Title Promoter Affiliations Abstract "DOT1l in Osteoarthritis: The DOTOS project will study the role of DOT1L in synovial joint development, homeostasis and disease with specific attention towards osteoarthritis (OA)," "Rik Lories" "Skeletal Biology and Engineering Research Center" "The DOTOS project will study the role of DOT1L in synovial joint development, homeostasis and disease with specific attention towards osteoarthritis (OA), one of the most common chronic diseases.We identified an association between the DOT1L (DOT1-like histone H3 methyltransferase) gene and OA. Histone methylation is a regulator of gene transcription. Some histone methylations result in increased gene expression, e.g. lysine methylation at lysine 79 in histone 3 (H3K79). DOT1L is the only known H3K79 methyltransferase. We demonstrated that DOT1L plays an important role in the canonical Wnt signaling cascade in a molecular complex involving TCF transcription factors.These observations stimulated us to now investigate the role of DOT1l in joint development and disease, processes associated with Wnt signaling.The key hypothesis for this project states that DOT1L and Wnt signalling are required for joint development and homeostasis but that their increased activation in progressive OA is detrimental to the joint.This project will teach us how DOT1L interacts with Wnts and other signalling pathways in joint biology and disease. In addition, we aim to develop a basis for future therapeutic approaches.Dr. Monteagudo, the candidate for the fellowship, will be trained in animal models and in translational research hypotheses. She will benefit from complementary skills training and interactions with industry to gain further maturity and independence as a researcher. This additional training will be beneficial to her career as well as to the European Research Area as there is a great societal need for translational researcher in the field of chronic joint diseases able to make links between basic biology and clinical questions. The project pays specific attention to cross-sectorial interactions and communication with the scientific community as well as with the primary stakeholders for osteoarthritis: the patients and population at risk." "Predicting outcome of total knee replacement surgery in patients with knee osteoarthritis: a prospective study on the role of phenoptypic characteristics related to osteoarthritis." "Mira Meeus" "Movement Antwerp (MOVANT)" "Even though a Total Knee Replacement (TKR) is an effective surgical treatment for end-stage knee osteoarthritis (KOA) and the majority of patients report substantial pain relief and functional improvement following this surgical procedure, literature shows that 20-40% of patients are dissatisfied with the postsurgical outcome.Given the high costs related to TKR surgery and the substantial number of patients who do not meet the level of improvement after surgery, the decision to implant a TKR should be very well-considered. It is crucial to improve our understanding of the mechanisms contributing to persisting pain and disability following TKR.There is growing body of research suggesting that in a subgroup of patients with KOA the clinical picture is dominated by sensitization of central nervous system pain pathways (i.e. central sensitization) rather than by structural dysfunctions causing nociceptive pain. Briefly, this means that the pain is to a considerable degree due to hypersensitivity of the central nervous system, rather than being just caused by structural joint damage.Therefore, with our current ongoing study (funded BOF-DOCPRO4 project initiated November 1st 2017) we aim to understand the role of central pain processing in addition to structural and functional impairments related to KOA to predict unsatisfactory outcome (in terms of pain, symptoms, physical performance and QOL) after a TKR in patients with KOA. However, within the context of recent research developments in OA and recent suggestions proposed in international literature, we would like to upgrade our current research project and add a few measurements. In very recent systematic reviews, several OA phenotypes have been proposed, which are in part in line with the aims of our current ongoing study. However, we additionally want to investigate to what extent metabolic and inflammatory factors are related to the clinical expression of OA and are contributing to prognosis and treatment response. Moreover, in literature, different phenotypes are hypothesised and it is also plausible that the proposed phenotypes are not complete distinct entities and that interactions may exist.Therefore, we want to upgrade our research study and add some measurements to investigate the role of different OA characteristics, namely structural joint damage, inflammatory and metabolic factors and pain processing factors, in the clinical expression of KOA before and after a TKR. Moreover, we aim to unravel the interrelationship between these factors and to determine different phenotypes in relation to the outcome and prognosis after TKR, since these phenotypes may be particularly important for tailored treatment. In order to reach these objectives, a longitudinal prospective study will be performed, with specific data collection presurgical (T0) and 6 months (T1) and 1 year (T2) postsurgical.The strength of our current research study (including the proposal to upgrade the project and to add measurements) is that we will examine all putative prognostic factors on the basis of the biopsychosocial model. Besides several psychological factors (cognitive emotional modulation), we assess biomechanical factors (i.e. structural impairments, such as radiographic severity of OA, and functional impairments such as muscle weakness and proprioceptive deficits) and metabolic and inflammatory factors, and examine the role of altered central pain processing. We want to define OA phenotypes that are easy interpretable and possibly related to the outcome and prognosis after TKR." "Predicting outcome after total knee replacement surgery in patients with knee osteoarthritis: a prospective study on the role of altered central pain processing in addition to structural and functional impairments related to knee osteoarthritis." "Mira Meeus" "Movement Antwerp (MOVANT)" "Even though a Total Knee Replacement (TKR) is an effective surgical treatment for end-stage knee osteoarthritis (KOA) and the majority of patients report substantial pain relief and functional improvement following this surgical procedure, literature shows that 20-40% of patients are dissatisfied with the postsurgical outcome. Similar to other chronic pain conditions, there is growing body of research suggesting that in a subgroup of patients with KOA the clinical picture is dominated by sensitization of central nervous system pain pathways (i.e. central sensitization) rather than by structural dysfunctions causing nociceptive pain. Briefly, this means that the pain is to a considerable degree due to hypersensitivity of the central nervous system, rather than being just caused by structural joint damage. Therefore, it is not surprising that surgical interventions such as TKRs do not guarantee pain reduction and functional recovery, as the pain goes beyond the joint. Given the high costs related to TKR surgery and the substantial number of patients who do not meet the level of improvement after surgery, the decision to implant a TKR should be very well-considered. It is crucial to improve our understanding of the mechanisms contributing to persisting pain and disability following TKR and it emphasizes the need for further research on the role of altered central pain processing in patients with end stage KOA awaiting TKR surgery.This research proposal has two main objectives:1) to unravel to which extent central pain processing and structural and functional impairments contribute to the clinical expression of KOA (pain, symptoms, physical performance and quality of life) in patients with end-stage KOA before (at baseline) and 6 months after primary TKR surgery. 2) to unravel which factors are predictive for an unsatisfactory outcome (in terms of pain, symptoms, physical performance and quality of life) 6 months and 1 year after a primary TKR. In order to reach these objectives, a longitudinal prospective study will be performed, with specific data collection presurgical (T0) and 6 months (T1) and 1 year (T2) postsurgical.This study allows identification of prognostic factors for unsatisfactory outcome in KOA patients after a primary TKR. Previous longitudinal studies investigating predictors of poor outcome after TKR, mainly focused on structural and functional factors related to the knee joint, while central pain processing was left unnoticed. Other studies mainly focused on psychological factors as potential predictors of poor outcome. The strength of the recent proposal is that we will examine all putative prognostic factors on the basis of the biopsychosocial model. Besides several psychological factors (cognitive emotional modulation), we assess biomechanical factors (i.e. structural impairments, such as radiographic severity of OA, and functional impairments such as muscle weakness and proprioceptive deficits) and examine the role of altered central pain processing measured in four ways (Pressure Pain Thresholds, Conditioned Pain Modulation, tactile acuity, Central Sensitization Inventory questionnaire). In this study, it is hypothesized that in patients with altered central pain processing an unsatisfactory effect of TKR surgery on KOA pain, symptoms, physical performance and quality of life can be expected, as there is no clear relation between peripheral input and perceived pain. It is possible that in this subgroup interventions aiming to desensitize the central nervous system might be more beneficial.In future interventional research, it can be clarified whether new interventions, such as cognitive-behavioral therapy or therapeutic pain neuroscience education, whether or not in combination with surgery, are useful. These new interventions target different aspects such as the central nervous system in contrast to therapeutic modalities that are only directed to structural knee joint pathology." "Unraveling Wnt Signaling in the Cartilage to Deal with Osteoarthritis." "Silvia Monteagudo" "Skeletal Biology and Engineering Research Center" "Osteoarthritis is the most common joint disorder worldwide, for which no cure exists. Increasing evidence suggests that the Wnt pathway plays a critical role in this disease and may be an effective target for therapy. However, modulation of this cascade to safeguard cartilage health remains a challenge, as we fail to fully understand how it is regulated. My research program aims to dissect molecular mechanisms that control the Wnt pathway in cartilage, to develop Wnt-based therapeutic strategies for osteoarthritis. I will build on previous knowledge and experience by investigating factors that potentiate DOT1L, an enzyme we identified to be a key Wnt pathway modulator in cartilage. Furthermore, I aim to discover novel elements that modulate the effects of the Wnt pathway using innovative screening technologies, and I will build on strong preliminary data revealing novel interactions of the Wnt pathway with the Insulin-like growth factor system. " "A micromechanical model of load transfer across the bone-cartilage interface to evaluate osteochondral remodelling in osteoarthritis." "Harry van Lenthe" "BioMechanics (BMe), University of Melbourne" "Micromechanical analysis of load transfer across the bone-cartilage interface in osteoarthritic knees Articular joints are complex structures that rely on biomechanical and biological integration of two strongly dissimilar tissues: the hard mineralized bone and the soft cartilage. Where bone and cartilage are joined, both tissues possess specific adaptation strategies to solve biomechanical and biological dissimilarities. Subchondral bone has the challenging task of safeguarding the thin, avascular and aneural layer of articular cartilage from biomechanical and biochemical damage. Articular cartilage is anchored to subchondral bone thanks to an interface of mineralized cartilage which, in turn, is glued to bone through a thin interlayer called the cement line. The composition, the biomechanical properties and possible role in damage resistance of the osteochondral junction are mostly unknown. Nevertheless, the behaviour of this multi-tissue region is of clinical interest, as this is the area where fracture occurs between bone and cartilage in osteoarthritis (OA). OA is the most prevalent chronic joint disease, and there is no cure.The aim of this project is to develop a computational framework that can accurately quantify (i) mechanical alterations (expressed in stresses and strains) in the transition zone between cartilage and bone; and (ii) transport of biological factors across the bone-cartilage interface. In collaboration with Dr Stok (University of Melbourne) the models will be validated using detailed ex vivo measurements of mechanical properties and fluid transport across the bone-cartilage interface in healthy and osteoarthritic human knees. The models will help further our understanding on the role of biomechanical factors in the onset and progression of osteoarthritis." "Uncovering regulators of H3K79 methylation in cartilage to identify targets for osteoarthritis therapy" "Silvia Monteagudo" "Skeletal Biology and Engineering Research Center" "Osteoarthritis (OA), the most common chronic joint disease, is characterized by progressive damage to the articular cartilage, remodelling of the joint-associated bone, and inflammation. Current OA treatments are limited to pain relief, physiotherapy, or joint replacement surgery in severe cases, yet drugs that stop the disease progression are lacking. DOT1L is an enzyme that chemically modifies an amino-acid (Lysine at position 79) in the Histone-3 protein (H3K79) by adding a methyl group. We identified DOT1L as key protector of cartilage health and reported that DOT1L activity, indicated by the levels of H3K79 methylation (H3K79me), is reduced in OA compared to non-OA cartilage. Thus, maintaining H3K79me seems to be critical to preserve joint health and prevent the development or progression of OA. Here, we aim to uncover regulators of H3K79me using a dual strategy. First, we will identify which histone demethylase enzymes are responsible for the removal of methyl groups of H3K79 using a combination of in vitro, ex vivo, and in vivo techniques. Second, we will use a discovery approach based on a large-scale siRNA screening in a human articular chondrocyte cell line. We will investigate the therapeutic impact of targeting regulators identified using both approaches for OA in chondrocytes and explants from OA-patients and in well-established OA mouse models. This project could therefore identify new targets for therapy of a disease with an enormous medical need." "Unraveling a new molecular link between Wnt signaling and IGF1 in the chondrocyte and its therapeutic implications for osteoarthritis" "Silvia Monteagudo" "Skeletal Biology and Engineering Research Center" "Osteoarthritis is the most common chronic joint disease worldwide, inwhich progressive joint damage leads to pain and disability.Currently, no therapeutic strategies are available that revert or stopthe progression of the disease. In osteoarthritis, cartilage cells oftendevelop abnormal differentiation towards hypertrophy, whichcontributes to joint destruction. These changes are associated withexcessive activation of Wnt signaling. However, how Wnt signalingtriggers hypertrophic differentiation is largely unknown. We havepreliminary evidence that excessive Wnt increases local productionof insulin growth factor-1 (IGF1), a key player in the hypertrophyprocess in bone development. Here, we aim to find out how Wntincreases IGF1 and whether the downstream effects of thisinteraction impact osteoarthritis. We will also explore therapeuticimplications for the disease. We will use a translational researchapproach including state-of-the-art technologies in the analysis ofpatient-derived cells and explants, combined with different mousemodels of osteoarthritis. An important tool will be a new geneticmouse model with cartilage-specific inducible loss of the Igf1 gene. Asuccessful project will lead to the identification of molecular eventsthat trigger key disease-associated changes in cartilage, and maycontribute to opportunities for osteoarthritis therapy." "Investigating a new molecular link between Wnt signaling and IGF1 in osteoarthritis" "Silvia Monteagudo" "Skeletal Biology and Engineering Research Center" "Osteoarthritis, the most prevalent joint disease, is characterized by joint damage that leads to pain and disability, and lacks curative treatment. In osteoarthritis, cartilage cells often develop abnormal differentiation towards hypertrophy, which contributes to joint destruction. These changes are associated with excessive activation of Wnt signaling. However, how Wnt signaling triggers hypertrophic differentiation is largely unknown. We have preliminary evidence that excessive Wnt increases local production of insulin growth factor- 1 (IGF1), a key player in the hypertrophy process. Here, we aim to investigate the molecular mechanism underlying this interaction and how this contributes to osteoarthritis. A successful project will lead to the identification of molecular events that trigger key disease-associated changes in cartilage, and may contribute to opportunities for osteoarthritis therapy." "Functional biomarkers of cartilage mechanics in osteoarthritis – an MRI-based, multi-scale adaptive modeling framework to bridge from in vitro destructive testing to in vivo clinical applications" "Ilse Jonkers" "Human Movement Biomechanics Research Group" "Osteoarthritis (OA) is the most common joint disease and significantly impairs the quality of life of those affected by this painful progressive disease. As a consequence, the economic burden is high for both the individual and society. Today, no successful preventive interventions have been identified yet. It is however known that cartilage degeneration and loss of its unique mechanical properties is the hallmark of OA and that mechanical loading contributes to disease onset and progression. Therefore, it is crucial to study the mechanical and compositional properties of cartilage tissue in vivo. This will not only prepare for the development of innovative tissue engineering applications for OA treatment but might also leverage future clinical screening tools for early OA. Today, clinical MRI protocols document anatomical rather than mechanical characteristics of cartilage. Non-invasive approaches based on highfield MRI have emerged to characterize cartilage mechanical behavior, but due to the limited resolution of clinical MRI systems these approaches cannot be used as such in a clinical setting. With my fellowship I will introduce a disruptive integrated MRI-based multiscale modeling approach for characterization of cartilage mechanical and compositional properties that allows to bridge the gap between bench and bedside. I will integrate this approach with an adaptive algorithm to monitor and predict cartilage degeneration in knee OA patients." "Unraveling Wnt signaling in cartilage to deal with osteoarthritis" "Silvia Monteagudo" "Skeletal Biology and Engineering Research Center" "Osteoarthritis is the most common joint disorder worldwide, for which no cure exists. Increasing evidence suggests that the Wnt pathway plays a critical role in this disease and may be an effective target for therapy. However, modulation of this cascade to safeguard cartilage health remains a challenge, as we do not fully understand how it is regulated. My research program aims to dissect molecular mechanisms that control the Wnt pathway in cartilage, to develop Wnt-based therapeutic strategies for osteoarthritis. I will build on previous knowledge and experience by investigating factors that potentiate DOT1L, an enzyme we identified to be a key Wnt pathway modulator in cartilage. Furthermore, I aim to discover novel elements that modulate the effects of the Wnt pathway using innovative screening technologies, and I will build on strong preliminary data revealing novel interactions of the Wnt pathway."