scholarly journals The role of VNTR aggrecan gene polymorphism in the development of osteoarthritis in women

2018 ◽  
Vol 22 (7) ◽  
pp. 865-872
Author(s):  
D. A. Shapovalova ◽  
A. V. Tyurin ◽  
S. S. Litvinov ◽  
E. K. Khusnutdinova ◽  
R. I. Khusainova
Keyword(s):  
Connective Tissue ◽  
Variable Number ◽  
Pathological Process ◽  
Joint Disease ◽  
Vntr Locus ◽  
Knee Oa ◽  
Vntr Polymorphism ◽  
Homozygous Genotype ◽  
Compressive Loads ◽  
Nucleotide Repeats

Osteoarthritis (OA) is a common multifactorial joint disease. Undifferentiated connective tissue dysplasia (uCTD) is a genetically determined lesion of the connective tissue structures, including joints, and it can be one of the factors predisposing to development of OA. Solving the problem of comorbidity of OA and uCTD signs will contribute to the early diagnosis and prophylactics of OA. Aggrecan is one of the major structural components of cartilage and it provides the ability to resist compressive loads throughout life. We examined 316 women (mean age 50.5 ± 4.77) for signs of uCTD and OA. A study of the aggrecan gene (ACAN) VNTR polymorphism, which is represented by a variable number of 57 nucleotide repeats, was performed. We searched for associations between the VNTR locus and OA in general and with an account of the localization of the pathological process, as well as with the presence of uCTD signs. Twelve allelic variants and 24 genotypes of the VNTR polymorphism of the aggrecan gene (ACAN) were identified, the most frequent variants were alleles with 27, 28 and 26 repeats. A significance of allele *27 (х2= 6.297, p = 0.012, odds ratio (OR) = 1.50; 95 % confidence interval (CI) 1.09-2.05) in the development of OA in general, knee OA (х2= 4.613, p = 0.031, OR = 1.52; 95 % CI 1.04-2.23), and multiple OA (х2= 4.181, p = 0.04, OR = 1.68; 95 % CI 1.02-2.78) was revealed. Homozygous genotype *27*27 was associated with OA (х2= 3.921, р = 0.047, OR = 1.72; 95 % CI 1-2.96), and OA with uCTD signs in women (х2= 5.415, p = 0.019, OR = 2.34; 95 % CI 1.13-4.83).

scholarly journals Small Noncoding RNAs in Knee Osteoarthritis: The Role of MicroRNAs and tRNA-Derived Fragments

2021 ◽  
Vol 22 (11) ◽  
pp. 5711
Author(s):  
Julian Zacharjasz ◽  
Anna M. Mleczko ◽  
Paweł Bąkowski ◽  
Tomasz Piontek ◽  
Kamilla Bąkowska-Żywicka
Keyword(s):  
Knee Osteoarthritis ◽  
Noncoding Rnas ◽  
Pathological Process ◽  
Joint Disease ◽  
Limited Information ◽  
Genetic Changes ◽  
Small Noncoding Rnas ◽  
Knee Oa ◽  
Cartilage Homeostasis

Knee osteoarthritis (OA) is a degenerative knee joint disease that results from the breakdown of joint cartilage and underlying bone, affecting about 3.3% of the world's population. As OA is a multifactorial disease, the underlying pathological process is closely associated with genetic changes in articular cartilage and bone. Many studies have focused on the role of small noncoding RNAs in OA and identified numbers of microRNAs that play important roles in regulating bone and cartilage homeostasis. The connection between other types of small noncoding RNAs, especially tRNA-derived fragments and knee osteoarthritis is still elusive. The observation that there is limited information about small RNAs different than miRNAs in knee OA was very surprising to us, especially given the fact that tRNA fragments are known to participate in a plethora of human diseases and a portion of them are even more abundant than miRNAs. Inspired by these findings, in this review we have summarized the possible involvement of microRNAs and tRNA-derived fragments in the pathology of knee osteoarthritis.

scholarly journals POS0375 CHAPERONE-MEDIATED AUTOPHAGY IS A HALLMARK OF JOINT DISEASE IN OSTEOARTHRITIC PATIENTS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 418.1-418
Author(s):  
I. Lorenzo ◽  
U. Nogueira-Recalde ◽  
N. Oreiro ◽  
J. A. Pinto Tasende ◽  
M. Lotz ◽  
...  
Keyword(s):  
Lateral Meniscus ◽  
Joint Damage ◽  
Joint Disease ◽  
Expression Array ◽  
Knee Oa ◽  
Human Knee Joint ◽  
Gene And Protein Expression ◽  
Functional Consequences ◽  
Chaperone Mediated Autophagy ◽  
Grade Iii

Background:In Osteoarthritis (OA), defects in macroautophagy (autophagy) are evident and precede joint damage. Indeed, pharmacological activation of autophagy protects against joint damage.Objectives:Therefore, identifying hallmarks associated with specific autophagy subtypes could shed light to fundamental mechanisms of joint disease.Methods:A comparative analysis of 35 autophagy genes was performed from blood from the Prospective OA Cohort of A Coruña (PROCOAC). Non-OA subjects (Age:61,44±1,16 years; BMI:25,25±0,52; Females, n=18) and Knee OA subjects (Age:65,50±1,05 years; BMI:29,55±0,67; Females, n=18, OA grade III-IV) were profiled using an autophagy gene expression array by SYBR green qPCR. Confirmatory studies were performed in blood from Non-OA subjects (Age:60,13±1,12 years; BMI:24,85±0,59; Females; n=30) and Knee-OA subjects (Age:68,4±1,11 years; BMI:29,65±0,55; Females; n=30, OA grade III-IV) by Taqman qPCR. The candidate gene was evaluated in human knee joint tissues (cartilage, meniscus, ligaments, synovium) with different KL grades (Age: KL0=28,3±4,50; KL2=77±6,08; KL4=62,3±3,05, n=3) and in both spontaneous aging (2, 6, 12, 18, and 30 months old, n=3) and surgically-induced OA (10 weeks after surgery, n=4) in mice by IHC. The functional consequences were studied in T/C28a2 and primary human OA chondrocytes. Autophagy, FOXO, Chaperone-mediated autophagy (CMA), inflammation, and cellular senescence were analyzing by gene and protein expression. Moreover, oxidative stress and cell death were evaluated by FACS. The contribution of CMA to chondrocyte homeostasis was evaluated by studying the capacity of CMA to restore proteostasis upon autophagy deficiency by siATG5.Results:15 autophagy-related genes were significantly downregulated in blood from knee OA patients compared to non-OA patients. No significant upregulation was found for any studied gene, although a trend towards upregulation was found in genes involved in the mTOR pathway. Four key autophagy-related genes, including ATG16L2, ATG12, ATG4B and MAP1LC3B were found downregulated in knee OA patients. Interestingly, HSP90AA1 and HSPA8, CMA markers involved in stress response and protein folding, were downregulated. Confirmatory studies showed a significant downregulation of MAP1LC3B and HSP90AA1 in blood from knee OA patients. Remarkably, HSP90A was found reduced in femoral cartilage (medial and lateral), meniscus and ACL. Moreover, this reduction was higher in medial cartilage compared to lateral cartilage and meniscus, while in synovial membrane, HSP90A expression was found increased. This expression signature was dependent on OA grade severity. In addition, we observed a decrease of HSP90A with aging and OA in mice. The functional consequences of HSP90AA1 gene silencing are related to an increase in NFκB, MMP13, and p16 expression. Interestingly, LAMP2A, a key CMA mediator, HSPA8, MAP1LC3B and FoxO1 expression were upregulated in chondrocytes with HSP90AA1 deficiency, which might indicate an early response to maintain homeostasis. On the other hand, LAMP2A protein is decreased upon HSP90AA1 deficiency, while LC3II and p62 were increased, indicating a failure in the autophagy flux that leads to impaired lysosomal degradation.Moreover, p21, p16 and prbS6 were increased upon HSP90AA1 deficiency, besides increasing mitochondrial ROS production and apoptosis. ATG5 silencing blocks autophagy by reducing LC3II and increasing prbs6, p62, p16 and p21. Interestingly, LAMP2A and HSP90A were found increased, indicating a possible compensative activation of CMA in response to autophagy defects. These results support that HSP90A has an important role in chondrocyte homeostasis by participating in the cross-talk between CMA and autophagy.Conclusion:Taking together, we identified HSP90A, a CMA regulator, as critical in chondrocyte homeostasis. These disease mechanisms are relevant in OA and constitute hallmarks potentially useful to prevent OA progression.References:[1]Caramés B, et al. Arthritis Rheum. 2010, 2015;[2]Caramés B, et al. Ann Rheum Dis. 2012.Disclosure of Interests:None declared

scholarly journals Geno-phenotypic characteristics of Ehlers–Danlos syndrome: difficulties of disease type identification and approaches to pathogenetic treatment

2021 ◽  
Vol 66 (1) ◽  
pp. 22-30
Author(s):  
E. A. Nikolaeva ◽  
A. N. Semyachkina
Keyword(s):  
Connective Tissue ◽  
Clinical Symptoms ◽  
Molecular Genetic ◽  
Symptomatic Treatment ◽  
Pathological Process ◽  
Social Adaptation ◽  
Molecular Defect ◽  
Ehlers Danlos Syndrome ◽  
Pathogenetic Therapy ◽  
Danlos Syndrome

Veltischev Researchand Clinical Institutefor Pediatricsofthe Pirogov Russian National Research Medical University, Moscow, Russia The article presents modern data on the most common monogenic connective tissue disease – Ehlers–Danlos syndrome. The authors describe two previous classifications of the syndrome: Berlin (1988) classification, which distinguishes 11 types of the disease, and Beyton (1998) classification, which includes 6 types of the syndrome and takes into account the results of molecular genetic studies. Particular attention is paid to a new classification, proposed by the International Consortium in 2017. This classification is based on the clinical and molecular genetic data and unites 13 types of Ehlers–Danlos syndrome, divided in 7 groups (A–G), depending on the main molecular defect. This defect determines the violation of various collagen structures (primary, spatial, cross-linking) and others constituents of the connective tissue (myomatrix, glycosaminoglycans, complement component, etc.). The classification provides general clinical symptoms for all types of the disease and comprehensive information on the specific signs of each of the 13 types of the syndrome.The authors discuss approaches to the pathogenetic therapy of the syndrome, the possibilities of symptomatic treatment, including both medications of different spectrum of action, and physiotherapeutic measures, exercise therapy. The complex of the listed therapeutic measures is aimed at stabilizing the main pathological process, preventing complications, improving the patient’s quality of life and social adaptation. The authors emphasize that correct patient management, targeted medical supervision and medical genetic counseling requires molecular genetic verification of the diagnosis.

scholarly journals USP7 Inhibition Alleviates H2O2-Induced Injury in Chondrocytes via Inhibiting NOX4/NLRP3 Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Gang Liu ◽  
Qingbai Liu ◽  
Bin Yan ◽  
Ziqiang Zhu ◽  
Yaozeng Xu
Keyword(s):  
Treatment Options ◽  
Current Treatment ◽  
Pathological Process ◽  
Joint Disease ◽  
Matrix Remodeling ◽  
Ros Production ◽  
Caspase 1 ◽  
Enhanced Production

Osteoarthritis (OA), the most common form of arthritis, is a very common joint disease that often affects middle-aged to elderly people. However, current treatment options for OA are predominantly palliative. Thus, understanding its pathological process and exploring its potential therapeutic approaches are of great importance. Rat chondrocytes were isolated and exposed to hydrogen peroxide (H2O2) to mimic OA. The effects of H2O2 on ubiquitin-specific protease 7 (USP7) expression, reactive oxygen species (ROS) levels, proliferation, inflammatory cytokine release, and pyroptosis were measured. USP7 was knocked down (KD) or overexpressed to investigate the role of USP7 in OA. Co-immunoprecipitation (Co-IP) was used to study the interaction between USP7 and NAD(P)H oxidases (NOX)4 as well as NOX4 ubiquitination. NOX4 inhibitor was applied to study the involvement of NOX4 in USP7-mediated OA development. USP7 inhibitor was given to OA animals to further investigate the role of USP7 in OA in vivo. Moreover, H2O2 treatment significantly increased USP7 expression, enhanced ROS levels, and inhibited proliferation in rat chondrocytes. The overexpression of USP7 enhanced pyroptosis, ROS production, interleukin (IL)-1β and IL-18 levels, and the expression level of NLRP3, GSDMD-N, active caspase-1, pro-caspase-1, matrix metalloproteinases (MMP) 1, and MMP13, which was abolished by ROS inhibition. The USP7 KD protected rat chondrocytes against H2O2-induced injury. Co-IP results showed that USP7 interacted with NOX4, and USP7 KD enhanced NOX4 ubiquitinylation. The inhibition of NOX4 blocked the pro-OA effect of USP7. Moreover, the USP7 inhibitor given to OA animals suppressed OA in vivo. USP7 inhibited NOX4 ubiquitination for degradation which leads to elevated ROS production. ROS subsequently activates NLPR3 inflammasome, leading to enhanced production of IL-1β and IL-18, GSDMD-N-dependent pyroptosis, and extracellular matrix remodeling. Thus, UPS7 contributes to the progression of OA via NOX4/ROS/NLPR3 axis.

scholarly journals Differentiation of Strains of Xylella fastidiosa by a Variable Number of Tandem Repeat Analysis

2001 ◽  
Vol 67 (9) ◽  
pp. 4091-4095 ◽  
Author(s):  
Helvécio Della Coletta-Filho ◽  
Marco Aurélio Takita ◽  
Alessandra Alves de Souza ◽  
Carlos Ivan Aguilar-Vildoso ◽  
Marcos Antonio Machado
Keyword(s):  
Tandem Repeat ◽  
Rapd Analysis ◽  
Xylella Fastidiosa ◽  
Variable Number ◽  
Randomly Amplified Polymorphic Dna ◽  
Dinucleotide Repeats ◽  
Ecological Analysis ◽  
Repeat Analysis ◽  
Maximum Value ◽  
Nucleotide Repeats

ABSTRACT Short sequence repeats (SSRs) with a potential variable number of tandem repeat (VNTR) loci were identified in the genome of the citrus pathogen Xylella fastidiosa and used for typing studies. Although mono- and dinucleotide repeats were absent, we found several intermediate-length 7-, 8-, and 9-nucleotide repeats, which we examined for allelic polymorphisms using PCR. Five genuine VNTR loci were highly polymorphic within a set of 27 X. fastidiosa strains from different hosts. The highest average Nei's measure of genetic diversity (H) estimated for VNTR loci was 0.51, compared to 0.17 derived from randomly amplified polymorphic DNA (RAPD) analysis. For citrus X. fastidiosa strains, some specific VNTR loci had a Hvalue of 0.83, while the maximum value given by specific RAPD loci was 0.12. Our approach using VNTR markers provides a high-resolution tool for epidemiological, genetic, and ecological analysis of citrus-specific X. fastidiosa strains.

scholarly journals Association between the polymorphism of IL-17A and IL-17F gene with knee osteoarthritis risk: a meta-analysis based on case-control studies

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Feifan Lu ◽  
Pei Liu ◽  
Qidong Zhang ◽  
Weiguo Wang ◽  
Wanshou Guo
Keyword(s):  
Knee Osteoarthritis ◽  
Gene Polymorphisms ◽  
Meta Analysis ◽  
Case Control ◽  
Joint Disease ◽  
Cochrane Library ◽  
Case Control Studies ◽  
Knee Oa ◽  
Statistical Heterogeneity ◽  
Bone Changes

Abstract Background Knee osteoarthritis is a joint disease which is characterized by degeneration of articular cartilage and subsequent subchondral bone changes. Polymorphisms of IL-17A/F gene were the recognized candidate genes associated with knee osteoarthritis risk although the results were conflicting. The aim of this study was to determine whether IL-17A(rs2275913) and IL-17F(rs763780) polymorphisms confer susceptibility to knee osteoarthritis. Method Literature search was performed in PubMed, Medline, Cochrane Library, Web of science, Embase, and Google Scholar (last search was updated on June 20, 2019), and assessing this association was performed by calculating odds ratios with 95% confidence intervals. Statistical heterogeneity was quantitatively evaluated by using the Q statistic with its p value and I2 statistic. Result Six case-control based studies were included involving IL-17A(rs2275913) (2134 cases and 2306 controls) and IL-17F(rs763780) (2134 cases and 2426 controls). The overall analysis suggested that the A allele of the rs2275913 polymorphism, and the C allele of the rs763780 polymorphism in the IL-17 gene may increase the risk of OA. However, subgroup analysis revealed that no association between IL-17A(rs2275913) gene and knee OA risk was found in Caucasian population. Conclusions This meta-analysis revealed that the IL-17A(rs2275913) gene polymorphisms may increase the risk of knee OA in Asians, and the IL-17F(rs763780) gene polymorphisms may increase the risk of knee OA both in Asians and Caucasians. However, because of the limitations of the present study, additional larger studies are needed to confirm our findings in the future.

Association of a Variable Number of Tandem Repeats (VNTR) in Glycoprotein Ibα and HPA-2 Alloantigens

1994 ◽  
Vol 72 (05) ◽  
pp. 757-761 ◽  
Author(s):  
S Simsek ◽  
P M M Bleeker ◽  
C E van der Schoot ◽  
A E G Kr von dem Borne
Keyword(s):  
Amino Acid ◽  
Tandem Repeats ◽  
Mononuclear Cells ◽  
Human Platelet ◽  
Strong Association ◽  
Variable Number ◽  
Platelet Glycoprotein ◽  
Globular Domain ◽  
Vntr Polymorphism ◽  
Pcr Products

SummaryThe human platelet alloantigen HPA-2 (Koa/Kob) system is involved in two clinical syndromes, neonatal alloimmune thrombocytopenia and platelet transfusion refractoriness. Wb have previously described that the human platelet alloantigens HPA-2a(Kob) and HPA-2b(Koa), are caused by a Thrl45Met amino acid polymorphism in the N-terminal globular domain of the human platelet glycoprotein (GP) Ibα. In the present study the question was addressed as to whether a genetic association exists between this Thrl45Met polymorphism and the recently described variable number of tandem repeat (VNTR) polymorphism in GP Ibα. Such an association has already been suggested by serological analysis (Ishida et al., 1991). This VNTR polymorphism results from a 13-amino-acid sequence repeat in the macroglycopeptide region of GP Ibα. Therefore, we developed a PCR method to analyze the VNTR region of 106 normal individuals who were also analyzed for the HPA-2 polymorphism. In this method genomic DNA derived from mononuclear cells was purified, the polymorphic region was amplified by PCR and was electrophoresed on agarose gels. Differences in the size of the PCR products made VNTR typing possible. Genotyping for the HPA-2 system was done by allele-specific restriction site analysis of PCR products with the restriction enzyme Sfa NI. The DNA derived from 12 HPA-2 (a-b+) subjects, contained only the B variant (with 3 repeats) of the VNTR polymorphism. The D variant (with 1 repeat) was only found in HPA-2a positive individuals. The C variant (with 2 repeats) was found to be strongly associated with HPA-2a. However, two members of a family with a HPA-2 (a+b+) genotype were found to be homozygous for the C variant of the VNTR polymorphism. This shows that the C variant can also be associated with HPA-2b. The A variant (with 4 repeats) was not encountered in the population studied. The strong association of HPA-2 and VNTR polymorphism, lying 761 bp apart on the GP Ibα gene, indicates linkage disequilibrium.

scholarly journals Divergent Mononuclear Cell Participation and Cytokine Release Profiles Define Hip andKnee Osteoarthritis

2019 ◽  
Vol 8 (10) ◽  
pp. 1631 ◽  
Author(s):  
Grieshaber-Bouyer ◽  
Kämmerer ◽  
Rosshirt ◽  
Nees ◽  
Koniezke ◽  
...  
Keyword(s):  
T Cells ◽  
Knee Osteoarthritis ◽  
Mononuclear Cell ◽  
Synovial Membrane ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Joint Disease ◽  
Cytokine Release ◽  
Knee Oa ◽  
Release Profiles

Osteoarthritis (OA) is a progressive joint disease driven by a blend of inflammatory and biomechanical processes. Studies using human samples to understand inflammatory mechanisms in OA frequently recruit OA patients with different affected joints, even though recent evidence indicates that OA is a heterogeneous disease which only culminates in a common end point. Differences in age of onset and the dynamics of disease progression suggest that different joints may represent different disease entities, thereby diluting the discovery potential in a combined analysis. We hypothesized that different OA joints may also differ in immunopathology within the synovium. To investigate this hypothesis, we profiled the immune cell contribution (flow cytometry) and cytokine release profiles (ELISA) in purified synovial membrane mononuclear cells from 50 patients undergoing either hip (n = 34) or knee (n = 16) replacement surgery. Unsupervised computational approaches were used for disease deconstruction. We found that hip and knee osteoarthritis are not identical in respect to the inflammatory processes that take place in the synovial membrane. Instead, we report that principally CD14+ macrophages are expanded fourfold in the synovial membrane of patients with knee OA compared to hip OA, with a trend to higher expression in CD8+ T cells, while CD4+ T cells, B cells, and NK cells were found at comparable quantities. Upon isolation and culture of cells from synovial membrane, isolates from hip OA released higher concentrations of Eotaxin (CCL11), G-CSF, GM-CSF, INF-γ, IP-10 (CXCL10), TNF-α, MIP-1α (CCL3), MIP-1β (CCL4), IL-4, IL-10, IL-17, and lower concentrations of stem cell factor (SCF), thereby highlighting the difference in the nature of hip and knee osteoarthritis. Taken together, this study establishes hip and knee OA as immunologically distinct types of OA, and creates a resource of the cytokine expression landscape and mononuclear cell infiltration pattern of patients with hip and knee osteoarthritis.

scholarly journals A variable number of tandem repeats locus within the human complement C2 gene is associated with a retroposon derived from a human endogenous retrovirus.

1992 ◽  
Vol 175 (6) ◽  
pp. 1783-1787 ◽  
Author(s):  
Z B Zhu ◽  
S L Hsieh ◽  
D R Bentley ◽  
R D Campbell ◽  
J E Volanakis
Keyword(s):  
Tandem Repeats ◽  
Average Length ◽  
Endogenous Retrovirus ◽  
Variable Number ◽  
Human Endogenous Retrovirus ◽  
Vntr Locus ◽  
Length Polymorphisms ◽  
Mouse Mammary Tumor ◽  
Tumor Virus ◽  
The Difference

We have previously described multiallelic restriction fragment length polymorphisms of the C2 gene, suggesting the presence of a variable number of tandem repeats (VNTR) locus. We report here the cloning and sequencing of the polymorphic fragments from the two most common alleles of the gene, a and b. The results confirm the presence of a VNTR locus consisting of a nucleotide sequence, 41 bp in average length, repeated tandemly 23 and 17 times in alleles a and b, respectively. The difference in the number of repeats between the two alleles is due to the deletion/insertion of two noncontiguous segments, 143 and 118 bp long, of allele a, and of a 40-bp segment of allele b. The VNTR region is associated with a SINE (short interspersed sequence)-type retroposon, SINE-R.C2, located within the third intron of the C2 gene. SINE-R.C2 is a member of a previously described large retroposon family of the human genome, apparently derived from the human endogenous retrovirus, (HERV) K10, which is homologous to the mouse mammary tumor virus.

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