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 Contribution of Infrapatellar Fat Pad and Synovial Membrane to Knee Osteoarthritis Pain

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Elisa Belluzzi ◽  
Elena Stocco ◽  
Assunta Pozzuoli ◽  
Marnie Granzotto ◽  
Andrea Porzionato ◽  
...  
Keyword(s):  
Synovial Membrane ◽  
Adult Population ◽  
Joint Damage ◽  
Joint Disease ◽  
Infrapatellar Fat Pad ◽  
Fat Pad ◽  
Pain Mechanisms ◽  
Knee Oa ◽  
New Findings

Osteoarthritis (OA) is the most common form of joint disease and a major cause of pain and disability in the adult population. Interestingly, there are patients with symptomatic OA displaying pain, while patients with asymptomatic OA that do not experience pain but show radiographic signs of joint damage. Pain is a complex experience integrating sensory, affective, and cognitive processes related to several peripheral and central nociceptive factors besides inflammation. During the last years, the role of infrapatellar fat pad (IFP), other than the synovial membrane, has been investigated as a potential source of pain in OA. Interestingly, new findings suggest that IFP and synovial membrane might act as a functional unit in OA pathogenesis and pain. The present review discuss the role of IFP and synovial membrane in the development of OA, with a particular focus on pain onset and the possible involved mediators that may play a role in OA pathology and pain mechanisms. Inflammation of IFP and synovial membrane may drive peripheral and central sensitization in KOA. Since sensitization is associated with pain severity in knee OA and may potentially contribute to the transition from acute to chronic, persistent pain in knee OA, preventing sensitization would be a potentially effective and novel means of preventing worsening of pain in knee OA.

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 Recent advances in understanding and managing psoriatic arthritis

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2670 ◽  
Author(s):  
Dafna D. Gladman
Keyword(s):  
Psoriatic Arthritis ◽  
Early Diagnosis ◽  
Clinical Laboratory ◽  
Joint Damage ◽  
Screening Tools ◽  
Therapeutic Interventions ◽  
Joint Disease ◽  
New Therapeutic Approaches ◽  
Recent Advances ◽  
And Function

This article reviews recent advances in psoriatic arthritis (PsA) over the past several years with emphasis on early diagnosis, better understanding of pathogenesis, and new therapeutic approaches. Early diagnosis is important, since people who present late do not fare as well. There are a number of clinical, laboratory, and ultrasound features that can help identify patients destined to develop PsA, and several screening tools have been developed. It is recognized that genetic and epigenetic factors, as well as T cells and cytokines, play a role in the pathogenesis of PsA, and several targets have been identified for therapeutic interventions. New therapies have been developed and tested in PsA and have been found to be highly effective for both skin and joint manifestations of the disease. The expectation is that, in the future, PsA patients will be treated early and more aggressively and that there will not be significant progression of joint damage. Moreover, with effective treatment of the skin and joint disease and management of risk factors for the comorbidities, we can expect to reduce their occurrence and further reduce the excess mortality and reduced quality of life and function in these patients.

Do Radiographic Joint Damage and Disease Activity Influence Functional Disability Through Different Mechanisms? Direct and Indirect Effects of Disease Activity in Established Rheumatoid Arthritis

2013 ◽  
Vol 40 (9) ◽  
pp. 1505-1512 ◽  
Author(s):  
Sandhya C. Nair ◽  
Johannes W.J. Bijlsma ◽  
Jacobien H. van der Werf ◽  
Maaike J. van der Veen ◽  
Suzanne P. Linn-Rasker ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Functional Disability ◽  
Functional Decline ◽  
Joint Damage ◽  
Treatment Strategies ◽  
Joint Disease ◽  
Influence Functional ◽  
Over Time ◽  
Predictive Effect

Objective.To explore the relationship between rheumatoid arthritis (RA) disease activity and functional disability over time, considering indirect (predictive) and direct (concurrent) associations as well as the influence of radiographic joint damage and treatment strategy.Methods.Functional disability [Health Assessment Questionnaire (HAQ)], disease activity [28-joint Disease Activity Score (DAS28)], and radiographic joint damage [Sharp/van der Heijde score (SHS)] were measured in 4 consecutive randomized controlled trials with increasingly intensive (tight control) treatment strategies. Average followup time for the 3 cohorts was 97, 53, and 50 months, respectively. Next to current DAS28, the previous DAS28 was used to study the predictive effect of a change in DAS28 on progression of functional disability (HAQ). Finally, it was investigated whether SHS mediated the predictive effect of DAS28.Results.In patients treated with intensive treatment strategies, the progression of HAQ over time was statistically significantly less (p < 0.0001). The predictive influence of DAS28 on HAQ progression increased over the duration of the disease. SHS was not found to influence HAQ progression and did not mediate the predictive effect of DAS28. In the less intensively treated patients, the direct effect of disease activity decreased with disease duration, and contrarily, SHS did influence HAQ progression, but was not found to (fully) mediate the predictive effect of DAS28.Conclusion.In patients with RA treated with modern treatment strategies, there is less functional decline over time. Further, disease activity does predict functional decline but joint damage does not. This might indicate that factors associated with cumulative disease activity but not visible on radiographs can influence functional decline in patients with RA. This further underlines the importance of disease activity as a treatment target in early RA and in established RA.

scholarly journals Faecal microbiota transplantation from metabolically compromised human donors accelerates osteoarthritis in mice

2020 ◽  
Vol 79 (5) ◽  
pp. 646-656 ◽  
Author(s):  
ZeYu Huang ◽  
Jing Chen ◽  
BoLei Li ◽  
Benhua Zeng ◽  
Ching-Heng Chou ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Gut Microbiome ◽  
Joint Damage ◽  
The Other ◽  
Gut Permeability ◽  
Microbial Composition ◽  
Germ Free ◽  
Knee Oa ◽  
Inflammatory Protein ◽  
Faecal Samples

ObjectivesEmerging evidence suggests that the microbiome plays an important role in the pathogenesis of osteoarthritis (OA). We aimed to test the two-hit model of OA pathogenesis and potentiation in which one ‘hit’ is provided by an adverse gut microbiome that activates innate immunity; the other ‘hit’ is underlying joint damage.MethodsMedical history, faecal and blood samples were collected from human healthy controls (OA-METS-, n=4), knee OA without metabolic syndrome (OA+METS-, n=7) and knee OA with metabolic syndrome (OA+METS+, n=9). Each group of human faecal samples, whose microbial composition was identified by 16S rRNA sequencing, was pooled and transplanted into germ-free mice 2 weeks prior to meniscal/ligamentous injury (MLI) (n≥6 per group). Eight weeks after MLI, mice were evaluated for histological OA severity and synovitis, systemic inflammation and gut permeability.ResultsHistological OA severity following MLI was minimal in germ-free mice. Compared with the other groups, transplantation with the OA+METS+ microbiome was associated with higher mean systemic concentrations of inflammatory biomarkers (interleukin-1β, interleukin-6 and macrophage inflammatory protein-1α), higher gut permeability and worse OA severity. A greater abundance of Fusobacterium and Faecalibaterium and lesser abundance of Ruminococcaceae in transplanted mice were consistently correlated with OA severity and systemic biomarkers concentrations.ConclusionThe study clearly establishes a direct gut microbiome-OA connection that sets the stage for a new means of exploring OA pathogenesis and potentially new OA therapeutics. Alterations of Fusobacterium, Faecalibaterium and Ruminococcaceae suggest a role of these particular microbes in exacerbating OA.

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.

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 The N-Acetyl Phenylalanine Glucosamine Derivative Attenuates the Inflammatory/Catabolic Environment in a Chondrocyte-Synoviocyte Co-Culture System

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Stefania Pagani ◽  
Manuela Minguzzi ◽  
Laura Sicuro ◽  
Francesca Veronesi ◽  
Spartaco Santi ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Primary Cells ◽  
Catabolic Enzymes ◽  
Disease Modifying Therapy ◽  
Gene And Protein Expression ◽  
Disease Modifying

Abstract Osteoarthritis (OA), the most prevalent degenerative joint disease, still lacks a true disease-modifying therapy. The involvement of the NF-κB pathway and its upstream activating kinases in OA pathogenesis has been recognized for many years. The ability of the N-acetyl phenylalanine glucosamine derivative (NAPA) to increase anabolism and reduce catabolism via inhibition of IKKα kinase has been previously observed in vitro and in vivo. The present study aims to confirm the chondroprotective effects of NAPA in an in vitro model of joint OA established with primary cells, respecting both the crosstalk between chondrocytes and synoviocytes and their phenotypes. This model satisfactorily reproduces some features of the previously investigated DMM model, such as the prominent induction of ADAMTS-5 upon inflammatory stimulation. Both gene and protein expression analysis indicated the ability of NAPA to counteract key cartilage catabolic enzymes (ADAMTS-5) and effectors (MCP-1). Molecular analysis showed the ability of NAPA to reduce IKKα nuclear translocation and H3Ser10 phosphorylation, thus inhibiting IKKα transactivation of NF-κB signalling, a pivotal step in the NF-κB-dependent gene expression of some of its targets. In conclusion, our data confirm that NAPA could truly act as a disease-modifying drug in OA.

Musculoskeletal Pathologies in Children with Haemophilia Evaluated using a Standardised Physical Joint Scoring System to Assess Disability

2011 ◽  
Vol 07 (01) ◽  
pp. 76 ◽  
Author(s):  
Sonata Saulyte Trakymiene ◽  
Keyword(s):  
Treatment Efficacy ◽  
Scoring System ◽  
Joint Damage ◽  
Joint Disease ◽  
Severe Haemophilia ◽  
International Consensus ◽  
Health Score ◽  
Haemophilic Arthropathy ◽  
Joint Health ◽  
Joint Assessment

Repeated bleeding into the joints leads to the development of chronic and progressive joint disease in 90% of people with severe haemophilia. Owing to recurrent haemarthroses, musculoskeletal outcome remains an important hallmark of treatment efficacy in haemophilia. Physical joint assessment is commonly used to measure structural and functional joint damage. With the development and introduction of prophylaxis, the most widely used instruments for the assessment of haemophilic arthropathy were found to lack sensitivity to detect the earliest signs of joint disease. To address these inadequacies, a new international consensus tool, the Haemophilia Joint Health Score (HJHS), was developed. The HJHS appears to be a sensitive, reliable and valid tool. However, the HJHS needs further evaluation in various patient populations to assess its applicability and usefulness.

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).

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