage that mimics nonproliferative diabetic retinopathy (NPDR) and mild proliferative diabetic retinopathy (PDR). METHODS: Rhodopsin and VEGF expression was assessed up to postnatal day (P)28. Vascular and retinal changes were charted at P7 and P28 using sections and wholemounts stained with hematoxylin and eosin or isolectin IB4 Griffonia simplicifolia Samples were examined using light, fluorescence, and confocal microscopy. RESULTS: Rhodopsin was detected at P5 and reached mature levels by P15; VEGF protein expression was transient, peaking at P10 to P15. In wild-type (wt) mice at P7, vessels had formed in the nerve fiber/retinal ganglion cell layer and showed a centroperipheral maturational gradient; some capillaries had formed a second bed on the vitread side of the inner nuclear layer (INL). By P28, the retinal vasculature had three mature capillary beds, the third abutting the sclerad aspect of the INL. In tr029VEGF mice, capillary bed formation was accelerated compared with that in wt, with abnormal vessels extending to the sclerad side of the INL by P7 and abnormally penetrating the photoreceptors by P28. Compared with P7, vascular lesions were more numerous at P28 when capillary dropout was also evident. At both stages, retinal layers were thinned most where abnormal vessel growth was greatest. CONCLUSIONS: Concomitant damage to the vasculature and neural retina at early stages in tr029VEGF suggest that both tissues are affected, providing opportunities to examine early cellular events that lead to long-term disease.

Animals↗
PubMed2003

Cardiac electrophysiologic abnormalities in the CREBA133 transgenic mouse model of idiopathic dilated cardiomyopathy.

INTRODUCTION: We hypothesized that the transgenic mice expressing a dominant-negative form of the CREB transcription factor (CREBA133) under the control of the cardiac myocyte-specific alpha-MHC promoter and displaying dilated cardiomyopathy would exhibit electrophysiologic abnormalities similar to those observed in human cardiomyopathy. METHODS AND RESULTS: Invasive electrophysiologic studies were performed on two age groups of mice: 11-week-old mice (n = 20, 9 transgenic mice and 11 wild-type controls) and 17-week-old mice (n = 16, 7 transgenic mice and 9 wild-type controls). Five additional transgenic mice underwent ambulatory ECG monitoring to determine the cause of death. The 11-week-old CREBA133 transgenic mice had longer PR and AH intervals than 11-week-old wild-type controls (P < 0.001), whereas at 17 weeks of age the transgenic mice also demonstrated increased HV intervals and widened QRS duration (P < 0.05). At both 11 weeks and 17 weeks of age, AV Wenckebach cycle length, 2:1 AV cycle length, and AV nodal functional and effective refractory periods were significantly longer in transgenic mice than in controls (P < 0.05). Although no ventricular arrhythmias were inducible at 11 weeks of age, at 17 weeks of age, ventricular tachycardia was induced in 4 of the 7 CREBA133 transgenic mice but in none of the 9 wild-type controls. All 5 CREBA133 transgenic mice that underwent ambulatory ECG monitoring revealed high-grade AV block, but not ventricular arrhythmia, at the time of death. CONCLUSION: These data suggest that CREBA133 transgenic mice manifest abnormalities of AV nodal and infra-Hisian conduction and inducibility of ventricular arrhythmia, which are characteristics of human dilated cardiomyopathy.

Animals↗
PubMed1991

Formation of the tetraploid intermediate is associated with the development of cells with more than four centrioles in the elastase-simian virus 40 tumor antigen transgenic mouse model of pancreatic cancer.

The development of pancreatic cancer in transgenic mice expressing the simian virus 40 tumor antigen placed under controlling regions of the elastase I gene is characterized by the sequential appearance of tetraploid and then multiple aneuploid cell populations. Pancreatic tissues from such transgenic mice were studied between 8 and 32 days of age. Virtually 100% of acinar cell nuclei had immunohistochemically detectable tumor antigen by 18 days. Tetraploid cells were demonstrated by DNA content flow cytometry by 20 days and were associated with the appearance of interphase cells that had 5-11 centrioles per cell in single thin sections of pancreatic tissue examined by electron microscopy. Mitotic cells also were observed that had 5 or more centrioles per cell that were incorporated into the poles of bipolar or at least tripolar spindle apparatuses. These observations indicate that formation of the tetraploid intermediate in the diploid----tetraploid----aneuploid sequence of pancreatic tumor formation in elastase-simian virus 40 tumor antigen transgenic mice is accompanied by the development of cells with 5 or more centrioles that can be incorporated into the poles of abnormal mitotic spindles. We speculate that cells with more than 4 centrioles are predisposed to the formation of multipolar mitoses that may yield daughter cells with chromosomal gains and losses, resulting in the subsequent development of aneuploid tumors.

Animals↗
PubMed1996

DNA-mediated immunization in a transgenic mouse model of the hepatitis B surface antigen chronic carrier state.

Transgenic mice expressing the sequences coding for the envelope proteins of the hepatitis B virus (HBV) in the liver have been used as a model of the HBV chronic carrier state. We evaluated the possibility of inducing a specific immune response to the viral envelope antigens and thus potentially controlling chronic HBV infection. Using HBV-specific DNA-mediated immunization in this transgenic model, we show that the immune response induced after a single intramuscular injection of DNA resulted in the complete clearance of circulating hepatitis B surface antigen and in the long-term control of transgene expression in hepatocytes. This response does not involve a detectable cytopathic effect in the liver. Adoptive transfer of fractionated primed spleen cells from DNA-immunized mice shows that T cells are responsible for the down-regulation of HBV mRNA in the liver of transgenic mice. To our knowledge, this is the first demonstration of a potential immunotherapeutic application of DNA-mediated immunization against an infectious disease and raises the possibility of designing more effective ways of treating HBV chronic carriers.

Animals↗
PubMed2005

Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease.

Human amyloid precursor protein (hAPP) transgenic mice with high levels of amyloid-beta (Abeta) develop behavioral deficits that correlate with the depletion of synaptic activity-related proteins in the dentate gyrus. The tyrosine kinase Fyn is altered in Alzheimer's disease brains and modulates premature mortality and synaptotoxicity in hAPP mice. To determine whether Fyn also modulates Abeta-induced behavioral deficits and depletions of synaptic activity-dependent proteins, we overexpressed Fyn in neurons of hAPP mice with moderate levels of Abeta production. Compared with nontransgenic controls and singly transgenic mice expressing hAPP or FYN alone, doubly transgenic FYN/hAPP mice had striking depletions of calbindin, Fos, and phosphorylated ERK (extracellular signal-regulated kinase), impaired neuronal induction of Arc, and impaired spatial memory retention. These deficits were qualitatively and quantitatively similar to those otherwise seen only in hAPP mice with higher Abeta levels. Surprisingly, levels of active Fyn were lower in high expresser hAPP mice than in NTG controls and lower in FYN/hAPP mice than in FYN mice. Suppression of Fyn activity may result from dephosphorylation by striatal-enriched phosphatase, which was upregulated in FYN/hAPP mice and in hAPP mice with high levels of Abeta. Thus, increased Fyn expression is sufficient to trigger prominent neuronal deficits in the context of even relatively moderate Abeta levels, and inhibition of Fyn activity may help counteract Abeta-induced impairments.

Alzheimer Disease↗
PubMed2003

Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein.

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR). The nuclear inclusions consisting of the mutant AR protein are characteristic and combine with many components of ubiquitin-proteasome and molecular chaperone pathways, raising the possibility that misfolding and altered degradation of mutant AR may be involved in the pathogenesis. We have reported that the overexpression of heat shock protein (HSP) chaperones reduces mutant AR aggregation and cell death in a neuronal cell model (Kobayashi et al., 2000). To determine whether increasing the expression level of chaperone improves the phenotype in a mouse model, we cross-bred SBMA transgenic mice with mice overexpressing the inducible form of human HSP70. We demonstrated that high expression of HSP70 markedly ameliorated the motor function of the SBMA model mice. In double-transgenic mice, the nuclear-localized mutant AR protein, particularly that of the large complex form, was significantly reduced. Monomeric mutant AR was also reduced in amount by HSP70 overexpression, suggesting the enhanced degradation of mutant AR. These findings suggest that HSP70 overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR, probably caused by enhanced mutant AR degradation. Our study may provide the basis for the development of an HSP70-related therapy for SBMA and other polyQ diseases.

Animals↗
PubMed2005

The disease progression in the keratin 14 IL-4-transgenic mouse model of atopic dermatitis parallels the up-regulation of B cell activation molecules, proliferation and surface and serum IgE.

We have previously characterized the keratin 14 interleukin-4-transgenic (IL-4-Tg) mouse model of atopic dermatitis as a chronic pruritic inflammatory skin disease typified by skin infiltration of inflammatory cells and early up-regulation of Th2 cytokines and late surge of Th1 cytokines. In the present study, we examined the involvement of B cells. Systematic examinations of the following immunological parameters on B cells were carried out in non-Tg control mice and in IL-4-Tg mice at before disease onset and early and late disease stages so that we could determine the immunological sequence of events leading to the disease development: surface expressions of IA/IE, activation and costimulatory molecules, proliferation under LPS or IgM stimulation, quantification of cell surface and serum IgE, IgG1, and IgG2a. Our results showed that as the disease progresses from before onset to early disease and to late disease, there is a parallel increase in surface markers of B cell activation (IA/IE, CD44, CD69, CD80 and CD86), in B cell proliferation, and in cell surface and serum IgE. Significant increases of Th2-driven serum IgG1 and IgE in early disease was followed by significant increase of Th1-driven IgG2a in late disease. Importantly the significant increases of activation molecule (IA/IE), proliferation (to LPS), and surface IgE on B cells of the IL-4-Tg mice precedes the up-regulation of serum IgE and disease onset. These data suggest that activated B cells may play a role in atopic dermatitis disease development by up-regulating serum IgE concentration, which serves as a marker of disease onset.

Animals↗
PubMedDate not supplied

Oxymetholone: II. Evaluation in the Tg-AC transgenic mouse model for detection of carcinogens.

Several rodent models are under examination as possible alternatives to the classical 2-yr carcinogenicity bioassay. The Tg.AC transgenic mouse has been proposed as a shorter term model offering the possibility of detecting nongenotoxic and genotoxic carcinogenic agents. Retrospective studies of chemicals with established carcinogenic potential have revealed a close correlation between classical bioassay results and the production of skin tumors in the Tg.AC mouse model. Oxymetholone is a synthetic testosterone derivative that is a suspected carcinogen but has shown no evidence of genotoxic activity in a comprehensive battery of genetic toxicity assays. It currently is being tested by the National Toxicology Program (NTP) in a 2-yr rat carcinogenicity bioassay. Because of its nongenotoxicity and the ongoing chronic bioassay, oxymetholone was considered an ideal candidate for a prospective evaluation of the predictive validity of the Tg.AC dermal carcinogenicity model. Consequently, a 6-mo dermal study with oxymetholone in the Tg.AC mouse model was initiated and completed prior to disclosure of the NTP rat bioassay results. In this study, male and female hemizygous Tg.AC mice, 7-8 wk old, were housed individually in suspended plastic cages. An area of dorsal skin was shaved to accommodate dermal applications of 200-microl doses of vehicle control (acetone), drug (1.2, 6.0, or 12 mg oxymetholone in dimethylsulfoxide:acetone, 20:80), or positive control (1.25 microg 12-o-tetradecanoyl-phorbol-13-acetate [TPA]) solutions. Mice received oxymetholone or acetone daily or TPA twice weekly for 20 wk followed by a 6-wk recovery period. The acetone control groups exhibited low spontaneous incidences of papillomas, whereas dermal application of oxymetholone produced dose-related increases in the numbers of papilloma-bearing mice and the numbers of papillomas per animal. Females showed a somewhat greater response to the androgen than did the males. TPA caused an unequivocal increase in papillomas, with males exhibiting a greater response than females. The results of this study indicate that this nongerotoxic androgenic compound possesses proliferative properties. The results predict that chronic systemic administration of oxymetholone will most likely be associated with increased incidences of neoplasms.

Anabolic Agents↗
PubMed2004

Magnetic resonance imaging reveals neuronal degeneration in the brainstem of the superoxide dismutase 1 transgenic mouse model of amyotrophic lateral sclerosis.

Magnetic resonance imaging (MRI) is becoming the preferred neuroimaging modality for the diagnosis of human amyotrophic lateral sclerosis (ALS). A useful animal model of ALS is the superoxide dismutase 1G93A G1H transgenic mouse, which shows many of the clinico-pathological features of the human condition. We have employed a 4.7-Tesla MRI instrument to determine whether a noninvasive imaging approach can reveal pathological changes in the nervous system of this animal model. Our T2-weighted MRI revealed consistent changes in brain and brainstem of these mice. Hyperintensities, indicative of neuropathology, were observed in several areas including the nucleus ambiguus, facial nucleus, trigeminal motor nucleus, rostroventrolateral reticular nucleus, lateral paragigantocellular nucleus and the substantia nigra. Histology analysis including neuronal counts of the imaged brains confirmed the T2-weighted MRI findings. Enlarged ventricles and hypointense striations, indicative of global atrophy, were also observed in the brain and cerebellum. This atrophy was confirmed by fresh brain weight data. The extensive global degeneration involving multiple structures suggests a multisystem disease that is similar to human ALS.

Animals↗