scholarly journals Spontaneous Facet Joint Osteoarthritis in NFAT1-Mutant Mice

2021 ◽  
Author(s):  
Jinxi Wang ◽  
Qinghua Lu ◽  
Matthew J. Mackay ◽  
Xiangliang Liu ◽  
Yi Feng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Scoring System ◽  
Structural Changes ◽  
Facet Joint ◽  
Mutant Mice ◽  
Facet Joints ◽  
Wild Type ◽  
Tissue Specific ◽  
Facet Joint Osteoarthritis ◽  
Gene And Protein Expression

ABSTRACTObjectivesAlthough rodent models of traumatically or chemically induced intervertebral facet joint osteoarthritis (FJOA) were previously described, the characteristics of spontaneous FJOA animal models have not been documented. This study aimed to identify the characteristics of a murine model of spontaneous FJOA and its underlying mechanisms.MethodsThe lumbar facet joints of mutant mice carrying a disrupted NFAT1 (nuclear factor of activated T cells 1) allele and of wild-type control mice were examined by histochemistry, quantitative gene expression analysis, immunohistochemistry, and histomorphometry using a novel FJOA scoring system at 2, 6, 12, and 18 months of age. The reproducibility of the FJOA scoring system was analyzed by inter-observer and intra-observer variability tests. Tissue-specific histomorphometric and gene expression changes were statistically analyzed.ResultsNFAT1-mutant facet joints displayed dysfunction of articular chondrocytes and synovial cells with aberrant gene and protein expression in cartilage and synovium as early as 2 months, followed by osteoarthritic structural changes such as articular surface fissuring and chondro-osteophyte formation at 6 months. Deeper cartilage lesions, synovitis, separation of cartilage from thickened subchondral bone, and tissue-specific molecular and cellular alterations in NFAT1-mutant facet joints became evident at 12 and 18 months. Osteoarthritic structural changes were not detected in wild-type facet joints at any ages, though age-related cartilage degeneration was observed at 18 months.ConclusionsUsing NFAT1-mutant mice, this study has identified for the first time an animal model of spontaneous FJOA with age-dependent osteoarthritic characteristics, developed the first FJOA scoring system, and elucidated the molecular mechanisms of NFAT1 mutation-mediated FJOA.

scholarly journals Transgenic Approaches for Cyanogen Reduction in Cassava

2007 ◽  
Vol 90 (5) ◽  
pp. 1450-1455 ◽  
Author(s):  
Dimuth Siritunga ◽  
Richard Sayre
Keyword(s):  
Gene Expression ◽  
Potential Benefit ◽  
Fold Increase ◽  
Selective Inhibition ◽  
Alternative Strategy ◽  
Specific Inhibition ◽  
Cyanogenic Glycoside ◽  
Wild Type ◽  
Hydroxynitrile Lyase ◽  
Tissue Specific

Abstract For cassava to become a safe and acceptable crop, it is necessary to reduce the cyanogen levels in cassava foods. While this objective can be achieved by processing procedures, recent findings have shown that it is also possible to achieve it by suppression of cyanogen synthesis or by accelerating cyanogen turnover and volatilization. In 2003, cyanogen-free cultivars were generated by selective inhibition CYP79D1/D2 gene expression. The CYP79D1/D2 enzymes catalyze the first-dedicated step in cyanogen synthesis. Tissue-specific inhibition of CYP79D1/D2 expression in leaves lead to a 99 reduction in root cyanogen levels, indicating that the cyanogenic glycoside, linamarin, is synthesized in leaves and transported to roots. An alternative strategy to the reduce cyanogen content is to enhance cyanogen detoxification and cyanide volatilization during processing. This strategy has the advantage that cyanogen levels in unprocessed roots are not altered, potentially providing protection against herbivory and/or theft. To produce cultivars that promote rapid cyanide volatilization, hydroxynitrile lyase (HNL), which catalyzes the last step in cyanogenesis, was overexpressed in roots. Elevated HNL activity resulted in a 3-fold increase in the rate of cyanogen turnover. Importantly, the cyanogen content of the transformed and wild-type plants was identical, a potential benefit for farmers.

Clockmutation facilitates accumulation of cholesterol in the liver of mice fed a cholesterol and/or cholic acid diet

2008 ◽  
Vol 294 (1) ◽  
pp. E120-E130 ◽  
Author(s):  
Takashi Kudo ◽  
Mihoko Kawashima ◽  
Toru Tamagawa ◽  
Shigenobu Shibata
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Cholic Acid ◽  
Mouse Liver ◽  
Clock Genes ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mutant Mice ◽  
Wild Type ◽  
Clock Mutant

Cholesterol (CH) homeostasis in the liver is regulated by enzymes of CH synthesis such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and catabolic enzymes such as cytochrome P-450, family 7, subfamily A, and polypeptide 1 (CYP7A1). Since a circadian clock controls the gene expression of these enzymes, these genes exhibit circadian rhythm in the liver. In this study, we examined the relationship between a diet containing CH and/or cholic acid (CA) and the circadian regulation of Hmgcr, low-density lipoprotein receptor ( Ldlr), and Cyp7a1 gene expression in the mouse liver. A 4-wk CA diet lowered and eventually abolished the circadian expression of these genes. Not only clock genes such as period homolog 2 (Drosophila) ( Per2) and brain and muscle arnt-like protein-1 ( Bmal1) but also clock-controlled genes such as Hmgcr, Ldlr, and Cyp7a1 showed a reduced and arrhythmic expression pattern in the liver of Clock mutant mice. The reduced gene expression of Cyp7a1 in mice fed a diet containing CA or CH + CA was remarkable in the liver of Clock mutants compared with wild-type mice, and high liver CH accumulation was apparent in Clock mutant mice. In contrast, a CH diet without CA only elevated Cyp7a1 expression in both wild-type and Clock mutant mice. The present findings indicate that normal circadian clock function is important for the regulation of CH homeostasis in the mouse liver, especially in conjunction with a diet containing high CH and CA.

Iron absorption and hepatic iron uptake are increased in a transferrin receptor 2 (Y245X) mutant mouse model of hemochromatosis type 3

2007 ◽  
Vol 292 (1) ◽  
pp. G323-G328 ◽  
Author(s):  
S. F. Drake ◽  
E. H. Morgan ◽  
C. E. Herbison ◽  
R. Delima ◽  
R. M. Graham ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Transferrin Receptor ◽  
Mutant Mouse ◽  
Hereditary Hemochromatosis ◽  
Mutant Mice ◽  
Wild Type ◽  
Hepcidin Expression ◽  
Fe Uptake ◽  
Type 3

Hereditary hemochromatosis type 3 is an iron (Fe)-overload disorder caused by mutations in transferrin receptor 2 (TfR2). TfR2 is expressed highly in the liver and regulates Fe metabolism. The aim of this study was to investigate duodenal Fe absorption and hepatic Fe uptake in a TfR2 (Y245X) mutant mouse model of hereditary hemochromatosis type 3. Duodenal Fe absorption and hepatic Fe uptake were measured in vivo by 59Fe-labeled ascorbate in TfR2 mutant mice, wild-type mice, and Fe-loaded wild-type mice (2% dietary carbonyl Fe). Gene expression was measured by real-time RT-PCR. Liver nonheme Fe concentration increased progressively with age in TfR2 mutant mice compared with wild-type mice. Fe absorption (both duodenal Fe uptake and transfer) was increased in TfR2 mutant mice compared with wild-type mice. Likewise, expression of genes participating in duodenal Fe uptake ( Dcytb, DMT1) and transfer (ferroportin) were increased in TfR2 mutant mice. Nearly all of the absorbed Fe was taken up rapidly by the liver. Despite hepatic Fe loading, hepcidin expression was decreased in TfR2 mutant mice compared with wild-type mice. Even when compared with Fe-loaded wild-type mice, TfR2 mutant mice had increased Fe absorption, increased duodenal Fe transport gene expression, increased liver Fe uptake, and decreased liver hepcidin expression. In conclusion, despite systemic Fe loading, Fe absorption and liver Fe uptake were increased in TfR2 mutant mice in association with decreased expression of hepcidin. These findings support a model in which TfR2 is a sensor of Fe status and regulates duodenal Fe absorption and liver Fe uptake.

Cervical Facet Dysfunction

2018 ◽  
Author(s):  
Sandeep Amin
Keyword(s):  
Structural Changes ◽  
Facet Joint ◽  
Diagnostic Tools ◽  
Evidence Based ◽  
Facet Joints ◽  
Whiplash Injuries ◽  
Axial Neck Pain ◽  
Cervical Facet ◽  
Cervical Facet Joint ◽  
Specific Orientation

Cervical facet dysfunction poses a diagnostic and therapeutic dilemma in patients with axial neck pain due to either degenerative changes or whiplash injuries as it presents with a paucity of diagnostic radiologic or examination findings. The specific orientation of the cervical facet joints renders them particularly vulnerable to whiplash injury. This chapter examines the clinically relevant anatomy with nuances unique to the cervical spine, etiology of the structural changes, diagnostic tools, and treatment of cervical facet dysfunction. Understanding the relevant anatomy and referral patterns of cervical facet joints allows for more targeted diagnosis and treatment. There are strong evidence-based options in the treatment of cervical facet joint dysfunction.

scholarly journals Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jessica A. Jiménez ◽  
Travis S. Ptacek ◽  
Alex H. Tuttle ◽  
Ralf S. Schmid ◽  
Sheryl S. Moy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cerebral Cortex ◽  
Er Stress ◽  
Stop Codon ◽  
Autism Spectrum ◽  
Mutant Mice ◽  
Wild Type ◽  
Age Related ◽  
Transcriptional Changes ◽  
Regulated Gene Expression

Abstract Background Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. Methods We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months). Results Chd8V986*/+ mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8V986*/+ mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8V986*/+ crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8V986*/+ mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8V986*/+ mice, whereas genes associated with the c-MET signaling pathway were increased in expression. Limitations It is unclear whether the transcriptional changes observed with age in Chd8V986*/+ mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. Conclusions Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8V986*/+ mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8V986*/+ mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice.

Abstract 632: Aortic Dilatation in Marfan Syndrome: A Result of Amplification of Molecular Mechanisms of Aging?

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Michael A Hagler ◽  
Grace Casaclang-Verzosa ◽  
Bin Zhang ◽  
Carolyn Roos ◽  
Nassir Thalji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Marfan Syndrome ◽  
Aortic Root ◽  
Expression Patterns ◽  
Mutant Mice ◽  
Aortic Dilatation ◽  
Mrna Levels ◽  
Wild Type ◽  
Fibrillin 1 ◽  
Tgf Β1

Marfan syndrome (MFS) is a genetic disease with a mutation for the microfibrillar constituent protein fibrillin-1 being the most prevalent. MFS is often associated with progressive aortic root dilation, ultimately progressing to aortic aneurysm and dissection. While recent work has shown that increased angiotensin-II receptor type-1 and transforming growth factor beta (TGF-β) signaling contributes to aneurysm formation in aorta, efficacious therapeutic targets remain elusive. Given previous reports of progeriod phenotypes in a subset of Marfan patients, we sought to determine whether there are molecular changes that are consistent with accelerated aging in a mouse model of Marfan syndrome. In mice carrying a loss-of-function mutation in fibrillin-1, we assessed aortic root dimensions by echocardiography and gene expression levels of TGF-β1-3, runt related transcription factor 2 (RUNX2), and the cellular senescent marker CDKN2A by quantitative real time PCR at 3 and 14 months of age. As expected, aortic sinus dimensions did not change significantly with aging in wild type mice, but increased dramatically in fibrillin-1 mutant mice compared to wild-type littermate controls and with age (p < 0.05 for both). TGF-β1 ligand expression paralleled age and disease-dependent changes in aortic dimensions, however TGF-β2 and TGF-β3 mRNA levels did not. Aortic dilatation was associated with increased gene expression of RUNX2 with aging and in marfanoid mice. Interestingly, fibrillin-1 mutant mice demonstrated marked increases in expression of the anti-proliferative cell-cycle checkpoint protein CDKN2A at both time points, and correlated with changes in TGF-β1 (R 2 =0.54) and RUNX2 (R 2 =0.69) mRNA. CDNK2A gene expression patterns, however, demonstrated a poor correlation with expression of TGF-β2 and TGF-β3 (R 2 =0.04 and 0.06. respectively). Collectively, these data lend insight into novel mechanisms that may regulate development of aortic root dilation in patients MFS and are the first to implicate increased senescent cell burden in Marfan syndrome. Furthermore, we propose that clearance of senescent cells could be a viable therapeutic intervention to slow progression aortic root-dilation and aneurysm in patients with Marfan syndrome.

scholarly journals Organism-wide single-cell transcriptomics of long-lived C. elegans daf-2-/- mutants reveals tissue-specific reprogramming of gene expression networks

2019 ◽  
Author(s):  
Jessica L. Preston ◽  
Nicholas Stiffler ◽  
Maggie Weitzman
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Expression Profiles ◽  
Regulation Of Gene Expression ◽  
Gene Expression Profiles ◽  
Machine Learning Algorithms ◽  
Wild Type ◽  
Tissue Specific ◽  
C Elegans ◽  
Specific Regulation

AbstractA critical requirement for a systems-level understanding of complex biological processes such as aging is the ability to directly characterize interactions between cells and tissues within a multicellular organism. C. elegans nematodes harboring mutations in the insulin-like receptor daf-2 exhibit dramatically-increased lifespans. To identify tissue-specific biochemical mechanisms regulating aging plasticity, we single-cell sequenced 3’-mRNA libraries generated from seven populations of whole day-one adult wild-type and daf-2-/- worms using the 10x ChromiumV1™platform. The age-synchronized samples were bioinformatically merged into a single aligned dataset containing 40,000 age-synchronized wild-type and daf-2-/- cellular transcriptomes partitioned into 101 clusters, using unsupervised machine-learning algorithms to identify common cell types. Here we describe the basic features of the adult C. elegans single-cell transcriptome and summarize functional alterations observed in the gene expression profiles of long-lived daf-2-/- worms. Comprehensive methods and datasets are provided. This is the first study to directly quantify cell-specific differential gene expression between two age-synchronized, genetically-distinct populations of multicellular organisms. This novel approach answers fundamental questions regarding tissue-specific regulation of gene expression and helps to establish a foundation for a comprehensive C. elegans single-cell gene expression atlas.

scholarly journals Elevated inflammatory gene expression in intervertebral disc tissues in mice with ADAM8 inactivated

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yejia Zhang ◽  
Zuozhen Tian ◽  
David Gerard ◽  
Lutian Yao ◽  
Frances S. Shofer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intervertebral Disc ◽  
Inflammatory Markers ◽  
Polarized Light ◽  
Mutant Mice ◽  
Wild Type ◽  
Fiber Assembly ◽  
Complete Inactivation ◽  
Elevated Expression ◽  
Inflammatory Processes

AbstractWe found ADAM8 enzymatic activity elevated in degenerative human intervertebral disc (IVD). Here, we examined the discs in ADAM8-inactivation mice that carry a mutation preventing self-activation of the enzyme. Surprisingly, elevated gene expression for inflammatory markers (Cxcl1, IL6) was observed in injured discs of ADAM8 mutant mice, along with elevated expression of type 2 collagen gene (Col2a1), compared with wild type controls. Injured annulus fibrosus of mutant and wild type mice contained a higher proportion of large collagen fibers compared with intact discs, as documented by microscopic examination under circular polarized light. In the intact IVDs, Adam8EQ mouse AF contained lower proportion of yellow (intermediate) fiber than WT mice. This suggests that ADAM8 may regulate inflammation and collagen fiber assembly. The seemingly contradictory findings of elevated inflammatory markers in mutant mice and excessive ADAM8 activity in human degenerative discs suggest that ADAM8 may interact with other enzymatic and pro-inflammatory processes needed for tissue maintenance and repair. As a future therapeutic intervention to retard intervertebral disc degeneration, partial inhibition of ADAM8 proteolysis may be more desirable than complete inactivation of this enzyme.

Effect of CT-based attenuation correction on uptake ratios in skeletal SPECT

2007 ◽  
Vol 46 (01) ◽  
pp. 38-42 ◽  
Author(s):  
V. Schulz ◽  
I. Nickel ◽  
A. Nömayr ◽  
A. H. Vija ◽  
C. Hocke ◽  
...  
Keyword(s):  
Vertebral Body ◽  
Facet Joint ◽  
One Dimension ◽  
Patient Specific ◽  
Data Sets ◽  
Facet Joints ◽  
Lumbar Vertebral Body ◽  
Ct System ◽  
Ct Data ◽  
Attenuation Corrected

SummaryThe aim of this study was to determine the clinical relevance of compensating SPECT data for patient specific attenuation by the use of CT data simultaneously acquired with SPECT/CT when analyzing the skeletal uptake of polyphosphonates (DPD). Furthermore, the influence of misregistration between SPECT and CT data on uptake ratios was investigated. Methods: Thirty-six data sets from bone SPECTs performed on a hybrid SPECT/CT system were retrospectively analyzed. Using regions of interest (ROIs), raw counts were determined in the fifth lumbar vertebral body, its facet joints, both anterior iliacal spinae, and of the whole transversal slice. ROI measurements were performed in uncorrected (NAC) and attenuation-corrected (AC) images. Furthermore, the ROI measurements were also performed in AC scans in which SPECT and CT images had been misaligned by 1 cm in one dimension beforehand (ACX, ACY, ACZ). Results: After AC, DPD uptake ratios differed significantly from the NAC values in all regions studied ranging from 32% for the left facet joint to 39% for the vertebral body. AC using misaligned pairs of patient data sets led to a significant change of whole-slice uptake ratios whose differences ranged from 3,5 to 25%. For ACX, the average left-to-right ratio of the facet joints was by 8% and for the superior iliacal spines by 31% lower than the values determined for the matched images (p <0.05). Conclusions: AC significantly affects DPD uptake ratios. Furthermore, misalignment between SPECT and CT may introduce significant errors in quantification, potentially also affecting leftto- right ratios. Therefore, at clinical evaluation of attenuation- corrected scans special attention should be given to possible misalignments between SPECT and CT.

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