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Projekte des Forschungsverbundes Osteoarthrose – OVERLOAD-PrevOp

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SP O1: Association between Varus and Valgus Aberration, Load characteristics, and Osteoarthritis of the knee in a Normal population (AVALON)

C. Perka, Head & J. Fussi, Dept. of Orthopedic Surgery, Center for Musculoskeletal Surgery (CMSC) & D.Stengel, UKB Berlin/ Charité – Universitätsmedizin Berlin & C. O. Schmidt, K. Hegenscheid, University Medicine of Greifswald (UMG)

Abstract: Overload caused by varus or valgus deformation may increase the risk of cartilage degeneration. However, clinical evidence is conflicting and major population-based studies lack routine full leg imaging. Understanding alignment-associated degenerative changes may help to prevent or even rectify tissue damage of the knee. The Study of Health in Pomerania (SHIP) is a population-based study providing data necessary to address the mentioned objectives. To utilize resources more efficiently, the original investigation plan based on the full longitudinal SHIP cohort was skipped in favor of a nested-case control study. This study will correlate measures of exposure (i.e., limb axes, and varus and valgus deviations) and outcome (i.e., risk of osteoarthritis), and semi-quantitative changes osteoarthritis-associated changes of the affected knee joint(s) (as expressed by the Whole-Organ MRI Score [WORMS]) (Peterfy CG et al. Osteoarthritis Cartilage 2004;12:177-90).

During scheduled follow-up examinations of SHIP participants (covering an observation interval of about 6 years) those with osteoarthritis (cases) will be identified in the entire cohort according to a valid practical MRI grading system (Park HJ et al. Eur J Radiol 2013;82:112-7). Controls will be selected considering known confounders and risk factors for osteoarthritis available in SHIP and matched to cases in an adequate ratio using innovative techniques. We will determine crude and adjusted relative risks of osteoarthritis, as well as variability in knee alignment and its time-dependent change.

Current population-based evidence suggests that there will be sufficient variability in limb axis alignment for modeling associations with the endpoints of interest (Sharma L et al. Ann Rheum Dis 2010;69:1940-5). With different assumptions and several scenarios (e.g., varying baseline risks of osteoarthritis, different correlation between multiple predictor variables, and others), the available sample size will allow for detecting odds ratios (OR) below 2.0 even using conservative test criteria. The sample size will also allow for both gender stratification and the evaluation of longitudinal changes in limb axes to detect small and medium sized effects (0.1-0.2) using appropriate and meaningful indices (e.g. standardized effect sizes) and statistical procedures.

For both consortia, the epidemiological study in OVERLOAD will provide a valuable overview about the distribution of limb axes and anatomical variants in healthy and osteoarthritis patients, and also contributes significant information for the intervention trial in PrevOP. Automated imaging markers developed in projects SP2 Overload (Eckstein) and SP4 PrevOP (Zachow), may be applied to data from SHIP for further assessment. 

SP O2: Imaging of early (pre-radiographic) joint tissue degeneration and OA progression using advanced MRI-based biomarkers

F. Eckstein, F. Roemer, W. Wirth, Chondrometrics GmbH

Abstract:  No successful structural therapy for osteoarthritis  has been developed to date because of the lack of early diagnostic methods. Once detected by radiography, degeneration is potentially too far advanced for successful intervention. Magnetic resonance imaging (MRI) has been used to delineate synovial structures and measure cartilage thickness in knees with established OA. However, early "pre-radiographic" structural changes that may provide potentially easier targets for biomechanical or pharmacological treatments are currently unknown. Here we propose a model of early human knee osteoarthritis, in order to establish potent imaging outcomes and predictors of the initial phase of the disease, applicable to other consortium projects (DUDA, MADRY). To achieve this, Chondrometrics will analyse imaging data from the Osteoarthritis Initiative (OAI) public data base using its quality controlled and validated manual segmentation approach and using analysis technology. The group by Zachow/Ertel will perform fully automated segmentations of the same image data sets. A similarity index of the segmentations, agreement of cartilage volume/thickness results (cross-sectional and longitudinal), and potential synergy of both segmentation and analysis approaches will be evaluated. These results will provide valuable insights into specific tissue pathologies and clinical variables that predict development of early osteoarthritis  , including, among others, adipose tissue and muscle mass, cartilage composition (i.e. the cartilage transverse relaxation time T2), bone marrow-, meniscus- and cartilage- lesions. Given the role of muscle in biomechanically protecting the joint from overload, the endocrine role of adipose tissue and pro-inflammatory effects of adipokines and the adipose tissue effects on muscle quality, muscle and local adipose tissue content are of particular interest. In addition, the HEGE and BERGMANN projects will provide models for estimating medial knee load from alignment, limb length, pelvic width, weight and muscle mass using measurements that are available from the OAI. Based on these, we will correlate estimates of joint loading and regional tissue strain to regional structural change in early incident osteoarthritis  . Current therapies of OA include surgical correction of mal-alignment, exercise and diet. This study will support the development of various quality controlled and automated imaging markers for monitoring the efficacy of prevention of and therapy for early osteoarthritis  that will be translatable to a large German cohort (PERKA) and to future clinical trials.

SP O3: Knee Kinematics: Joint laxity, losteoarthritisding and onset of cartilage degeneration under extreme conditions

G. Duda, T. Jung, Charité- Universitätsmedizin Berlin & D. Arampatzis, HU Sports science & T. Pap, Uni Münster & Olympic Center Berlin

Abstract: It is generally assumed that laxity of the knee joint is a precursor of osteoarthritis. Quite recently, animal experiments indicated a direct correlation between joint laxity and cartilage damage. However, some individuals seem to be able to cope with joint laxity ("copers") and stabilise it by muscle activity while others do not ("non-copers"). While some knowledge exists on knee joint losteoarthritisding, details on the laxity (anterior-posterior (AP) & rotational) have yet to be elucidated. Understanding the losteoarthritisding and differentiating between "copers" and "non-copers" is critical for the assessment of risk and disease progression on a mechano-biological and structural level and is the basis for a science-based preventive approsteoarthritisch to joint degeneration. Sports, especially under competitive conditions, lead to extreme losteoarthritisds in the joints and cause joint laxity. Both challenge the cartilage capacity to withstand high shear and rotational movements. In this sense, sports and sport injuries to the knee represent a model system to study the early onset of osteoarthritis and without interfering metabolic disorders. Our longitudinal study will investigate the passive and active stability in standardized athlete cohorts that are suffering from an anterior cruciate ligament (ACL) rupture. The influence of a specific training regime on knee joint stability, cartilage degeneration and the consequent changes in serum markers will be investigated in non-coper athletes that are at a higher risk of developing early cartilage degeneration. The expertise from the PrevOP partners will help to keep the patients involved throughout the training intervention. With the gosteoarthritisl of identifying the consequence of joint laxity on cartilage degeneration, we aim to investigate conservative training methods that prevent early onset of osteoarthritis. Serum and imaging markers, which prove to be valid early osteoarthritis indicators, will be provided to the PrevOP consortium partners.

SP O4: Understanding, analysing and reducing knee joint loading

G. Bergmann, Charité- Universitätsmedizin Berlin

Abstract: Osteoarthritis of the knee joint is influenced by the internal joint contact forces. Their magnitudes and medio-lateral distribution are co-factors for cartilage degradation, mostly starting at the medial compartment. A deceleration of osteoarthritis progression and a reduction of pain could be achieved if joint forces are reduced or shifted more to the lateral side.

A direct relation between external knee adduction moment (EKAM) and medial-side knee contact force (MKCF) is a widely accepted opinion. Several studies assessed the effect of wedged shoes, valgus braces, osteotomies and other methods by analyzing changes of the EKAM. However, no verified facts about the correlation EKAM   MKCF exist. Our own data showed that a reduced EKAM is not a reliable predictor for a load reduction.

As one of only two groups worldwide, we can measure the tibio-femoral contact forces and their distribution in the joint by instrumented implants with telemetric data transmission. Synchronous gait analyses allow detailed investigations of the relations between external and internal loads.
We plan to

• Review the concept that the maximum EKAM is a reliable measure for the maximum medial knee load.
• Investigate the biomechanical mechanisms of gait modifications in detail.
• Analyze the efficiency of various methods for reducing the MKCF. Some may become obsolete, effective ones could be optimized.
• Provide partner groups with detailed data about loading of the knee joint including gait and anatomical data of our telemetric patients. This allows verifying loads determined by analytical and stresses/strains calculated by FE models. These loads could cause increased movements in the knee and thereby influence the progress of osteoarthritis

SP O5: In vivo and in silico analyses in humans: Cartilage loading of patients' individual knees – the role of soft tissue structures

H.-C. Hege, & M. Weiser, Zuse Institute Berlin, G. Duda, & C. Perka, Charité

Abstract: While a relationship between knee joint laxity and osteoarthritis  is often assumed, the exact mechanism is not yet fully understood. It is not clear how the local loading conditions change after the loss of the ACL as a passive stabilizer, and how active stabilization via muscle contraction affects the local cartilage loading. Such knowledge will enable crucial understanding on how training methods might affect osteoarthritis progression on a biomechanical level. Comparing the dynamic cartilage pressure distributions of "copers", who stabilize their knees actively, with "non-copers" will provide an additional level of insight to the analysis of cartilage degeneration performed in SP3 in the same cohorts. To achieve this goal, the study will develop and validate a computational musculoskeletal model with two levels of detail: A multibody model of the entire lower limb coupled with a detailed finite element (FE) model of the knee joint. Tools for automated image segmentation from PrevOP SP4 will be used and complemented by patient specific mesh generation. This will allow us to analyse a large cohort of patients. The model will be validated against in vivo measured loads at the knee and hip joints provided by SP4. Combined with the results of SP3 and the homeostasis model of PrevOP SP5 this study will allow us to compare the potential consequences of increased axial joint loads due to active stabilization with the potentially increased shear loads due to a lack of stability. The models will also be used to estimate the load variation within the general population, based on anatomical variation within the large SHIP cohort. New application-specific visual data analysis tools will support the interpretation and comparison of the cohort data.

SP O6: Combined preclinical in vivo and clinical in silico modelling of pathological cartilage loading damage and osteoarthritis

H. Madry, M. Cucchiarini, Saarland University & G. Duda, Charité

Abstract: Although it is clear that specific molecular events and pathological mechanical loading are both associated with the onset of early cartilage degeneration, to date a direct link between them has not been established. This proposal aims to study the pathological and clinical consequences of axial mal-alignment-induced cartilage overloading and its therapeutic redistribution in a preclinical animal model of early osteoarthritis. In a sheep HTO model of varus and valgus alignment, pathological cartilage loading damage and the onset of osteoarthritis following partial medial meniscectomy will be studied at the molecular (VORTKAMP, PAP), cellular, biochemical (PAP, SCHULZE-TANZIL, KNAUS) and microstructural (CHONDROMETRICS, ZACHOW) level in the medial femoro-tibial osteochondral unit and compared with non-osteotomized controls. Biomarkers tested will be similar than in the FELSENBERG clinical trial. Relevant sheep tissue samples (e.g. muscle) will be also provided to clarify pro-algesic and analgesic mechanisms (MACHELSKA). Within this project, our knowledge of the effect of loading on osteoarthritic cartilage degradation over time will be significantly improved. This data will be also used by HEGE, VON KLEIST to compute and by DUDA to analyze and correlate musculoskeletal loading patterns in the sheep hind limb. It therefore provides the basis to connect osteoarthritic degeneration to mechanical tissue strains in overloaded knee compartments. Finally, clinical data from the association between axial mal-alignment, load characteristics, and osteoarthritis (PERKA) will be compared with these preclinical correlations to better tailor therapeutic HTO interventions in patients. This project therefore serves as a pillar to bridge the understanding of developmental determinants of loads, the mechano-sensitive signaling with the tissue imaging and the human situation as assessed in the other collaborative projects.

SP P4: Analysis and quantification of morphological and structural changes in cartilage; assessment of existing and derivation of new image-based scores for gradual cartilage loss

S. Zachow, Zuse Institute Berlin (ZIB)

Abstract: The aim of this project is to assess and to quantitatively analyse morphological and structural changes in cartilage with respect to different levels of exercise to support the hypothesis that cartilage competence is maintained through muscle strengthening. It is assumed that morphology and structure of cartilage and muscle as well as progression of osteoarthritis can be quantitatively assessed with medical imaging techniques. The proposed work program is focussed on monitoring and analysis of changes in cartilage volume, shape, and quality   based on different but combined medical imaging modalities and its relation to existing osteoarthritis scores.

SP O8: Mechanosensitive signalling complexes as early targets of post-traumatic osteoarthritis (OA)

T. Pap & J. Bertrand, IEMM, Uniklinikum Münster

Abstract: Articular cartilage has a special importance for reducing mechanical stress during movement, and multiple lines of evidence suggest that overload translates into a specific chondrocyte response leading to osteoarthritis. The question, however, of how chondrocytes sense mechanical stress and how this results in the loss of their phenotypic stability remains largely unclear. We hypothesise that mechano-sensitive signaling complexes as composed of adhesion molecules and membrane anchored calcium channels are important mediators and, thus, therapeutic targets of osteoarthritis. Recent work of our group has identified syndecans (sdc's), particularly sdc-4, as surface molecule on chondrocytes, the loss or inhibition of which leads to resistance against osteoarthritis. Of note, sdc-4 regulates the expression of transient receptor potential calcium channels (TRPC) that can sense mechanical stress and regulate the response to factors involved in maintaining the phenotypic stability of chondrocytes. According to our hypothesis sdc's and TRPCs are key parts of mechanosensitive signaling complexes in chondrocytes, and based on our above data we plan to use a combined approach of well established molecular and cell biology techniques as well as preclinical in vivo models of osteoarthritis  available both in the OVERLOAD and the PreVOP consortium to study the function of TRPCs (TRPC6, TRPC1) in chondrocytes and the interplay between sdc's (sdc-1, sdc-4) and these TRPCs. A focus will be on the characterization of signaling pathways that trigger the phenotypic switch in chondrocytes as induced by mechanical and non-mechanical stress. Using TRPC activators and inhibitors together with genetically modified mice we will dissect the role of TRPCs from sdc- mediated effects and study the underlying pathways. Overall this study will aim at elucidating the therapeutic potential of sdc- and TRPC- blockade to prevent and treat mechanically- induced changes in chondrocytes and provide the data to the members of both the OVERLOAD and the PrevOP consortium.

SP P1: Effect of candidate mediators regulated by exercise on osteoarthritis (OA) in the mouse model

G. Schulze-Tanzil, Department of Special Orthopaedic and Trauma Surgery, Laboratory for Experimental Orthopaedic Surgery, Charité, CBF, Berlin.

Abstract: Muscular activity can lead to a melioration of osteoarthritis. However, which mediators are modulated by exercise, ageing and gender in osteoarthritis patients remains unclear. Therefore, the interplay between particular exercise-regulated candidate mediators, complement activation and cartilage will be analysed to assess their influence on osteoarthritis progression using a mouse model and in vitro/situ analysis of human samples. Exercise-dependent mediators will be investigated in a surgically induced early osteoarthritis mice model (medial collateral ligament and meniscus transection). A whole body vibration based training protocol will be developed and applied to adult female and male mice (> 2,5 month old) for 6-12 weeks post surgical osteoarthritisinduction. The control group receives no training. Subsequently, the expression (as well as zone- and lesion-dependent distribution) of mediators/receptors which might be chondroprotective and associated with physical activity such as IL-6, IL-101,2, complement factors, and the mechano-growth factor IGF-IEc will be studied in the OAK mice joint cartilage, other joint tissues, blood and Musculus quadriceps femoris samples in response to the training conditions. Particularly, the activation and regulation of complement activity, which has been strongly implicated in osteoarthritis3,4,5will be analysed in view of the training procedures and using complement inhibitors. Concerning complement activity/regulation split fragments (C3a, C5a), anaphylatoxin receptors (C3aR, C5aR) and complement inhibiting regulatory proteins (CRPs) will be analysed. For comparison of results, deduced from the animal study, human cartilage samples (derived from OA cartilage versus healthy cartilage) will be used (age 40-80 years, female and male patients) to analyse the expression profile of the same mediators in human cartilage and age- and gender-related differences. Stimulation of cultured human chondrocytes with recombinant mediators will be used to estimate the effect of particular muscle-derived mediators on chondrocytes and samples from the clinical trial (SP6).

SP P2: Impact of BMP signalling and biomechanical loading on MSCs and hypertrophic chondrocytes

P. Knaus, Institute of Chemistry and Biochemistry, Freie Universität of Berlin

Abnormally hypertrophic differentiation of chondrocytes and dysbalanced extracellular matrix remodelling in articular cartilage is connected with the development of osteoarthritis . Members of the TGFβ and BMP superfamily of growth and differentiation factors are fine-tuning this process 1. Both stimulatory and inhibitory factors have been described and pathological conditions have been shown to arise from deregulation of these fundamental signalling pathways. Here we will investigate the impact of biomechanical stimulation on (1) the expression of BMP signalling components, (2) mobilisation and migration of mesenchymal stem cells (MSCs) and precursor cells, (3) differentiation of MSCs under the influence of distinct BMPs and (4) cytoskeletal rearrangements in MSCs and precursor cells. These studies will take gender, age and physical training (under/or without defined motivation conditions) into consideration.

SP P3: Regulation of pain in experimental osteoarthritis – the impact of physical training on endogenous pro-algesic and analgesic mechanisms

H. Machelska, Department of Anesthesiology and Intensive Care Medicine, Charité-Campus Benjamin Franklin, Berlin

Abstract: Pain is a debilitating sign of osteoarthritis and it impairs the function and quality of life. Current pharmacological and surgical treatments are unsatisfactory and produce serious adverse effects. We propose that physical training improves osteoarthritis pain by down-regulation of pro-algesic mediators and up-regulation of analgesic mediators. As an osteoarthritis model we will employ a traumatic injury of the knee in mice, while exercise will be performed using a rodent vibration device. In these conditions we will analyze the expression of various pro-algesic and analgesic mediators along the nociceptive pathways using biochemical and molecular biology methods, and investigate the functional contribution of the mediators to pain control by means of in vivo behavioral tests. Additionally, the mediators will be examined in tissue samples from patients with osteoarthritis . These studies will provide new insights into mechanisms of possible analgesic actions of vibration-based exercise in osteoarthritis  pain. By promoting the use of endogenous painkillers in response to physical training, our studies offer a potential approach for safe control of pain in osteoarthritis.

SP P4: Analysis and quantification of morphological and structural changes in cartilage; assessment of existing and derivation of new image-based scores for gradual cartilage loss

S. Zachow, Zuse Institute Berlin (ZIB)

Abstract: The aim of this project is to assess and to quantitatively analyse morphological and structural changes in cartilage with respect to different levels of exercise to support the hypothesis that cartilage competence is maintained through muscle strengthening. It is assumed that morphology and structure of cartilage and muscle as well as progression of osteoarthritis can be quantitatively assessed with medical imaging techniques. The proposed work program is focussed on monitoring and analysis of changes in cartilage volume, shape, and quality   based on different but combined medical imaging modalities and its relation to existing osteoarthritis scores.

SP P5: Integrative mathematical modelling of physiological- and molecular factors of osteoarthritis of the knee

M. v. Kleist (DFG-NWGL), C. Schütte, Inst. of Mathematics and
Computer Science, Freie Universität of Berlin

Abstract: Osteoarthritis of the knee (OAK) is a complex multi-factorial condition that is characterised by a lack of hyaline cartilage self repair 1, inflammation & pain 2. As for many other multi-factorial conditions, computational models may be useful tools of direct clinical relevance that allow studying the interaction of putative factors. Within this subproject, we want to develop a comprehensive computational model of cartilage homeostasis that will help us to understand and to evaluate the onset and progression of OAK. While the underlying mechanisms of OAK remain unknown, several factors have been previously associated with osteoarthritis  and studied in isolation, such as cell density-dependent extracellular matrix (EM) generation 3,4, EM metabolism 5, the effect of nutrient gradients 5,6 and the influence of (mechano-) growth factors 7.

Our research group has a broad expertise in interdisciplinary research in biomedicine 8,11 with a particular focus on mechanistic mathematical modelling 8,9 including in vitro to in vivo extrapolation, as well as the analysis of complex clinical samples 10. Within this consortium, we aspire to combine biochemical data from PrevOP subprojects SP1-3 (inflammation, cartilage self-repair & pain) and OVERLOAD projects SP5, 7-8 (fluid transport, mechano-sensitive signalling, cartilage self-repair), to successively develop mathematical models of cartilage homeostasis. Particularly, integration of results from OVERLOAD SP5 may allow to couple image-derived clinical data to metabolic events in the cartilage. The developed comprehensive model of OAK will further our understanding of the  disease and the interplay of the mentioned factors, provide insights into disease mechanisms and strategies for its prevention (like, e.g. physical training). The aim of the project is thus to provide a translational framework between in vitro bio-molecular studies, ex vivo analysis, animal models and human patients with OAK (clinical projects in PrevOP/OVERLOAD).

SP P6: Clinical Trial: Preventing the impairment of primary Osteoarthritis by high impact long-term Physical exercise regimen (PrevOP)

Dieter Felsenberg, Wolfgang Ertel, Zully Ritter, Gabriele Armbrecht, Hendrikje Börst, Kay Raum (all from Charité-Universitätsmedizin Berlin), Peter Martus (Eberhard Karls University Tübingen)

SP P7: Clinical Trial: Self-regulatory interventions to facilitate physical exercise maintenance

Nina Knoll, Ralf Schwarzer (Freie Universität Berlin)

Background: The main objectives for physical activity prescribed to persons at risk for knee osteoarthritis (OAK) are enhancing the mobility and required range of motion of the joint and increasing the strength and endurance of the muscles. This requires voluntary action and, therefore, becomes subject to adherence failure. There is no medical solution to this problem, but a psychological program could make a substantial contribution. Supervised individualized exercise therapy and self-management techniques have been shown to enhance exercise adherence. Using the Health Action Process Approach (HAPA) as a theoretical backdrop, SPP7 aims to develop and evaluate a theory-based psychological adherence program (PAP) that is performed on top of the main medical trial (MMT; SPP6, Felsenberg et al.) and is designed to strengthen long-term self-management in the maintenance of MMT-condition-specific physical activity throughout a 24-month period. Increased physical activity is proposed to be a behavioral predictor of reduced OAK symptoms (as assessed by the WOMAC). Primary hypothesis: Positive effects of a psychological adherence program on OAK symptoms (i.e., WOMAC scores; primary endpoint) will be mediated via increases in physical activity (objectively assessed; key secondary endpoint). The effect of physical activity on OAK symptoms will be further moderated by MMT-group membership.

Method: Following baseline and prior to randomization all participants (N=240) will receive a basic knowledge transfer/motivational treatment.  Participants from each MMT-condition (MMT-HIE, n=80; MMT-LIE, n=80; MMT-CTRL, n=80) will then be further randomized either to a control group (PAP-CTRL, n = 120) or a multi-phase psychological adherence program (PAP-I, n = 120) with several additional motivational (e.g., decisional balance, recall of mastery, goal setting) as well as volitional (e.g., action and coping planning, action control) intervention components implemented. The main intervention delivery modes will be written materials and computer-assisted telephone interviews (CATIs), conducted by trained research assistants. The control group will not receive further psychological treatment, only assessments. Over the course of 2 years, total of 5 measurement points in time will include self-report questionnaires as well as accelerometer-based assessments of physical activity. Assessments of self-reports will take place at months 0 (baseline), 6, 12, 18, 24; accelerometer assessments will take place at months 0, 12, 24. Primary efficacy endpoint are  OAK symptoms (i.e., WOMAC scores). Key secondary endpoint(s) include frequency and duration of moderate and vigorous physical activity using accelerometers; self-reported physical activity, log sheets of MMT-adherence in physical exercise sessions, several social-cognitive predictors of change in physical activity, emotional well-being, and pain.