Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Cartilage is an important tissue in the skeleton. During skeletal development transient cartilage forms a template for the skeletal elements before it is replaced by bone. In the joints a non-transient form of cartilage, the articular cartilage, caps the ends of the bones and ensures very low friction between the bones to support mobility. Damage to this articular cartilage is a main feature of joint diseases. Osteoarthritis is the most common chronic joint disease, affecting millions of people world-wide and is characterized by progressive structural damage to the articular cartilage and the underlying subchondral bone, leading to pain and disability. Currently, no disease modifying treatments are available for patients with osteoarthritis, thereby defining an important unmet medical need.The Wnt signaling pathway has been identified as a key player in cartilage development, homeostasis and disease. Hyperactivation of Wnt signaling inhibits early cartilage differentiation but stimulates the last stages of the developmental differentiation process. In the articular cartilage, low levels of active Wnt signaling appear important for cell survival, but hyperactivation of the pathway is associated with abnormal differentiation of the cells and an increase in the production of tissue-destructive enzymes thereby contributing to disease processes active in osteoarthritis. Hence, Wnt signaling is considered to be a therapeutic target for this disease. Therefore, understanding of the mechanisms that regulate this pathway in cartilage is important.In this thesis, two regulatory mechanisms are investigated and demonstrated. First, activation of Wnt signaling is demonstrated to be dependent on the presence of heparin sulfate proteoglycans. Exostosin-1 (Ext1) encodes a glycosyltransferase that is required for heparan sulfate (HS) chain elongation in proteoglycan biosynthesis. HS chains serve as binding partners for signaling proteins, affecting their distribution and activity. In knockdown experiments in a chondrocyte development model, HS levels were reduced and this positively impacted on chondrogenic differentiation and proteoglycan accumulation. Ext1 knock-down reduced active Wnt signaling. Conversely, Ext1 overexpressing cells, with higher HS content, showed decreased chondrogenic differentiation and enhanced Wnt. Wnt signaling activation led to a down-regulation of Ext1 expression in chondrocytes.EXT1 therefore affects chondrogenic differentiation of precursor cells, in part via changes in the activity of Wnt signaling. As Wnt signaling also controls Ext1 expression, a regulatory loop between EXT1 and Wnt signaling during chondrogenesis is proposed.Second, interactions between Wnt signaling and intracellular multifunctional molecule ANP32A were demonstrated. ANP32A was previously shown to protect against cartilage damage by limiting oxidative stress through regulation of key anti-oxidant regulator molecule ATM expression. However, anti-oxidant treatment only partially rescued joint damage in Anp32a KO mice with osteoarthritis. Analysis of global gene expression levels by microarray in the articular cartilage of Anp32a KO mouse cartilage suggested that ANP32A also can regulate Wnt signaling. Lack of Anp32a in a cartilage differentiation process resulted in inhibition of differentiation and lack of proteoglycan accumulation, associated with Wnt hyper-activation. In human and mouse articular cartilage, Anp32a deficiency was also linked to hyper-activation of Wnt signaling.Therefore, this work reveals that EXT1 and ANP32A regulate the activity of Wnt signaling and can be considered potential targets to modulate this pathway in the treatment of osteoarthritis.

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Psoriasis artritis (PsA) is een chronische inflammatoire spondyloartritis die progressieve aantasting van de gewrichten veroorzaakt. PsA kan ook extra-articulaire symptomen veroorzaken en gaat ook gepaard met comorbiditeiten. Recent zijn heel wat nieuwe therapieën ontwikkeld voor de behandeling van PsA. Voornamelijk de ontwikkeling van nieuwe biologicals heeft voor een grote verbetering in symptoomcontrole gezorgd. Echter 30 tot 40% van de patiënten vertoont geen goede respons op deze therapieën; bovendien is er ook nog een grote heterogeniteit van symptomen. Dit zorgt ervoor dat de behandeling van PsA een grote uitdaging is waardoor meer en meer de vraag komt naar Personalized Medicine. Deze literatuurstudie geeft een overzicht van alle factoren die mogelijk de respons op therapie kunnen voorspellen en kunnen bijdragen tot de keuze van therapie om op deze manier Personalized Medicine mogelijk te maken. Een grote rol is weggelegd voor de biomarkers waarvan bewezen is dat ze niet alleen een belangrijke rol kunnen spelen in de vroegtijdige diagnose van PsA maar ook belangrijk zijn bij het voorspellen en bepalen van de therapeutische respons en het bepalen van de ziekteactiviteit. Deze literatuurstudie geeft ook een overzicht van de rol van het bepalen van het immunfenotype, therapeutische monitoring en het principe van de farmacogenetica bij patiënten met PsA.

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Introduction Psoriatic arthritis (PsA) is a rheumatological disease which combines a skin condition called psoriasis with joint involvement which is primarily characterised by chronic inflammation of the synovium. One of the main accompanying symtoms with arguably the most adverse effect on quality of life is the psychosocial burden of severe fatigue. This study aimed to describe its prevalence and characteristics, as well as identify associations of fatigue with demographic and clinical variables. Methods Questionnaires were filled out by 463 participants of the Belgian Epidemiological Psoriatic Arthritis Study (BEPAS). The study was approved by the ethics committee and all patients provided informed consent. A selection of demographic and clinical variables as well as measurements of fatigue of this database were analysed using IBM SPSS Statistics. Results Gradation of fatigue was positively correlated with female gender, enthesitis, arthritis, psoriasis guttata, Crohn's disease, medication use (analgesics, anti-TNF, NSAIDs), reduced quality of life (daily activities, pain or discomfort, anxiety or depression, mobility and selfcare), psoriasis (psoriasis guttata, DLQI, PASI and BSA), biochemical inflammation (CRP), and physicians global assessment. Gradation of fatigue was negatively correlated with HLA-B27 carriership and hypercholesterolemia. Conclusion Fatigue is prevalent among PsA patients and is strongly correlated with quality of life. There are little demographic or clinical variables that can predict for severe fatigue. Keywords Psoriasis, arthritis, psoriatic arthritis, fatigue, quality of life