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PubMed2006

Effect of orally administered rolipram, a phosphodiesterase 4 inhibitor, on a mouse model of the dermatitis caused by 2,4,6-trinitro-1-chlorobenzene (TNCB)-repeated application.

The purpose of this study was to evaluate the efficacy of rolipram, a phosphodiesterase (PDE) 4 inhibitor, in a mouse model of dermatitis induced by repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB). BALB/c mice were sensitized with 0.3% w/v TNCB applied to the ear on day -7, followed by application three times a week from day 0. Rolipram, prednisolone and cyclosporine A were administered orally once daily from day 0 to 21. Rolipram at a dose of 10 mg/kg/day significantly inhibited the ear thickness and the increase in cytokine levels and enzyme activity in the ear. Interleukin (IL)-4 production was markedly decreased in cervical lymph node cells from animals treated with rolipram at a dose of 10 mg/kg/day. Prednisolone and cyclosporine A significantly reduced ear thickness. These compounds significantly decreased the total cell and lymphocyte number of the cervical lymph nodes. Furthermore, prednisolone markedly suppressed body weight gain, and cyclosporine A significantly increased the serum total IgE concentration compared with that in the vehicle-treated control. Rolipram, unlike prednisolone and cyclosporine A, did not influence body weight and the total IgE concentration in the serum. The present results suggest that the PDE4 inhibitor is a promising oral medicine for the treatment of chronic skin inflammatory diseases.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Knockout mouse models to study Wnt signal transduction.

Wnt signal transduction is crucial for maintaining the balance between proliferation and differentiation throughout embryogenesis and postnatal life. Here, we provide a comprehensive overview of the conventional knockout mouse studies of both the canonical and the noncanonical Wnt pathways during mammalian development. Many of these knockout mice display early embryonic lethality, underscoring the fundamental importance of Wnt signal transduction, but precluding functional analyses at later stages. Use of conditional or inducible mouse models will enable us to study the role of Wnt signaling during later stages of development and adult life. Furthermore, genomic-scale approaches and advanced imaging techniques could provide a means to start dissecting the mechanism behind the observed phenotypes.

Alleles↗
PubMed2003

Physiological role of AMP-activated protein kinase (AMPK): insights from knockout mouse models.

AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To understand better the physiological role of the catalytic AMPK subunit isoforms, we generated two knockout mouse models with the alpha1 (AMPK alpha 1(-/-)) and alpha 2 (AMPK alpha 2(-/-)) catalytic subunit genes deleted. No defect in glucose homoeostasis was observed in AMPK alpha 1(-/-) mice. On the other hand, AMPK alpha 2(-/-) mice presented high plasma glucose levels and low plasma insulin concentrations in the fed period and during the glucose tolerance test. Nevertheless, in isolated AMPK alpha 2(-/-) pancreatic islets, glucose-stimulated insulin secretion was not affected. Surprisingly, AMPK alpha 2(-/-) mice were insulin-resistant and had reduced muscle glycogen synthesis as assessed in vivo by the hyperinsulinaemic euglycaemic clamp procedure. Reduction of insulin sensitivity and glycogen synthesis were not dependent on the lack of AMPK in skeletal muscle, since mice expressing a dominant inhibitory mutant of AMPK in skeletal muscle were not affected and since insulin-stimulated glucose transport in incubated muscles in vitro was normal in AMPK alpha 2(-/-) muscles. Furthermore, AMPK alpha 2(-/-) mice have a higher sympathetic tone, as shown by increased catecholamine urinary excretion. Increased adrenergic tone could explain both decreased insulin secretion and insulin resistance observed in vivo in AMPK alpha 2(-/-) mice. We suggest that the alpha2 catalytic subunit of AMPK plays a major role as a fuel sensor by modulating the activity of the autonomous nervous system in vivo.

AMP-Activated Protein Kinases↗
PubMedDate not supplied

The 1997 Lindberg Award. Effects of burn injury on bone and growth in a mouse model.

Bone growth and remodeling are inhibited by severe burns in adult and pediatric patients, resulting in alterations in linear growth, bone mass, osteoporosis, and increased risk for pathologic fractures. This study of a mouse model of burn injury showed skeletal changes similar to those reported in patients with burn injuries. Baseline, control, sham, and burned mice were injected with fluorescent markers calcein and tetracycline for histomorphometric analysis. Total femur dry and ash weights and total calcium content were significantly lower 10 days after burn injury compared with sham and control animals. There also were decreases in the percentage of fluorochrome-labeled bone surfaces and bone formation rates in the burn-injured mice compared with control and sham mice; however, there were no differences in the mineral apposition rates. This model now provides an opportunity to examine cellular and molecular mechanisms contributing to skeletal pathology in a well-defined burn injury model.

Animals↗
PubMed1989

Lethal infection by Bordetella pertussis mutants in the infant mouse model.

Different aspects of lethal infection of infant mice with Bordetella pertussis were examined. Mutants deficient in vir-regulated genes were tested for the ability to cause a lethal infection in the infant mouse model. Adenylate cyclase toxin-hemolysin and pertussis toxin were required to cause a lethal infection at low doses. Mixed infection caused by challenging the mice with an equal number of pertussis toxin and adenylate cyclase toxin-hemolysin mutants at a dose at which neither alone was lethal was also unable to cause a lethal infection. Production of the filamentous hemagglutinin and the dermonecrotic toxin was not required to cause a lethal infection. Nine other mutants in vir-regulated genes whose phenotypes have yet to be determined were also tested. Only two of these mutants were impaired in the ability to cause a lethal infection. Expression of fimbriae does not appear to affect the dose required to cause a lethal infection; however, fimbrial expression was correlated with the later stages of a nonlethal, persistent infection. Growth of the bacteria in MgSO4, a condition which reversibly suppresses expression of the genes required for virulence, did not alter the ability of the bacteria to cause a lethal infection. Auxotrophic mutants deficient in leucine biosynthesis were as virulent as the parental strain; however, mutants deficient in methionine biosynthesis were less virulent. A B. parapertussis strain was much less effective in promoting a lethal infection than any of the wild-type B. pertussis strains examined. A persistent infection in the lungs was observed for weeks after challenge for mice given a sublethal dose of B. pertussis, and transmission from infected infants to the mother was never observed.

Adenylate Cyclase Toxin↗
PubMed1998

Dietary polyunsaturated fatty acids decrease anti-dsDNA and anti-cardiolipin antibodies production in idiotype induced mouse model of systemic lupus erythematosus.

OBJECTIVE: To examine the effect of diets with different polyunsaturated fatty acid contents, including linseed oil which contains 70% omega-3 fatty acids, on autoantibody production in idiotype induced mouse model of systemic lupus erythematosus (SLE). METHODS: Five different fats were fed to mice with induced SLE and antibody titers to anti-DNA and anti-cardiolipin were determined and histological examination of kidneys were carried out. RESULTS: SLE mice fed linseed oil showed lower titers of antibodies to DNA and to cardiolipin and less severe kidney damage than mice fed other diets, including fish oil. CONCLUSION: Use of linseed oil may attenuate the severity of SLE and this diet may be recommended for other auto-immune diseases as well.

Animals↗
PubMed2005

Correlation of disease evolution with progressive inflammatory cell activation and migration in the IL-4 transgenic mouse model of atopic dermatitis.

Atopic dermatitis is a chronic inflammatory skin disease characterized by inflammatory cell infiltration in the skin. In order to assess the roles of inflammatory cells in this disease, we analysed the activation status and surface markers of various leucocytes in the IL-4 transgenic mouse model of atopic dermatitis, by flow cytometry, immuofluorescence microscopy, and T cell proliferation assays. The studies were performed with a nontransgenic mouse control and transgenic mice at three disease stages: before disease onset, early skin disease, and late skin disease, so that we can delineate the immunological sequence of events. As the skin disease evolves, the skin draining lymph node cells from IL-4-Tg mice show a spontaneous proliferation and a progressively enhanced proliferative response to stimulants including anti-CD3, Con A, PHA, and Staphylococcus enterotoxins A and B. As the disease evolves, the percent of lymphoid organ T cells expressing activation molecules (CD44 and CD69) and costimulatory molecules (ICOS and PD-1) are progressively increased; the percent and total number of T cells are reduced in an incremental manner in the secondary lymphoid organs while the number of T cells infiltrating the skin increases in an incremental fashion; the total number of dendritic antigen presenting cells, macrophages, and NK cells gradually increases in the lymphoid organs. Collectively, our results suggest that there is a continued and progressive migration of activated inflammatory cells from the secondary lymphoid organs into the skin where they participate in immune responses resulting in the pathology associated with inflammation.

Animals↗
PubMed2005

The role of p53-mediated apoptosis as a crucial anti-tumor response to genomic instability: lessons from mouse models.

Genomic instability is a major force driving human cancer development. A cellular safeguard against such genetic destabilization, which can ensue from defects in telomere maintenance, DNA repair, and checkpoint function, is activation of the p53 tumor suppressor protein, which commonly responds to these DNA damage signals by inducing apoptosis. If, however, p53 becomes inactivated, as is typical of many tumors and pre-cancerous lesions, then cells with compromised genome integrity pathways survive inappropriately, and the accrual of oncogenic lesions can fuel the carcinogenic process. Studies of mouse models have been instrumental in providing support for this idea. Mouse knockouts in genes important for telomere function, DNA damage checkpoint activation and DNA repair - both non-homologous end joining and homologous recombination - are prone to the development of genomic instability. As a consequence of these DNA damage signals, p53 becomes activated in cells of these mutant mice, leading to the induction of apoptosis, sometimes at the expense of organismal viability. This apoptotic response can be rescued through crosses to p53-deficient mice, but has dire consequences: mice predisposed to genomic instability and lacking p53 are susceptible to tumorigenesis. Thus p53-mediated apoptosis provides a crucial tumor suppressive mechanism to eliminate cells succumbing to genomic instability.

Animals↗
PubMed1998

Development and characterization of immortalized fibroblastoid cell lines from an FA(C) mouse model.

Fanconi anemia (FA) is an autosomal recessive disorder, characterised by multiple congenital malformations, bone marrow failure and a predisposition to developing malignancies, especially leukemia. FA cells show increased levels of spontaneous chromosomal aberrations and a hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC) and diepoxybutane (DEB). There are at least eight complementation groups involved in FA, and the genes for two of these groups, FA(A) and FA(C), have been isolated and cloned. Mouse models for FA(C) have been developed by replacing exon 8 or exon 9 of Fac with the neo gene. Mice homozygous for Fac mutations show reduced fertility and hypersensitivity to induction of chromosomal aberrations by MMC and DEB. To facilitate the study of cellular defects in vitro, transformed mouse fibroblast cell lines were established. Cell-killing experiments and cytogenetic analyses were performed on these cells following treatment with MMC and DEB. Fac-/- showed significant hypersensitivity to MMC and DEB as compared with Fac+/+ and +/- for both cellular phenotypes. This is consistent with results obtained from similar studies on human fibroblasts and lymphoblastoid cell lines. Therefore, these isogenic transformed mouse fibroblasts provide as in vitro model for further investigation of the hypersensitivity of Fanconi anemia cells to DNA cross-linking agents.

Animals↗
PubMed2000

Mouse models of alpha-synucleinopathy and Lewy pathology.

The discovery of two missense mutations (A53T and A30P) in the gene encoding the presynaptic protein alpha-synuclein (alphaSN) that are genetically linked to rare familial forms of Parkinson's disease and its accumulation in Lewy bodies and Lewy neurites has triggered several attempts to generate transgenic mice overexpressing human alphaSN. Analogous to a successful strategy for the production of transgenic animal models for Alzheimer's disease we generated mice expressing wildtype and the A53T mutant of human alphaSN in the nervous system under control of mouse Thy1 regulatory sequences. These animals develop neuronal alpha-synucleinopathy, striking features of Lewy pathology, neuronal degeneration and motor defects. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions, suggesting that alphaSN may interfere with a universal mechanism of synapse maintenance. Thy1-transgene expression of wildtype human alphaSN resulted in comparable pathological changes thus supporting a central role for mutant and wildtype alphaSN in familial and idiopathic forms of diseases with neuronal alpha-synucleinopathy and Lewy pathology. The mouse models provide means to address fundamental aspects of alpha-synucleinopathy and to test therapeutic strategies.

Amino Acid Substitution↗
PubMed2004

A mouse model of classical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration.

Mutations in the CLN2 gene, which encodes a lysosomal serine protease, tripeptidyl-peptidase I (TPP I), result in an autosomal recessive neurodegenerative disease of children, classical late-infantile neuronal ceroid lipofuscinosis (cLINCL). cLINCL is inevitably fatal, and there currently exists no cure or effective treatment. In this report, we provide the characterization of the first CLN2-targeted mouse model for cLINCL. CLN2-targeted mice were fertile and apparently healthy at birth despite an absence of detectable TPP I activity. At approximately 7 weeks of age, neurological deficiencies became evident with the onset of a tremor that became progressively more severe and was eventually accompanied by ataxia. Lifespan of the affected mice was greatly reduced (median survival, 138 d), and extensive neuronal pathology was observed including a prominent accumulation of cytoplasmic storage material within the lysosomal-endosomal compartment, a loss of cerebellar Purkinje cells, and widespread axonal degeneration. The CLN2-targeted mouse therefore recapitulates much of the pathology and clinical features of cLINCL and represents an animal model that should provide clues to the normal cellular function of TPP I and the pathogenic processes that underlie neuronal death in its absence. In addition, the CLN2-targeted mouse also represents a valuable model for the evaluation of different therapeutic strategies.

Aminopeptidases↗
PubMed2004

Novel progestogenic activity of environmental endocrine disruptors in the upregulation of calbindin-D9k in an immature mouse model.

Endocrine disruption is a major global health concern in the industrialized world. The induction of uterine calbindin-D9k (CaBP-9k), which belongs to a large family of intracellular calcium binding proteins, was used to assess the exposure of endocrine disruptors (EDs) in an immature mouse model. Sex steroid hormones have been demonstrated to regulate uterine CaBP-9k expression in the uterus of rats and mice. In particular, the mouse CaBP-9k gene was predominantly regulated by progesterone (P4), whereas rat CaBP-9k was mainly induced by 17-beta-estradiol (E2) in the uterus. In the present study, immature (14-day-old) female mice were injected with 4-tert-octylphenol (OP), nonylphenol (NP), bisphenol A (BPA), E2, or P4 to determine their effects on uterine CaBP-9k mRNA and protein expression. In addition, to specify estrogenic or progestogenic activity of EDs in the regulation of CaBP-9k, the mice were co-treated with ICI 182,780, an estrogen receptor (ER) antagonist, or RU486, a progesterone receptor (PR) antagonist,. Treatments with OP, NP, or BPA resulted in an increase in CaBP-9k mRNA and protein in the uterus of immature mice in a dose-dependent and time-dependent manner. The EDs-induced expression of CaBP-9k mRNA and protein was reversed or abolished by pretreatment with RU486 or ICI 182,780, suggesting that these synthetic chemicals may have both progestogenic and estrogenic properties by acting through PR or ER in the induction of uterine CaBP-9k mRNA and protein in this model. These results describe a novel in vivo model for detection of both estrogenic and progestogenic activities of EDs in the induction of CaBP-9k mRNA and protein in the uterus of immature mice.

Animals↗
PubMed2003

Inhibition of calcium uptake via the sarco/endoplasmic reticulum Ca2+-ATPase in a mouse model of Sandhoff disease and prevention by treatment with N-butyldeoxynojirimycin.

Gangliosides are found at high levels in neuronal tissues where they play a variety of important functions. In the gangliosidoses, gangliosides accumulate because of defective activity of the lysosomal proteins responsible for their degradation, usually resulting in a rapidly progressive neurodegenerative disease. However, the molecular mechanism(s) leading from ganglioside accumulation to neurodegeneration is not known. We now examine the effect of ganglioside GM2 accumulation in a mouse model of Sandhoff disease (one of the GM2 gangliosidoses), the Hexb-/- mouse. Microsomes from Hexb-/- mouse brain showed a significant reduction in the rate of Ca2+-uptake via the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), which was prevented by feeding Hexb-/- mice with N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of glycolipid synthesis that reduces GM2 storage. Changes in SERCA activity were not due to transcriptional regulation but rather because of a decrease in Vmax. Moreover, exogenously added GM2 had a similar effect on SERCA activity. The functional significance of these findings was established by the enhanced sensitivity of neurons cultured from embryonic Hexb-/- mice to cell death induced by thapsigargin, a specific SERCA inhibitor, and by the enhanced sensitivity of Hexb-/- microsomes to calcium-induced calcium release. This study suggests a mechanistic link among GM2 accumulation, reduced SERCA activity, and neuronal cell death, which may be of significance for delineating the neuropathophysiology of Sandhoff disease.

1-Deoxynojirimycin↗
PubMed1997

A mouse model for X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with impaired beta-oxidation of very long chain fatty acids (VLCFAs) and reduced function of peroxisomal very long chain fatty acyl-CoA synthetase (VLCS) that leads to severe and progressive neurological disability. The X-ALD gene, identified by positional cloning, encodes a peroxisomal membrane protein (adrenoleukodystrophy protein; ALDP) that belongs to the ATP binding cassette transporter protein superfamily. Mutational analyses and functional studies of the X-ALD gene confirm that it and not VLCS is the gene responsible for X-ALD. Its role in the beta-oxidation of VLCFAs and its effect on the function of VLCS are unclear. The complex pathology of X-ALD and the extreme variability of its clinical phenotypes are also unexplained. To facilitate understanding of X-ALD pathophysiology, we developed an X-ALD mouse model by gene targeting. The X-ALD mouse exhibits reduced beta-oxidation of VLCFAs, resulting in significantly elevated levels of saturated VLCFAs in total lipids from all tissues measured and in cholesterol esters from adrenal glands. Lipid cleft inclusions were observed in adrenocortical cells of X-ALD mice under the electron microscope. No neurological involvement has been detected in X-ALD mice up to 6 months. We conclude that X-ALD mice exhibit biochemical defects equivalent to those found in human X-ALD and thus provide an experimental system for testing therapeutic intervention.

Adrenoleukodystrophy↗
PubMedDate not supplied

A common phenotype associated with atherogenesis in diverse mouse models of vascular lipid lesions.

The introduction of a range of different genetic modifications in mice results in altered lipoprotein metabolism and the development of vascular lipid lesions. At present, however, it is unclear to what extent the molecular events underlying lipid lesion formation are similar in these different mouse models of atherosclerosis. The aim of this study was to compare the protein expression pattern of lipid lesions from seven different mouse lines with varying susceptibility to vascular lipid lesion development, to determine to what extent lesions induced by different genetic interventions have a similar composition. The proteins we have measured, using quantitative immunofluorescence, are proteins whose expression is known to be modulated during atherogenesis in humans, including plasminogen activator inhibitor (PAI)-1, transforming growth factor (TGF)-beta 1, osteopontin and the macrophage marker CD11b. In all the mice lines we have investigated, PAI-1 was elevated wherever lesions developed. Active TGF-beta was depressed in the vessel wall of mice which developed lipid lesions, particularly in the intima. In contrast, TGF-beta 1 antigen (active plus latent TGF-beta 1) was increased at lesion sites. Accumulation of osteopontin and, with the marked exception of apolipoprotein(a) transgenic mice, tissue macrophages occurred at sites of lipid deposition in the vessel wall. Each lesion, irrespective of its size and the mouse strain in which it developed, had similar amounts of PAI-1, active TGF-beta and osteopontin per unit area of lesion. These data are consistent with a common phenotype accompanying atherogenesis, irrespective of the genetic basis of susceptibility.

Animals↗
PubMed2005

PET imaging of brain with the beta-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer's disease.

PURPOSE: The purpose of this study was to evaluate the capacity of [11C]6-OH-BTA-1 and positron emission tomography (PET) to quantify beta-amyloid (Abeta) plaques in the Tg2576 mouse model of Alzheimer's disease (AD). METHODS: PET imaging was performed with the NIH ATLAS small animal scanner in six elderly transgenic mice (Tg2576; age 22.0+/-1.8 months; 23.6+/-2.6 g) overexpressing a mutated form of human beta-amyloid precursor protein (APP) known to result in the production of Abeta plaques, and in six elderly wild-type litter mates (age 21.8+/-1.6 months; 29.5+/-4.7 g). Dynamic PET scans were performed for 30 min in each mouse under 1% isoflurane inhalation anesthesia after a bolus injection of 13-46 MBq of [11C]6-OH-BTA-1. PET data were reconstructed with 3D OSEM. On the coronal PET image, irregular regions of interest (ROIs) were placed on frontal cortex (FR), parietal cortex (PA), striatum (ST), thalamus (TH), pons (PO), and cerebellum (CE), guided by a mouse stereotaxic atlas. Time-activity curves (TACs) (expressed as percent injected dose per gram normalized to body weight: % ID-kg/g) were obtained for FR, PA, ST, TH, PO, and CE. ROI-to-CE radioactivity ratios were also calculated. Following PET scans, sections of mouse brain prepared from anesthetized and fixative-perfused mice were stained with thioflavin-S. RESULTS: TACs for [11C]6-OH-BTA-1 in all ROIs peaked early (at 30-55 s), with radioactivity washing out quickly thereafter in both transgenic and wild-type mice. Peak uptake in all regions was significantly lower in transgenic mice than in wild-type mice. During the later part of the washout phase (12-30 min), the mean FR/CE and PA/CE ratios were higher in transgenic than in wild-type mice (1.06+/-0.04 vs 0.98+/-0.07, p=0.04; 1.06+/-0.09 vs 0.93+/-0.08 p=0.02) while ST/CE, TH/CE, and PO/CE ratios were not. Ex vivo staining revealed widespread Abeta plaques in cortex, but not in cerebellum of transgenic mice or in any brain regions of wild-type mice. CONCLUSION: Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Abeta plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Abeta plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Abeta plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.

Alzheimer Disease↗
PubMed2001

Expression of Sox9 and type IIA procollagen during attempted repair of articular cartilage damage in a transgenic mouse model of osteoarthritis.

OBJECTIVE: To determine the capacity of chondrocytes in aging and degenerating articular cartilage to produce major components of the extracellular matrix and maintain the normal structure of articular cartilage in a transgenic mouse model of osteoarthritis. METHODS: Transcription factor Sox9 was used as an indicator of the activation and maintenance of the articular chondrocyte phenotype. Knee joints of Del1 mice carrying 6 copies of the pro alpha1(II) collagen transgene with a short deletion mutation were analyzed at the age of 10 days and at 2, 3, 4, 6, 9, and 15 months by Northern hybridization, RNase protection assay, quantitative reverse transcription-polymerase chain reaction, and immunohistochemistry. Nontransgenic littermates were used as controls. RESULTS: We demonstrated the presence of Sox9 in articular chondrocytes during development, growth, and aging, with the highest messenger RNA levels during the period of rapid growth. With the appearance of degenerative lesions in articular cartilage, 2 repair processes were observed. Local proliferation and activation of chondrocytes rich in Sox9, surrounded by type IIA procollagen and proteoglycans, was seen in articular cartilage. In contrast, metabolically inactive chondrocytes were observed at the margins of the defects. They were devoid of Sox9 and were surrounded by a proteoglycan-poor matrix. Sometimes, the lesions were filled with repair tissue that contained type III collagen but little proteoglycan or type II collagen. CONCLUSION: The results indicate that chondrocytes in mature articular cartilage are capable of inducing the production of Sox9 and type IIA procollagen, which is typical of early chondrogenesis. Degenerative defects in the knee joints of transgenic Del1 mice are associated with local activation of chondrocytes, which probably contributes to the repair process. In other areas, the repair process produces a noncartilaginous matrix, which is insufficient to maintain the integrity of articular cartilage and which allows degeneration to proceed.

Aggrecans↗
PubMed2006

Chronic administration of olanzapine induces metabolic and food intake alterations: a mouse model of the atypical antipsychotic-associated adverse effects.

RATIONALE: Most of atypical antipsychotics (AAPs) are highly related to a major risk of metabolic drawbacks leading to dyslipidemia and obesity. OBJECTIVE: To set up a mouse model of the AAP-associated weight gain in mice under the influence of chronic olanzapine regimen. MATERIALS AND METHODS: Female mice were housed in pairs and habituated to spontaneous feeding with a high-palatable diet (10% sucrose wet mash). Firstly, we orally administered olanzapine (0.75, 1.5 and 3 mg/kg), evaluating body weight and periuterine fat mass, as well as insulin, non-esterified fatty acids, triglycerides, and glucose levels. In a second experiment, we assessed the effect of olanzapine on energy expenditure through indirect calorimetry (IC). A third experiment was conducted to investigate the effects of olanzapine on a high fat-high sweet palatable diet (10% sucrose + 30% fat, HF-HS) in mice implanted with subcutaneous osmotic mini-pumps. Locomotor activity was also assessed. RESULTS: In experiment 1, the highest dose of chronically administered olanzapine (3 mg/kg) induced significant weight gain accompanied by augmentation of periuterine fat depots, with no changes in locomotor activity. In experiment 2, chronic administration did not alter energy expenditure, whereas, decreased respiratory quotient (RQ). In experiment 3, subcutaneously infused olanzapine evidenced a dose and time-dependent increase of body weight and HF-HS diet consumed. Notably, serum analyses revealed a hyperinsulinemia together with increased levels of triglycerides and glucose. CONCLUSIONS: In this study, we describe in female mice metabolic alterations matching the metabolic syndrome, thus resembling the clinical situation of schizophrenic patients taking AAPs.

Administration, Oral↗