Bone and joint disorders have an enormous personal- and societal impact. Diagnosis and treatment of these disorders are most efficient if targeted screening, accurate diagnosis, and targeted... Show moreBone and joint disorders have an enormous personal- and societal impact. Diagnosis and treatment of these disorders are most efficient if targeted screening, accurate diagnosis, and targeted treatment are available. To enable targeted screening, the population at risk must be well-defined, and categorized if required. Subsequently, screening- and diagnostic methods must have good, or excellent predictive value and finally, treatment must target the disease, thus spare healthy tissues and processes and thereby avoid adverse events.The aim of this thesis is to gain new insights about the diagnostic process- and treatment of pathological conditions of the bone and joints, namely male urological cancer-induced bone loss and inflammatory arthritis. Show less
Wissen, M.A.T. van; Berger, M.A.M.; Schoones, J.W.; Gademan, M.G.J.; Ende, C.H.M. van den; Vlieland, T.P.M.V.; Weely, S.F.E. van 2022
To assess the reporting quality of interventions aiming at promoting physical activity (PA) using a wearable activity tracker (WAT) in patients with inflammatory arthritis (IA) or hip/knee... Show moreTo assess the reporting quality of interventions aiming at promoting physical activity (PA) using a wearable activity tracker (WAT) in patients with inflammatory arthritis (IA) or hip/knee osteoarthritis (OA). A systematic search was performed in eight databases (including PubMed, Embase and Cochrane Library) for studies published between 2000 and 2022. Two reviewers independently selected studies and extracted data on study characteristics and the reporting of the PA intervention using a WAT using the Consensus on Exercise Reporting Template (CERT) (12 items) and Consolidated Standards of Reporting Trials (CONSORT) E-Health checklist (16 items). The reporting quality of each study was expressed as a percentage of reported items of the total CERT and CONSORT E-Health (50% or less = poor; 51-79% = moderate; and 80-100% = good reporting quality). Sixteen studies were included; three involved patients with IA and 13 with OA. Reporting quality was poor in 6/16 studies and moderate in 10/16 studies, according to the CERT and poor in 8/16 and moderate in 8/16 studies following the CONSORT E-Health checklist. Poorly reported checklist items included: the description of decision rule(s) for determining progression and the starting level, the number of adverse events and how adherence or fidelity was assessed. In clinical trials on PA interventions using a WAT in patients with IA or OA, the reporting quality of delivery process is moderate to poor. The poor reporting quality of the progression and tailoring of the PA programs makes replication difficult. Improvements in reporting quality are necessary. Show less
Roemer, F.W.; Jansen, M.; Marijnissen, A.C.A.; Guermazi, A.; Heiss, R.; Maschek, S.; ... ; Wirth, W. 2022
Background: The IMI-APPROACH cohort is an exploratory, 5-centre, 2-year prospective follow-up study of knee osteoarthritis (OA). Aim was to describe baseline multi-tissue semiquantitative MRI... Show moreBackground: The IMI-APPROACH cohort is an exploratory, 5-centre, 2-year prospective follow-up study of knee osteoarthritis (OA). Aim was to describe baseline multi-tissue semiquantitative MRI evaluation of index knees and to describe change for different MRI features based on number of subregion-approaches and change in maximum grades over a 24-month period.Methods: MRIs were acquired using 1.5 T or 3 T MRI systems and assessed using the semi-quantitative MRI OA Knee Scoring (MOAKS) system. MRIs were read at baseline and 24-months for cartilage damage, bone marrow lesions (BML), osteophytes, meniscal damage and extrusion, and Hoffa- and effusion-synovitis. In descriptive fashion, the frequencies of MRI features at baseline and change in these imaging biomarkers over time are presented for the entire sample in a subregional and maximum score approach for most features. Differences between knees without and with structural radiographic (R) OA are analyzed in addition.Results: Two hundred eighty-nine participants had readable baseline MRI examinations. Mean age was 66.6 +/- 7.1 years and participants had a mean BMI of 28.1 +/- 5.3 kg/m(2). The majority (55.3%) of included knees had radiographic OA. Any change in total cartilage MOAKS score was observed in 53.1% considering full-grade changes only, and in 73.9% including full-grade and within-grade changes. Any medial cartilage progression was seen in 23.9% and any lateral progression on 22.1%. While for the medial and lateral compartments numbers of subregions with improvement and worsening of BMLs were very similar, for the PFJ more improvement was observed compared to worsening (15.5% vs. 9.0%). Including within grade changes, the number of knees showing BML worsening increased from 42.2% to 55.6%. While for some features 24-months change was rare, frequency of change was much more common in knees with vs. without ROA (e.g. worsening of total MOAKS score cartilage in 68.4% of ROA knees vs. 36.7% of no-ROA knees, and 60.7% vs. 21.8% for an increase in maximum BML score per knee).Conclusions: A wide range of MRI-detected structural pathologies was present in the IMI-APPROACH cohort. Baseline prevalence and change of features was substantially more common in the ROA subgroup compared to the knees without ROA. Show less
Osteoarthritis is one of the most common musculoskeletal disorders. Despite its high prevalence, the pathogenesis of osteoarthritis is incompletely understood. A major risk factor for... Show moreOsteoarthritis is one of the most common musculoskeletal disorders. Despite its high prevalence, the pathogenesis of osteoarthritis is incompletely understood. A major risk factor for osteoarthritis is obesity. Not only due to increased mechanical stress, but also due to systemic factors such as lipids. Our knowledge on how lipids are involved in osteoarthritis is limited. Therefore, this thesis focusses on the association of lipids with hand and knee osteoarthritis. Firstly, we investigated the reproducibility of lipid measurements to guide future lipidomic research. Subsequently, comparison of the lipid profile of osteoarthritis patients in different disease stages showed that the lipid profile explained disease severity to a limited extent. We observed the strongest association of the lipid profile with hand pain, and no association with knee osteoarthritis. This suggests that lipotoxicity may play a larger role in the hand, while in the knee mechanical stress is more relevant. In addition, treatment with anti-inflammatory medication resulted in a change in lipid concentrations in patients with hand osteoarthritis, suggesting that lipids are involved in inflammation and/or pain processes. These insights may increase our understanding of osteoarthritis pathophysiology and lead to new targets for future development of disease modifying osteoarthritis medication. Show less
Diseases and injuries related to bone and cartilage severely affect the function of the musculoskeletal system. They affect the life quality of patients and make them unable to move. The... Show moreDiseases and injuries related to bone and cartilage severely affect the function of the musculoskeletal system. They affect the life quality of patients and make them unable to move. The peculiarities of bone and cartilage structures mean that the therapeutic and surgical treatments that have been developed till date have a lot of disadvantages and limitations. Consequently, the development of new strategies for administering drugs that favor localized delivery is very important to achieve increasingly better treatments.The design and preparation of platforms for this purpose is a constant challenge, and for this reason three types of matrices were designed and prepared in the thesis. The drugs encapsulated in these matrices were cefazolin sodium, betamethasone, dexamethasone sodium phosphate, and Etanercept (anti-TNF-α drug). We were able to show that our matrices modified the release of the incorporated molecules and the composition of the prepared materials played an important role in the kinetics of the release process. Physicochemical characterizations were carried out on all the materials, obtaining that in each case the morphology varied once modifications in the matrix composition had been introduced. Biological studies in vitro and in vivo showed the cytocompatibility of the materials and also the ability to help repair damaged cartilage. Show less
To advance development of effective disease modifying OA treatments, a better understanding of its pathophysiological mechanisms is necessary. By studyinga family with early onset OA and high... Show moreTo advance development of effective disease modifying OA treatments, a better understanding of its pathophysiological mechanisms is necessary. By studyinga family with early onset OA and high cartilage mineralization, a likely causal mutation in the TNF receptor superfamily member 11b (TNFRSF11B) encoding for osteoprotegerin (OPG) was identified. This mutation causes a 19 amino acid extension in the C-terminal domain of OPG (OPG-XL). OPG is a decoy receptor that competes with receptor activator of the nuclear KB factor (RANK) for the binding of nuclear factor KB ligand (RANKL). This triad is known for regulating the formation of osteoclasts, hence playing a critical role in bone remodeling. Given that TNFRSF11B is also one of the highest upregulated genes in OA lesioned cartilage as compared to preserved, this gene is likely underlying OA development and progression but its implication in cartilage homeostasis is as of yet unknown.Altogether, this thesis highlights the role of OPG in OA development by generating an OPG overexpression system in primary chondrocytes and by studying a rare mutation in TNFRSF11B. By further generating neo-cartilage, neo-bone and osteoclasts from the OPG-XL family members, we showed a bidirectional interplay of OPG-XL characterized by higher bone resorption and higher cartilage mineralization. Novel treatments for this family and extrapolation to common OA could be addressed on highly differentially expressed genes such as MGP and DIO2. Finally, the pleiotropy that OPG-XL showed indicates a beneficial or detrimental stage depending on the tissue, making OPG-XL, and likely OPG, a double-edged sword in OA development. Show less
This thesis aims to increase the understanding of human osteoarthritis pathophysiology by developing reliable biomimetic ex vivo human osteochondral explant models and focussing on the role of... Show moreThis thesis aims to increase the understanding of human osteoarthritis pathophysiology by developing reliable biomimetic ex vivo human osteochondral explant models and focussing on the role of osteoarthritis-relevant triggers (mechanical stress) and interacting genetic factors for developing treatment targets. Human aged joint tissues were collected in the Research in Articular Osteoarthritis Cartilage (RAAK) biobank. To add knowledge of the osteoarthritis pathophysiological processes, aged human ex vivo osteochondral explants were subject to three osteoarthritis-relevant triggers, being inflammation, hypertrophy and injurious mechanical stress. Next, knowledge on early initiating processes occurring in mechano-pathology was investigated by applying RNA-sequencing to cartilage of aged human osteochondral explants subjected to mechanical stress. In addition, to show that the human osteochondral explant model could also be used for genetic interaction studies, we investigated expression of the osteoarthritis risk gene MGP in relation to rs1800801 genotypes. By combining information from RNA-sequencing datasets of cartilage and bone with osteoarthritis-relevant triggers in cartilage and bone explants we investigated the role of MGP and vitamin K in osteoarthritis. Lastly, the injurious mechanical explant model was exploited to determine the effectivity of inhibiting the osteoarthritis risk gene DIO2 by iopanoic acid treatment either by burst or prolonged release from PLGA-PEG nanoparticles. Show less
The studies described in this thesis provides the field with valuable data on the potential therapeutic effects of fatty acids and specialized pro-resolving lipid mediators in rheumatoid arthritis... Show moreThe studies described in this thesis provides the field with valuable data on the potential therapeutic effects of fatty acids and specialized pro-resolving lipid mediators in rheumatoid arthritis and osteoarthritis. The omega-6 fatty acid AdA shows potent pro-resolving effects on the production of pro-inflammatory chemoattractantLTB4 with great promise to limit RA disease progression. In contrast to the promising potential therapeutic effects of AdA in RA, the evidence for pro-resolving effects in OA is still scarce. The results of the studies from this thesis show that neither LXA4, LXB4, RvE2 or Mar-1 were able to reduce OA disease activity in the experimental set-up we used. Finally, the studies described in this thesis show the utmost critical importance of the right sample preparation and storage for the intended subsequent analysis. Show less
The aim of this thesis was to combine transcriptomics, genetics and human disease modelling to obtain further insight into molecular processes underlying osteoarthritis. More specifically, we aimed... Show moreThe aim of this thesis was to combine transcriptomics, genetics and human disease modelling to obtain further insight into molecular processes underlying osteoarthritis. More specifically, we aimed to elucidate the role of long noncoding RNAs expression changes as aberrant epigenetic mechanism in regulating gene expression in chondrocytes. We identified previously unknown long noncoding RNAs associated with the osteoarthritic process and showed enrichment for cis¬-regulation of these long noncoding RNAs with target messenger RNAs.To provide insight in the etiology of osteoarthritis, causal pathways can be identified by unravelling the substantial genetic component. To this end, we investigated the biological functionality of the high-impact, pathogenic mutation identified in the gene fibronectin1 in an early-onset osteoarthritis family. We demonstrated that the identified causal missense mutation in the gelatin-binding domain of the extracellular matrix protein fibronectin resulted in significant decreased binding capacity to collagen type II.Finally, the common function of fibronectin1 was investigated in cartilage and what changes occur at the transcript level of fibronectin1 with osteoarthritis. Down-regulation of full-length fibronectin was unbeneficial for in vitro chondrogenesis, we hypothesize that this was caused by decreased availability of the classical integrin binding site of fibronectin. Show less
Loef, M.; Stadt, L. van de; Bohringer, S.; Bay-Jensen, A.C.; Mobasheri, A.; Larkin, J.; ... ; Kloppenburg, M. 2022
Objective: To investigate the association of the lipidomic profile with osteoarthritis (OA) severity, considering the outcomes radiographic knee and hand OA, pain and function. Design: We used... Show moreObjective: To investigate the association of the lipidomic profile with osteoarthritis (OA) severity, considering the outcomes radiographic knee and hand OA, pain and function. Design: We used baseline data from the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort, comprising persons with knee OA fulfilling the clinical American College of Rheumatology classification criteria. Radiographic knee and hand OA severity was quantified with Kellgren-Lawrence sum scores. Knee and hand pain and function were assessed with validated questionnaires. We quantified fasted plasma higher order lipids and oxylipins with liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based platforms. Using penalised linear regression, we assessed the variance in OA severity explained by lipidomics, with adjustment for clinical covariates (age, sex, body mass index (BMI) and lipid lowering medication), measurement batch and clinical centre. Results: In 216 participants (mean age 66 years, mean BMI 27.3 kg/m2, 75% women) we quantified 603 higher order lipids (triacylglycerols, diacylglycerols, cholesteryl esters, ceramides, free fatty acids, sphingomyelins, phospholipids) and 28 oxylipins. Lipidomics explained 3% and 2% of the variance in radiographic knee and hand OA severity, respectively. Lipids were not associated with knee pain or function. Lipidomics accounted for 12% and 6% of variance in hand pain and function, respectively. The investigated OA severity outcomes were associated with the lipidomic fraction of bound and free arachidonic acid, bound palmitoleic acid, oleic acid, linoleic acid and docosapentaenoic acid. Conclusions: Within the APPROACH cohort lipidomics explained a minor portion of the variation in OA severity, which was most evident for the outcome hand pain. Our results suggest that eicosanoids may be involved in OA severity. (c) 2022 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. Show less
Background: Total hip or knee arthroplasties (THA/TKA) show favorable long-term effects, yet the recovery process may take weeks to months. Physical therapy (PT) following discharge from hospital... Show moreBackground: Total hip or knee arthroplasties (THA/TKA) show favorable long-term effects, yet the recovery process may take weeks to months. Physical therapy (PT) following discharge from hospital is an effective intervention to enhance this recovery process. To investigate the relation between recovery and postoperative PT usage, including the presence of comorbidities, 6 months after THA/TKA.Methods: Multicenter, observational study in primary THA/TKA patients who completed preoperative and 6 months postoperative assessments. The assessments included questions on PT use (yes/no and duration; long term use defined as >= 12 weeks), comorbidities (musculoskeletal, non-musculoskeletal, sensory comorbidities and frequency of comorbidities). Recovery was assessed with the HOOS/KOOS on all 5 subdomains. Logistic regression with long term PT as outcome was performed adjusted for confounding including an interaction term (comorbidity*HOOS/KOOS-subdomain).Results: In total, 1289 THA and 1333 TKA patients were included, of whom 95% received postoperative PT, 56% and 67% received postoperative PT >= 12 weeks respectively. In both THA and TKA group, less improvement on all HOOS/KOOS domain scores was associated with >= 12 weeks of postoperative PT (range Odds Ratios 0.97-0.99). In the THA group the impact of recovery was smaller in patient with comorbidities as non- musculoskeletal comorbidities modified all associations between recovery and postoperative PT duration (Odds Ratios range 1.01-1.05). Musculoskeletal comorbidities modified the associations between Function-in-Daily-Living-and Sport-and-recreation recovery and postoperative PT. Sensory comorbidities only had an effect on Sport-and-recreation recovery and postoperative PT. Also the frequency of comorbidities modified the relation between Function-in-Daily-Living, pain and symptoms recovery and postoperative PT. In the TKA group comorbidity did not modify the associations.Conclusion: Worse recovery was associated with longer duration of postoperative PT suggesting that PT provision is in line with patients' needs. The impact of physical recovery on the use of long-term postoperative PT was smaller in THA patients with comorbidities. Show less
Purpose: Acromegalic arthropathy is a well-known phenomenon, occurring in most patients regardless of disease status. To date, solely hips, knees, hands, and spinal joints have been... Show morePurpose: Acromegalic arthropathy is a well-known phenomenon, occurring in most patients regardless of disease status. To date, solely hips, knees, hands, and spinal joints have been radiographically assessed. Therefore, this study aimed to assess the prevalence of joint symptoms and radiographic osteoarthritis (OA) of new, and established peripheral joint sites in well-controlled acromegaly. Methods: Fifty-one acromegaly patients (56% female, mean age 64 +/- 12 years) in long-term remission for 18.3 years (median, IQR 7.2-25.4) were included. Nineteen patients currently received pharmacological treatment. Self-reported joint complaints were assessed using standardized interviews. Self-reported disability of the upper and lower limbs, and health-related quality of life (HR-QoL) were evaluated using validated questionnaires. Radiographic OA [defined as Kellgren & Lawrence (KL) >= 2] was scored using (modified) KL methods. Results: Radiographic signs of OA were present in 46 patients (90.2%) with >= 2 joints affected in virtually all of these patients (N = 44; 95.7%). Radiographic MTP1 OA was as prevalent as radiographic knee OA (N = 26, 51.0%), and radiographic glenohumeral OA was similarly prevalent as hip OA [N = 21 (41.2%) vs. N = 24 (47.1%)]. Risk factors for radiographic glenohumeral OA were higher pre-treatment IGF-1 levels [OR 1.06 (1.01-1.12), P = 0.021], and current pharmacological treatment [OR 5.01 (1.03-24.54), P = 0.047], whereas no risk factors for MTP1 joint OA could be identified. Conclusion: Similar to previously-assessed peripheral joints, clinical and radiographic arthropathy of the shoulder and feet were prevalent in controlled acromegaly. Further studies on adequate management strategies of acromegalic arthropathy are needed. Show less
Hitzl, W.; Stamm, T.; Kloppenburg, M.; Ritter, M.; Gaisberger, M.; Zee-neuen, A. van der 2022
Background The present study aimed to predict the expected number of patients with osteoarthritis (OA) in Austria up to the year 2080. Methods Demographic data and population projections between... Show moreBackground The present study aimed to predict the expected number of patients with osteoarthritis (OA) in Austria up to the year 2080. Methods Demographic data and population projections between 2019 and 2080 were obtained from European authorities. Information about recent age- and sex-stratified prevalence of patients with self-reported physician-diagnosed OA was obtained from the Austrian Health Interview Survey (n = 15,771). Projections were stratified by age and sex; sensitivity analyses were performed based on aging, main (most likely), and growth scenarios of the population. Results Based on the projection, the overall increase in the total number of patients with OA from 2019 to 2080 will be 38% for men and women. In 2019, the highest number of OA-patients nested in the groups of persons aged 70-79 (n = 238,749) and 60-69 (n = 237,729) years. In 2080, the 80+ age group is predicted to have the highest number of OA with 421,548 individuals (i.e. factor 3.45 and factor 2.48 increase in the male and female group, respectively, compared to 2019), followed by the group aged 70-79 with 314,617 individuals (factor 1.45 and factor 1.28 increase in the male and female group, respectively, compared to 2019). Similar trends were found in the ageing and growing scenarios. Conclusions The projected increase in the occurrence of OA will likely lead to a substantial socioeconomic burden for the Austrian healthcare system in the near and far future. The current findings plead for the development of sustainable concepts for the treatment and prevention of OA by European authorities. Show less
Objective: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)... Show moreObjective: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-beta, under the transcriptional control of nuclear factor kappa-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA.Methods: In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 x 10(12)-1.2 x 10(13) genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-beta immune responses were evaluated. A data review committee provided safety recommendations.Results: Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-beta, nor IFN-beta antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose.Conclusion: Single IA doses of 0.6 x 10(12) or 1.2 x 10(12) ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. (C) 2021 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. Show less
