Heterogeneous accumulation of senescent cells expressing the senescence-associated secretory phenotype (SASP) affects tissue homeostasis which leads to diseases, such as osteoarthritis (OA). In... Show moreHeterogeneous accumulation of senescent cells expressing the senescence-associated secretory phenotype (SASP) affects tissue homeostasis which leads to diseases, such as osteoarthritis (OA). In this study, we set out to characterize heterogeneity of cellular senescence within aged articular cartilage and explored the presence of corresponding metabolic profiles in blood that could function as representative biomarkers. Hereto, we set out to perform cluster analyses, using a gene-set of 131 senescence genes (N = 57) in a previously established RNA sequencing dataset of aged articular cartilage and a generated metabolic dataset in overlapping blood samples. Using unsupervised hierarchical clustering and pathway analysis, we identified two robust cellular senescent endotypes. Endotype-1 was enriched for cell proliferating pathways, expressing forkhead box protein O4 (FOXO4), RB transcriptional corepressor like 2 (RBL2), and cyclin-dependent kinase inhibitor 1B (CDKN1B); the FOXO mediated cell cycle was identified as possible target for endotype-1 patients. Endotype-2 showed enriched inflammation-associated pathways, expressed by interleukin 6 (IL6), matrix metallopeptidase (MMP)1/3, and vascular endothelial growth factor (VEGF)C and SASP pathways were identified as possible targets for endotype-2 patients. Notably, plasma-based metabolic profiles in overlapping blood samples (N = 21) showed two corresponding metabolic clusters in blood. These non-invasive metabolic profiles could function as biomarkers for patient-tailored targeting of senescence in OA. Show less
Osteoarthritis (OA) is a prevalent age-related joint disease, determined by diverse changes in pathways maintaining articular cartilage and subchondral bone. This thesis aimed to identify and study... Show moreOsteoarthritis (OA) is a prevalent age-related joint disease, determined by diverse changes in pathways maintaining articular cartilage and subchondral bone. This thesis aimed to identify and study gene networks driving interacting etiopathophysiological OA processes in cartilage and subchondral bone. Hereto, characterization of the molecular landscape of bone and cartilage of OA patients showed 305 genes with similar direction of effect, including IL11 and CHADL. Moreover, to capture biological complexity and decipher underlying OA disease mechanisms a variety of human 3D cartilage and bone organoids models were exploited and a human osteochondral construct-on-a-chip was developed. Herein, we showed that the robust OA risk gene WWP2 may initiate OA, via aberrant responses in hypoxia-associated genes and a decrease in anabolic markers. Additionally we showed, as reflected by upregulation of SPP1 and downregulation of WNT16 in cartilage, that treatment of ex vivo human osteochondral explants with human recombinant IL11 does not necessarily has a beneficial outcome. Finally, to allow implementation of knowledge on diverse OA pathophysiological processes, the potency of circulating miRNAs to report on ongoing OA pathophysiological process in joint tissues was established. Such insights are crucial to stratify respective OA patients that require different therapeutic mode of action, towards precision medicine. Show less
ObjectivesIn osteoarthritis, methylation of lysine 79 on histone H3 (H3K79me), a protective epigenetic mechanism, is reduced. Histone methylation levels are dynamically regulated by histone... Show moreObjectivesIn osteoarthritis, methylation of lysine 79 on histone H3 (H3K79me), a protective epigenetic mechanism, is reduced. Histone methylation levels are dynamically regulated by histone methyltransferases and demethylases. Here, we aimed to identify which histone demethylases regulate H3K79me in cartilage and investigate whether their targeting protects against osteoarthritis. MethodsWe determined histone demethylase expression in human non-osteoarthritis and osteoarthritis cartilage using qPCR. The role of histone demethylase families and subfamilies on H3K79me was interrogated by treatment of human C28/I2 chondrocytes with pharmacological inhibitors, followed by western blot and immunofluorescence. We performed C28/I2 micromasses to evaluate effects on glycosaminoglycans by Alcian blue staining. Changes in H3K79me after destabilisation of the medial meniscus (DMM) in mice were determined by immunohistochemistry. Daminozide, a KDM2/7 subfamily inhibitor, was intra-articularly injected in mice upon DMM. Histone demethylases targeted by daminozide were individually silenced in chondrocytes to dissect their role on H3K79me and osteoarthritis. ResultsWe documented the expression signature of histone demethylases in human non-osteoarthritis and osteoarthritis articular cartilage. Inhibition of Jumonji-C demethylase family increased H3K79me in human chondrocytes. Blockade of KDM2/7 histone demethylases with daminozide increased H3K79me and glycosaminoglycans. In mouse articular cartilage, H3K79me decayed rapidly upon induction of joint injury. Early and sustained intra-articular treatment with daminozide enhanced H3K79me and exerted protective effects in mice upon DMM. Individual silencing of KDM7A/B demethylases in human chondrocytes demonstrated that KDM7A/B mediate protective effects of daminozide on H3K79me and osteoarthritis. ConclusionTargeting KDM7A/B histone demethylases could be an attractive strategy to protect joints against osteoarthritis. Show less
Tuerlings, M.; Janssen, G.M.C.; Boone, I.; Hoolwerff, M. van; Ruiz, A.R.; Houtman, E.; ... ; Meulenbelt, I. 2023
Objective: To explore the co-expression network of the osteoarthritis (OA) risk gene WWP2 in articular cartilage and study cartilage characteristics when mimicking the effect of OA risk allele... Show moreObjective: To explore the co-expression network of the osteoarthritis (OA) risk gene WWP2 in articular cartilage and study cartilage characteristics when mimicking the effect of OA risk allele rs1052429-A on WWP2 expression in a human 3D in vitro model of cartilage. Method: Co-expression behavior of WWP2 with genes expressed in lesioned OA articular cartilage (N = 35 samples) was explored. By applying lentiviral particle mediated WWP2 upregulation in 3D in vitro pellet cultures of human primary chondrocytes (N = 8 donors) the effects of upregulation on cartilage matrix deposition was evaluated. Finally, we transfected primary chondrocytes with miR-140 mimics to evaluate whether miR-140 and WWP2 are involved in similar pathways. Results: Upon performing Spearman correlations in lesioned OA cartilage, 98 highly correlating genes (| r| > 0.7) were identified. Among these genes, we identified GJA1, GDF10, STC2, WDR1, and WNK4. Sub-sequent upregulation of WWP2 on 3D chondrocyte pellet cultures resulted in a decreased expression of COL2A1 and ACAN and an increase in EPAS1 expression. Additionally, we observed a decreased expression of GDF10, STC2, and GJA1. Proteomics analysis identified 42 proteins being differentially expressed with WWP2 upregulation, which were enriched for ubiquitin conjugating enzyme activity. Finally, upregu-lation of miR-140 in 2D chondrocytes resulted in significant upregulation of WWP2 and WDR1. Conclusions: Mimicking the effect of OA risk allele rs1052429-A on WWP2 expression initiates detri-mental processes in the cartilage shown by a response in hypoxia associated genes EPAS1, GDF10, and GJA1 and a decrease in anabolic markers, COL2A1 and ACAN.(c) 2022 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/). Show less
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
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
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
Background: The Animated Activity Questionnaire (AAQ) was developed in the Netherlands to assess activity limitations in individuals with hip/knee osteoarthritis (HKOA). The AAQ is easy to... Show moreBackground: The Animated Activity Questionnaire (AAQ) was developed in the Netherlands to assess activity limitations in individuals with hip/knee osteoarthritis (HKOA). The AAQ is easy to implement and minimizes the disadvantages of questionnaires and performance-based tests by closely mimicking real-life situations. The AAQ has already been cross-culturally validated in six other countries. Objective: To assess the cross-cultural validity, the construct validity, the reliability of the AAQ in a Brazilian sample of individuals with HKOA, and the influence of formal education on the construct validity of the AAQ. Methods: The Brazilian sample (N = 200), mean age 64.4 years, completed the AAQ and the Western Ontario and McMaster Universities Index (WOMAC). A subgroup of participants performed physical function tests and completed the AAQ twice with a one-week interval. The Dutch sample (N = 279) was included to examine Differential Item Functioning (DIF) between the scores obtained in the Netherlands and Brazil. For this purpose, ordinal regression analyses were used to evaluate whether individuals with the same level of activity limitations from the two countries (the Dutch as the reference group) scored similarly in each AAQ item. To evaluate the construct validity, correlation coefficients were calculated between the AAQ, the WOMAC domains, and the performance-based tests. To evaluate reliability, the Cronbach's alpha coeffi-cient, the intraclass correlation coefficient, and the standard error of measurement (SEM) were calculated. Results: The AAQ showed significant correlations with all the WOMAC domains and performance -based tests (rho=0.46-0.77). The AAQ showed high internal consistency (Cronbach's alpha=0.94), excellent test-retest reliability (ICC2,1 = 0.98), and small SEM (2.25). Comparing to the scores from the Netherlands, the AAQ showed DIF in two items, however, they did not impact on the total AAQ score (rho=0.99). Conclusion: Overall, the AAQ showed adequate cross-cultural validity, construct validity, and reliability, which enables its use in Brazil and international/multicenter studies. (c) 2021 Associacao Brasileira de Pesquisa e Pos-Graduacao em Fisioterapia. Published by Elsevier Espana, S.L.U. All rights reserved. Show less
Houtman, E.; Tuerlings, M.; Riechelman, J.; Suchiman, E.H.E.D.; Wal, R.J.P. van der; Nelissen, R.G.H.H.; ... ; Meulenbelt, I. 2021
Background Failing of intrinsic chondrocyte repair after mechanical stress is known as one of the most important initiators of osteoarthritis. Nonetheless, insight into these early mechano... Show moreBackground Failing of intrinsic chondrocyte repair after mechanical stress is known as one of the most important initiators of osteoarthritis. Nonetheless, insight into these early mechano-pathophysiological processes in age-related human articular cartilage is still lacking. Such insights are needed to advance clinical development. To highlight important molecular processes of osteoarthritis mechano-pathology, the transcriptome-wide changes following injurious mechanical stress on human aged osteochondral explants were characterized. Methods Following mechanical stress at a strain of 65% (65%MS) on human osteochondral explants (n(65%MS) = 14 versus n(control) = 14), RNA sequencing was performed. Differential expression analysis between control and 65%MS was performed to determine mechanical stress-specific changes. Enrichment for pathways and protein-protein interactions was analyzed with Enrichr and STRING. Results We identified 156 genes significantly differentially expressed between control and 65%MS human osteochondral explants. Of note, IGFBP5 (FC = 6.01; FDR = 7.81 x 10(-3)) and MMP13 (FC = 5.19; FDR = 4.84 x 10(-2)) were the highest upregulated genes, while IGFBP6 (FC = 0.19; FDR = 3.07 x 10(-4)) was the most downregulated gene. Protein-protein interactions were significantly higher than expected by chance (P = 1.44 x 10(-15) with connections between 116 out of 156 genes). Pathway analysis showed, among others, enrichment for cellular senescence, insulin-like growth factor (IGF) I and II binding, and focal adhesion. Conclusions Our results faithfully represent transcriptomic wide consequences of mechanical stress in human aged articular cartilage with MMP13, IGF binding proteins, and cellular senescence as the most notable results. Acquired knowledge on the as such identified initial, osteoarthritis-related, detrimental responses of chondrocytes may eventually contribute to the development of effective disease-modifying osteoarthritis treatments. Show less
Houtman, E.; Almeida, R.C. de; Tuerlings, M.; Suchiman, H.E.D.; Broekhuis, D.; Nelissen, R.G.H.H.; ... ; Meulenbelt, I. 2021
Objective: We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human... Show moreObjective: We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human ex vivo osteochondral explants subjected to OA related stimuli. Given that MGP function depends on vitamin K bioavailability, we studied the effect of frequently prescribed vitamin K antagonist warfarin. Methods: Differential (allelic) mRNA expression of MGP was analyzed using RNA-sequencing data of human OA cartilage and subchondral bone. Human osteochondral explants were used to study exposures to interleukin one beta (IL-1b; inflammation), triiodothyronine (T3; Hypertrophy), warfarin, or 65% mechanical stress (65%MS) as function of rs1800801 genotypes. Results: We confirmed that the MGP risk allele rs1800801-T was associated with lower expression and that MGP was significantly upregulated in lesioned as compared to preserved OA tissues, mainly in risk allele carriers, in both cartilage and subchondral bone. Moreover, MGP expression was downregulated in response to OA like triggers in cartilage and subchondral bone and this effect might be reduced in carriers of the rs1800801-T risk allele. Finally, warfarin treatment in cartilage increased COL10A1 and reduced SOX9 and MMP3 expression and in subchondral bone reduced COL1A1 and POSTN expression. Discussion & conclusions: Our data highlights that the genetic risk allele lowers MGP expression and upon OA relevant triggers may hamper adequate dynamic changes in MGP expression, mainly in carti-lage. The determined direct negative effect of warfarin on human explant cultures functionally un-derscores the previously found association between vitamin K deficiency and OA. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
King, L.K.; Epstein, J.; Cross, M.; Buzzi, M.; Buttel, T.; Cembalo, S.M.; ... ; Guillemin, F. 2021
Objective: Towards developing an instrument to measure knee and hip osteoarthritis (KHOA) flare, the Out-come Measures in Rheumatology (OMERACT) Flares in OA Working Group first sought to identify... Show moreObjective: Towards developing an instrument to measure knee and hip osteoarthritis (KHOA) flare, the Out-come Measures in Rheumatology (OMERACT) Flares in OA Working Group first sought to identify and define relevant domains of flare in KHOA.Methods: Guided by OMERACT Filter 2.1, candidate domains were identified from data generated in inter-views, in English or French, with persons with KHOA and health professionals (HPs) who treat OA. The first and second rounds of an online Delphi process with patients and HPs, including researchers, selected rele-vant domains. The third round provided agreement on the selected domains and their definitions. At the vir-tual OMERACT 2020 workshop, the proposed domains and their definitions were discussed in facilitated breakout groups with patients and HPs. Participants then voted, with consensus set at >= 70%.Results: Qualitative interviews characterizing OA flare were completed with 29 persons with KHOA and 16 HPs. Content was analyzed and grouped into nine clusters. These candidate domains were included in two Delphi rounds, completed by 91 patients and 165 HPs then 50 patients and 116 HPs, per round, respectively. This resulted in selecting five relevant domains. A final Delphi round, completed by 38 patients and 89 HPs, provided agreement on these domains and their definitions. The OMERACT virtual vote included 27 patients and 106 HPs. The domains and their definitions were endorsed with >= 98% agreement. Domains include: Pain, Swelling, Stiffness, Psychological aspects, and Impact of symptoms, all defined "during flare".Conclusion: Using OMERACT methodology, we have developed five domains of KHOA flare that were highly endorsed by patients and HPs. (c) 2021 Elsevier Inc. All rights reserved. Show less
Li, R.; Boer, C.G.; Oei, L.; Medina-Gomez, C. 2021
Purpose of the review The human gut harbors a complex community of microbes that influence many processes regulating musculoskeletal development and homeostasis. This review gives an update on the... Show morePurpose of the review The human gut harbors a complex community of microbes that influence many processes regulating musculoskeletal development and homeostasis. This review gives an update on the current knowledge surrounding the impact of the gut microbiota on musculoskeletal health, with an emphasis on research conducted over the last three years. Recent findings The gut microbiota and their metabolites are associated with sarcopenia, osteoporosis, osteoarthritis, and rheumatoid arthritis. The field is moving fast from describing simple correlations to pursue establishing causation through clinical trials. The gut microbiota and their microbial-synthesized metabolites hold promise for offering new potential alternatives for the prevention and treatment of musculoskeletal diseases given its malleability and response to environmental stimuli. Show less
Houtman, E.; Hoolwerff, M. van; Lakenberg, N.; Suchiman, E.H.D.; Zwaag, E.V.V. van der van der; Nelissen, R.G.H.H.; ... ; Meulenbelt, I. 2021
Introduction: Likely due to ignored heterogeneity in disease pathophysiology, osteoarthritis (OA) has become the most common disabling joint disease, without effective disease-modifying treatment... Show moreIntroduction: Likely due to ignored heterogeneity in disease pathophysiology, osteoarthritis (OA) has become the most common disabling joint disease, without effective disease-modifying treatment causing a large social and economic burden. In this study we set out to explore responses of aged human osteochondral explants upon different OA-related perturbing triggers (inflammation, hypertrophy and mechanical stress) for future tailored biomimetic human models.Methods: Human osteochondral explants were treated with IL-1 beta (10 ng/ml) or triiodothyronine (T3; 10 nM) or received 65% strains of mechanical stress (65% MS). Changes in chondrocyte signalling were determined by expression levels of nine genes involved in catabolism, anabolism and hypertrophy. Breakdown of cartilage was measured by sulphated glycosaminoglycans (sGAGs) release, scoring histological changes (Mankin score) and mechanical properties of cartilage.Results: All three perturbations (IL-1 beta, T3 and 65% MS) resulted in upregulation of the catabolic genes MMP13 and EPAS1. IL-1 beta abolished COL2A1 and ACAN gene expression and increased cartilage degeneration, reflected by increased Mankin scores and sGAGs released. Treatment with T3 resulted in a high and significant upregulation of the hypertrophic markers COL1A1, COL10A1 and ALPL. However, 65% MS increased sGAG release and detrimentally altered mechanical properties of cartilage.Conclusion: We present consistent and specific output on three different triggers of OA. Perturbation with the pro-inflammatory IL-1 beta mainly induced catabolic chondrocyte signalling and cartilage breakdown, while T3 initiated expression of hypertrophic and mineralization markers. Mechanical stress at a strain of 65% induced catabolic chondrocyte signalling and changed cartilage matrix integrity. The major strength of our ex vivo models was that they considered aged, preserved, human cartilage of a heterogeneous OA patient population. As a result, the explants may reflect a reliable biomimetic model prone to OA onset allowing for development of different treatment modalities. Show less
In this thesis several aspects of complement proteins are described, from circulating levels in blood to their intracellular presence and from autoimmunity to the infectious disease tuberculosis.... Show moreIn this thesis several aspects of complement proteins are described, from circulating levels in blood to their intracellular presence and from autoimmunity to the infectious disease tuberculosis. We explored the local production of complement and we describe in Chapter 2 the production of C1q by chondrocytes. Additionally, studies addressing the potential intracellular C3 role are described in Chapter 3. The potential role of the complement system as biomarker was investigated by addressing the presence and concentrations of C1q in serum of patients with active tuberculosis and controls in Chapter 4. Like C1q, we also investigated the expression and concentration of the natural inhibitor C1-INH in Chapter 5. C1q protein was further analysed as biomarker for tuberculosis in experimental non-human primate models in Chapter 6. In this thesis, a newly identified case of a lupus patient is described with a complex medical history and a compound heterozygous deficiency of C1q in Chapter 7. To better comprehend a possible role of a prominent post-translational modification associated rheumatic disease, carbamylation, the interaction between carbamylated IgG was investigated in relation to the ability to activate the complement system. These studies are described in Chapter 8. Show less
