In the field of Osteoarthritis (OA) research the step from genetics to biological functionality, also named ‘functional genomics’, is necessary to allow valorisation of genetic findings, thereby... Show moreIn the field of Osteoarthritis (OA) research the step from genetics to biological functionality, also named ‘functional genomics’, is necessary to allow valorisation of genetic findings, thereby augmenting the need for functional data of disease relevant tissues. Even so, it was estimated that pursuing druggable targets directed by genetic studies are twice as often successful as compared to those without it. In this thesis we apply the functional genomics methodology, to proceed from a genetic association to mechanistic understanding of the effect of genetic variation on gene expression and epigenetic regulation contributing to OA susceptibility. Particularly we set out to characterize and validate the pathophysiological processes that underlie the role of DIO2/thyroid hormone signalling in the onset of OA after identifying the DIO2 gene as a OA susceptibility locus. The results in this thesis show that intracellular T3 levels should be strictly regulated via DIO2 upon mechanical loading of the cartilage, to ensure cartilage tissue homeostasis. Future endeavours should be designed to demonstrate that local inhibition of DIO2 by intra-articular admission of a deiodinase-inhibitor (Iopanoic acid), could be an effective therapy to alleviate the burden of OA thereby increasing mobility, well-being and quality of life particularly among elderly. Show less
Swart, N.M.; Oudenaarde, K. van; Reijnierse, M.; Nelissen, R.G.H.H.; Verhaar, J.A.N.; Bierma-Zeinstra, S.M.A.; Luijsterburg, P.A.J. 2016
Conclusion: An impaired glucose metabolism does not seem be related to OA. In men, an association was observed for fasting glucose concentrations and hand OA. Future studies should investigate the... Show moreConclusion: An impaired glucose metabolism does not seem be related to OA. In men, an association was observed for fasting glucose concentrations and hand OA. Future studies should investigate the presence of sex differences in the pathogenesis of hand OA. (C) 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
Conclusions: Assessment of progression in hand OA defined by JSW measurements is possible, but performs less well than progression defined by JSN scoring. Therefore, the value of JSW measurements... Show moreConclusions: Assessment of progression in hand OA defined by JSW measurements is possible, but performs less well than progression defined by JSN scoring. Therefore, the value of JSW measurements in hand OA clinical trials remains questionable. (C) 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
The pathogenesis of OA is largely unknown; however, several risk factors are known to contribute to disease development. Treatment modalities are currently limited to alleviation of symptoms. In... Show moreThe pathogenesis of OA is largely unknown; however, several risk factors are known to contribute to disease development. Treatment modalities are currently limited to alleviation of symptoms. In order to develop better treatment modalities, increase of the understanding of the underlying mechanisms leading to OA development may provide targets for disease modification. Furthermore, knowledge regarding appropriate outcome measures that can be applied in OA research has to be increased for adequate assessment of potential treatment effects. Therefore, part I of this thesis describes studies aiming to increase the understanding of mechanisms underlying the association between known risk factors and OA, especially focussing on obesity in relation to OA in weight-bearing and non-weight-bearing joints. Furthermore, it was investigated which specific structural abnormalities on specific locations within the knee joint could best discriminate presence of symptomatic OA, and impact of knee OA and its modifiable or preventable risk on health-related quality of life was evaluated. Part II of this thesis describes two systematic reviews, assessing available instruments for measurement of the domains pain, physical function, patient global assessment and imaging in hand OA in order to enable recommendations for use in clinical trials. Show less
Conclusion: Baseline structural damage and bone turnover activity, as reflected by BMLs, seem to be involved in knee OA progression. Moreover, progression in PFJ and TFJ seems to be related. (C)... Show moreConclusion: Baseline structural damage and bone turnover activity, as reflected by BMLs, seem to be involved in knee OA progression. Moreover, progression in PFJ and TFJ seems to be related. (C) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
Bomer, N.; Hollander, W. den; Ramos, Y.F.M.; Meulenbelt, I. 2015
Although osteoarthritis is a common disease, there are currently no disease-modifying availible. For a long time osteoarthritis was considered a purely degenerative disease without inflammation of... Show moreAlthough osteoarthritis is a common disease, there are currently no disease-modifying availible. For a long time osteoarthritis was considered a purely degenerative disease without inflammation of the synovium (synovitis). However, recent research has shown that synovitis is of importance in patients with osteoarthritis. Therefore, this thesis aimed to understand the role synovitis in ossteoarthritis. In the first part of this thesis, we investigated the nature of synovitis by examining the synovium of osteoarthritis patients using differnt laboratory techniques. Furthermore, we validated a new synovitis scoring system on MRI with contrast. In the second part of this thesis, we investigated role of synovitis in relation to clinical characteristics such as pain and structural damage. This thesis shows that synovial inflammation in osteoarthritis is not only frequently present, but may also play a role in the pathophysiology of osteoarthritis and development of clinical features. Results presented in this thesis provide insight into different aspects of synovial inflammation aimed at increasing our understanding of the pathophysiology of OA and aiding to the development of disease-modifying drugs in OA. Show less
