Osteoarthritis (OA) mainly affects the articular cartilage covering the bones. In this thesis we investigated the relation between levels of inflammatory mediators, genes involved in their... Show moreOsteoarthritis (OA) mainly affects the articular cartilage covering the bones. In this thesis we investigated the relation between levels of inflammatory mediators, genes involved in their regulation and the disease status of OA. We investigated the role of genetic variation at the interleukin(IL)-1 gene cluster in the innate bio-availability of IL-1beta. A haplotype that associated to low innate bio-availability also associated to higher hand OA scores. Although this is counterintuitive with respect to the generally accepted hypothesis that a pro-inflammatory status is detrimental to the cartilage it underlines a complex relationship between inflammation and OA. For the C-reactive protein we identified a haplotype associated to high CRP levels as well as to severe hand OA, which is more in line with expected directions of associations. Analysis of baseline cytokine and chemokine levels indicated that chemokine levels associated to hand OA scores, again with low levels associated to high OA scores. In a follow up functional genomic analysis of a previously identified OA susceptibility gene (DIO2) in our studies we show that the risk allele of this gene is transcribed at higher levels as compared to the non-risk allele. Furthermore, we showed increased DIO2 protein presence in OA affected cartilage. Show less
This thesis describes the long-term consequences of growth hormone and insulin-like growth factor I excess in patients cured from acromegaly for a mean duration of 17 years. Regarding the... Show moreThis thesis describes the long-term consequences of growth hormone and insulin-like growth factor I excess in patients cured from acromegaly for a mean duration of 17 years. Regarding the considerable prevalence of diverse morbidity in these patients, during the active phase of the disease but even more so after 17 years of disease cure, we suggest the screening of acromegalic patients on highly frequent comorbidities, such as osteoarthritis, vertebral fractures, colonic polyps, and colonic diverticulae. It is of great concern to recognize the long-term consequences of the disease in order to offer the patients adequate follow-up and multidisciplinary care. The aim should be to control the persisting complex morbidity as much as possible in order to prevent the patients from a further decrease in quality of life. The patients__ physician as well as the patient itself should be aware of the long-term consequences of acromegaly in order to eliminate surreal expectations concerning recovery of certain comorbidities. Show less
Het is nu gangbaar in de kliniek om aan de hand van een enkele biochemische component (een gen, eiwit of metaboliet) vast te stellen of iemand ziek is. Echter, met geavanceerde meettechnieken zijn... Show moreHet is nu gangbaar in de kliniek om aan de hand van een enkele biochemische component (een gen, eiwit of metaboliet) vast te stellen of iemand ziek is. Echter, met geavanceerde meettechnieken zijn we nu in staat zijn om tientallen tot zelfs honderden van deze componenten tegelijk te meten. Hierdoor krijgen onderzoekers een veel breder overzicht van wat er allemaal verandert tijdens een ziekte en kunnen er betere diagnostische tests worden ontwikkeld. Voor dit proefschrift heb ik mij verdiept in deze technieken en hun toepasbaarheid in artrose. Artrose is een veel voorkomende rheumatische aandoening waarvan de exacte oorzaak nog onduidelijk is. Ik heb vastgesteld dat er met name nog weinig bekend is over het aandeel van de afbraakproducten van eiwitten en van vetten. Ik heb de benodige meettechnieken opgezet om honderden van deze afbraaktproducten en vetten te kunnen meten. Hieruit bleek dat een onstekingsmediator zeer verhoogd is in artrose en dat de samenstelling van vetten in het bloed van artrose patienten anders is dan bij gezonde mensen. De vindingen van dit proefschrift geven de kracht van deze meettechnieken aan om bij te dragen tot verbeterde diagnostische tests. Show less
This dissertation describes a new model in which cartilage degradation can be studied. New cartilage is formed by bovine chondrocytes obtained from the slaughterhouse and cocultured with synovial... Show moreThis dissertation describes a new model in which cartilage degradation can be studied. New cartilage is formed by bovine chondrocytes obtained from the slaughterhouse and cocultured with synovial cells from rheumatoid arthritis (RA) patients to study the interaction between the chondrocytes and synoviocytes.The results of our study show that the role of synoviocytes in cartilage degradation is dependent on the presence of live chondrocytes. In osteoarthritis (OA) patients an increased level of advanced glycation endproducts (AGEs), which can bind to the receptor for AGEs (RAGE), is found in the cartilage. In RA patients, increased levels of AGEs and other RAGE-binding proteins is found in serum, synovial tissue and –fluid. We therefore studied the effect of RAGE activation on chondrocytes and synoviocytes from OA and RA patients and found that both chondrocytes and synoviocytes become more active and start to degrade cartilage. Blockade of RAGE activation might therefore be an interesting target in treatment of OA and RA patients. The synoviocytes in RA synovial tissue have an altered, aggressive phenotype and can degrade cartilage. Hereby, they share properties of fibrotic/tumorigenic cells. We found that healthy synoviocytes are epithelial-like cells and that synovial fluid from RA patients will induce a change in phenotype and production of proteins found in fibrotic/tumorigenic cells. BMP-7, a protein able to induce cartilage production by chondrocytes, is able to inhibit this change in phenotype and might therefore be an interesting target to prevent the alteration of synoviocyte phenotype. Show less
Osteoarthritis (OA) refers to a heterogeneous group of conditions. This thesis focuses on OA with a hereditary background; Familial OA at multiple joint sites and radiological hand OA at middle age... Show moreOsteoarthritis (OA) refers to a heterogeneous group of conditions. This thesis focuses on OA with a hereditary background; Familial OA at multiple joint sites and radiological hand OA at middle age. The main objective is to identify risk factors that play a role in the development of OA in order to gain further insight in the aetiology of OA. The secondary objective is to investigate factors that determine the outcome in OA. This thesis provides evidence that familial clustering of symptomatic OA is most prominent for hand and hip OA. In search for genetic risk factors, we present data suggesting that a proportion of the genetic susceptibility for OA at multiple sites is encoded by variation in innate cytokine activity. Further, we find HLA-DR antigens to be associated with radiological hand OA. In addition to genetic risk factors, this thesis demonstrates that other systemic risk factors such as hormonal status and local factors, to be important in the susceptibility of familial OA at multiple sites, underscoring the multicausal etioliology of this phenotype. Finally, this thesis addresses the resulting disability from OA. Using the International Classification of Functioning, Disability and Health as framework, we show illness perceptions and mental health to be important modifying factors in OA in the hands and lower extremities. Show less
Osteoarthritis of the knee is a chronic progressive joint disease leading to pain and loss of function in a considerable proportion of patients with great impact and consequences in the ageing... Show moreOsteoarthritis of the knee is a chronic progressive joint disease leading to pain and loss of function in a considerable proportion of patients with great impact and consequences in the ageing population of the industrialized world. Clinical symptoms and radiographs of the knee are normally used to monitor osteoarthritic changes in the knee. However, the correlation between radiographic osteoarthritic findings and clinical features is poor. Does MR imaging of the knee tell us more about the relation between osteoarthritic structural findings and clinical features? According to the present thesis, the answer is “No”. Most of the data presented in this thesis is based on a 1.5T longitudinal MR study called the “Genetica, Artrose & Progressie” (GARP) study. In the GARP study MR imaging findings were associated with clinical features of patients with OA, and it was concluded that there were no strong associations between the most important OA imaging findings and clinical features of patients with OA. These controversial findings are important findings with regards to future clinical trials, as it urges conservatism with regards to the idea of BME being an outcome measure for progression of the disease. Therefore, the current theses also strongly recommend a further quest to identify ideal parameters to quantify the progression of the disease. Show less
