Skeletal Biology and Engineering Research Center

Leuven, Belgium

Skeletal Biology and Engineering Research Center

Leuven, Belgium
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Karsdal M.A.,Nordic Bioscience A S | Bay-Jensen A.C.,Nordic Bioscience A S | Lories R.J.,Skeletal Biology and Engineering Research Center | Lories R.J.,University Hospitals Leuven | And 8 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Osteoarthritis (OA) is the most common form of arthritic disease, and a major cause of disability and impaired quality of life in the elderly. OA is a complex disease of the entire joint, affecting bone, cartilage and synovium that thereby presents multiple targets for treatment. This manuscript will summarise emerging observations from cell biology, preclinical and preliminary clinical trials that elucidate interactions between the bone and cartilage components in particular. Bone and cartilage health are tightly associated. Ample evidence has been found for bone changes during progression of OA including, but not limited to, increased turnover in the subchondral bone, undermineralisation of the trabecular structure, osteophyte formation, bone marrow lesions and sclerosis of the subchondral plate. Meanwhile, a range of investigations has shown positive effects on cartilage health when bone resorption is suppressed, or deterioration of the cartilage when resorption is increased. Known bone therapies, namely oestrogens, selective oestrogen receptor modifiers (SERMs), bisphosphonates, strontium ranelate, calcitonin and parathyroid hormone, might prove useful for treating two critical tissue components of the OA joint, the bone and the cartilage. An optimal treatment for OA likely targets at least these two tissue components. The patient subgroups for whom these therapies are most appropriate have yet to be fully defined but would likely include, at a minimum, those with high bone turnover.

Lories R.J.,Skeletal Biology and Engineering Research Center | Lories R.J.,University Hospitals Leuven | De Vlam K.,University Hospitals Leuven
Expert Opinion on Biological Therapy | Year: 2014

Introduction: Psoriatic arthritis is a common and often severe chronic joint disorder associated with the skin disease psoriasis (PsO). Treatment options for psoriatic arthritis patients have changed considerably over the last decade with the widespread use of biological therapies, in particular tumour necrosis factor inhibitors. Current clinical experience based on large registries and careful observations now allows us to understand the true value of these interventions in daily clinical practice. Areas covered: Literature searches were performed targeting effectiveness, drug survival, toxicity and safety of biological therapies as well as treatment strategies specifically focused on patients with psoriatic arthritis. Expert opinion: Tumour necrosis factor inhibition is a powerful and effective option for the treatment of severe psoriatic arthritis. The different available drugs have good survival rates and show an excellent balance between effectiveness and toxicity. Switching of inhibitor is feasible, but treatment changes should be carefully considered. Novel biological therapies are introduced into the market and will further provide better perspectives for the patient. New questions are also emerging: How to handle long-term remission, can biological therapies be successfully stopped and are co-morbidities sufficiently managed? These questions should be addressed for optimal long-term management of a severe chronic disease. © 2014 Informa UK, Ltd.

Thysen S.,Skeletal Biology and Engineering Research Center | Luyten F.P.,Skeletal Biology and Engineering Research Center | Luyten F.P.,University Hospitals Leuven | Lories R.J.,Skeletal Biology and Engineering Research Center | Lories R.J.,University Hospitals Leuven
Osteoarthritis and Cartilage | Year: 2015

Objective: To investigate the specific role of Frizzled-related protein (FRZB) and Secreted frizzled-related protein 1 (SFRP1) in the onset and progression of Osteoarthritis (OA) using Frzb-/- and Sfrp1-/- mice in the destabilization of medial meniscus model (DMM), a slowly progressing model of OA. Secreted frizzled-related proteins (SFRPs) were identified as secreted Wingless-type (Wnt) antagonists. The Wnt signaling cascade is a major regulator in cartilage development, homeostasis and degeneration. Methods: The DMM model was surgically induced in eight-week-old male C57/Bl6 Frzb-/-, Sfrp1-/- or wild-type mice by transection of the medial meniscotibial ligament. Cartilage damage in the femoral and tibial articular surfaces was calculated following the Osteoarthritis Research Society International (OARSI) histopathology initiative guidelines. Histomorphometry was used to evaluate the subchondral bone plate thickness. Results: OA severity scores were significantly higher in the tibia of Frzb-/- mice as compared to littermates, whereas no interaction was seen between genotype and intervention in Sfrp1-/- mice. Moreover, the DMM model resulted in significantly greater subchondral bone changes compared to sham but was not different between Frzb-/- mice and littermates. In contrast, the subchondral bone properties in Sfrp1-/- mice were significantly different from littermates. Conclusion: Using the DMM model, we demonstrated that FRZB and SFRP1 differentially modulate joint homeostasis in two distinct compartments of the joint. These data highlight the fine-tuning of Wnt signaling in joint homeostasis and disease, show differential regulation of the cascade in cartilage and subchondral bone, and provide further evidence for a role of endogenous Wnt modulators as key players in OA. © 2014 Osteoarthritis Research Society International.

Lories R.J.,Skeletal Biology and Engineering Research Center | Lories R.J.,University Hospitals Leuven | Haroon N.,University of Toronto
Best Practice and Research: Clinical Rheumatology | Year: 2014

The success of targeted therapies directed against tumor necrosis factor for patients with spondyloarthritis has shifted the focus of physicians and scientists towards the prevention of structural damage to the involved structures, in particular the sacroiliac joints and the spine, to avoid loss of function and disability. Structural damage to the skeleton as witnessed by radiography mainly consists of new bone formation potentially progressively leading to spine or joint ankylosis. This important long-term outcome parameter has been difficult to study, not alone because the time window for change may be long but also because human tissues with direct translational relevance are rarely available. Data from rodent models have identified growth factor signaling pathways as relevant targets. Both human and animal studies have tried to understand the link between inflammation and new bone formation. At the current moment, most evidence points towards a strong link between both but with the question still lingering about the sequence of events, disease triggers, and the interdependence of both features of disease. New discoveries such as a masterswitch T cell population that carries the IL23 receptor and the analysis of auto-antibodies directed again noggin and sclerostin are contributing to innovative insights into the pathophysiology of disease. Long-term data with tumor necrosis factor (TNF) inhibitors also suggest that some window of opportunity may exist to inhibit structural disease progression. All these data provide support for a further critical analysis of the available datasets and boost research in the field. The introduction of novel disease definitions, in particular the characterization of non-radiographic axial spondyloarthritis patients, will likely be instrumental in our further understanding of structural damage. © 2014 Elsevier Ltd. All rights reserved.

Verleyen D.,Skeletal Biology and Engineering Research Center | Luyten F.P.,Skeletal Biology and Engineering Research Center | Tylzanowski P.,Skeletal Biology and Engineering Research Center | Tylzanowski P.,Medical University of Lublin
PLoS ONE | Year: 2014

GPR22 is an orphan G protein-coupled receptor (GPCR). Since the ligand of the receptor is currently unknown, its biological function has not been investigated in depth. Many GPCRs and their intracellular effectors are targeted to cilia. Cilia are highly conserved eukaryotic microtubule-based organelles that protrude from the membrane of most mammalian cells. They are involved in a large variety of physiological processes and diseases. However, the details of the downstream pathways and mechanisms that maintain cilia length and structure are poorly understood. We show that morpholino knock down or overexpression of gpr22 led to defective left-right (LR) axis formation in the zebrafish embryo. Specifically, defective LR patterning included randomization of the left-specific lateral plate mesodermal genes (LPM) (lefty1, lefty2, southpaw and pitx2a), resulting in randomized cardiac looping. Furthermore, gpr22 inactivation in the Kupffer's vesicle (KV) alone was still able to generate the phenotype, indicating that Gpr22 mainly regulates LR asymmetry through the KV. Analysis of the KV cilia by immunofluorescence and transmission electron microscopy (TEM), revealed that gpr22 knock down or overexpression resulted in changes of cilia length and structure. Further, we found that Gpr22 does not act upstream of the two cilia master regulators, Foxj1a and Rfx2. To conclude, our study characterized a novel player in the field of ciliogenesis. © 2014 Verleyen et al.

Van Mechelen M.,Skeletal Biology and Engineering Research Center | Lories R.J.,Skeletal Biology and Engineering Research Center
Current Opinion in Rheumatology | Year: 2016

Purpose of review Novel clinical and animal model data support that biomechanical factors play a role in the onset and progression of spondyloarthritis. Bringing together these insights with the progress made in our understanding of the immunopathogenesis and genetic susceptibility of spondyloarthritis may provide new opportunities for better management. Recent findings Tail suspension prevents arthritis in a tumor necrosis factor overexpression model. A similar approach also reduces new bone formation after acute arthritis in mice. Physical labor is associated with disease severity, including structural disease progression. Sentinel immune cells in the enthesis provide a link between local damage and the development of inflammation. Loss of stability likely triggers tissue remodeling, including the formation of syndesmophytes. Improving muscle strength and control while avoiding excessive strain or overuse should be considered in the approach toward patients. New regulators of tissue turnover and remodeling are emerging including microRNAs. Summary Local damage may provide a trigger for spondyloarthritis. For structural disease progression loss of stability may be an important factor. Control of inflammation will prevent stability issues and improve the long-term prognosis of disease. Physical therapy will continue to provide benefit for patients in the short and in longterm management of disease. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved..

Westhovens I.,Skeletal Biology and Engineering Research Center | Lories R.J.,Skeletal Biology and Engineering Research Center | Westhovens R.,Skeletal Biology and Engineering Research Center | Verschueren P.,Skeletal Biology and Engineering Research Center | de Vlam K.,Skeletal Biology and Engineering Research Center
Clinical and Experimental Rheumatology | Year: 2014

Objective To report the incidence of malignancy in a large single-centre cohort in Belgium of patients with spondyloarthritis (SpA) treated with one or more anti-TNF therapies and to compare the results with the incidence of malignancy in the Belgian population. Methods From September 2000 until March 2010, all SpA patients that started treatment with one or more anti-TNF therapies were included in this single-centre prospective longitudinal observational study. The primary outcome of this study was the incidence of malignancy after starting anti-TNF treatment. Incidence rates were compared with the incidence rates of malignancy in Belgium in 2008 for the 45-50 year-old population, as documented by the Belgian Cancer Registry. Results 231 patients with a mean age of 47.86 y were included for a total of 1020.74 patient years of treatment and 1199.83 patient years follow-up after the start of treatment. In our study population, 6 out of 231 patients (2.6 %) developed a malignancy after the start of anti-TNF treatment. The overall incidence rate of malignancy in our study population is 500.1 per 100000 patient years, indicating a higher incidence compared to the Belgian population. We see a higher incidence rate in females as well in males; standardised incidence ratios are in the same range for both (154.3 for females and 130.6 for males). Conclusion We see a tendency towards a higher incidence of malignancy in SpA patients treated with anti-TNF therapy. However, it is not clear whether this increased risk is disease-related or treatment-related. © Clinical and Experimental Rheumatology 2014.

Maes C.,Skeletal Biology and Engineering Research Center
Seminars in Cell and Developmental Biology | Year: 2016

Endochondral ossification, the mechanism responsible for the development of the long bones, is dependent on an extremely stringent coordination between the processes of chondrocyte maturation in the growth plate, vascular expansion in the surrounding tissues, and osteoblast differentiation and osteogenesis in the perichondrium and the developing bone center. The synchronization of these processes occurring in adjacent tissues is regulated through vigorous crosstalk between chondrocytes, endothelial cells and osteoblast lineage cells. Our knowledge about the molecular constituents of these bidirectional communications is undoubtedly incomplete, but certainly some signaling pathways effective in cartilage have been recognized to play key roles in steering vascularization and osteogenesis in the perichondrial tissues. These include hypoxia-driven signaling pathways, governed by the hypoxia-inducible factors (HIFs) and vascular endothelial growth factor (VEGF), which are absolutely essential for the survival and functioning of chondrocytes in the avascular growth plate, at least in part by regulating the oxygenation of developing cartilage through the stimulation of angiogenesis in the surrounding tissues. A second coordinating signal emanating from cartilage and regulating developmental processes in the adjacent perichondrium is Indian Hedgehog (IHH). IHH, produced by pre-hypertrophic and early hypertrophic chondrocytes in the growth plate, induces the differentiation of adjacent perichondrial progenitor cells into osteoblasts, thereby harmonizing the site and time of bone formation with the developmental progression of chondrogenesis. Both signaling pathways represent vital mediators of the tightly organized conversion of avascular cartilage into vascularized and mineralized bone during endochondral ossification. © 2016.

Dirckx N.,Skeletal Biology and Engineering Research Center | Van Hul M.,Skeletal Biology and Engineering Research Center | Maes C.,Skeletal Biology and Engineering Research Center
Birth Defects Research Part C - Embryo Today: Reviews | Year: 2013

During endochondral bone development, bone-forming osteoblasts have to colonize the regions of cartilage that will be replaced by bone. In adulthood, bone remodeling and repair require osteogenic cells to reach the sites that need to be rebuilt, as a prerequisite for skeletal health. A failure of osteoblasts to reach the sites in need of bone formation may contribute to impaired fracture repair. Conversely, stimulation of osteogenic cell recruitment may be a promising osteo-anabolic strategy to improve bone formation in low bone mass disorders such as osteoporosis and in bone regeneration applications. Yet, still relatively little is known about the cellular and molecular mechanisms controlling osteogenic cell recruitment to sites of bone formation. In vitro, several secreted growth factors have been shown to induce osteogenic cell migration. Recent studies have started to shed light on the role of such chemotactic signals in the regulation of osteoblast recruitment during bone remodeling. Moreover, trafficking of osteogenic cells during endochondral bone development and repair was visualized in vivo by lineage tracing, revealing that the capacity of osteoblast lineage cells to move into new bone centers is largely confined to undifferentiated osteoprogenitors, and coupled to angiogenic invasion of the bone-modeling cartilage intermediate. It is well known that the presence of blood vessels is absolutely required for bone formation, and that a close spatial and temporal relationship exists between osteogenesis and angiogenesis. Studies using genetically modified mouse models have identified some of the molecular constituents of this osteogenic-angiogenic coupling. This article reviews the current knowledge on the process of osteoblast lineage cell recruitment to sites of active bone formation in skeletal development, remodeling, and repair, considering the role of chemo-attractants for osteogenic cells and the interplay between osteogenesis and angiogenesis in the control of bone formation. Birth Defects Research (Part C) 99:170-191, 2013. © 2013 Wiley Periodicals, Inc.

Carter S.L.,Skeletal Biology and Engineering Research Center | Lories R.J.,Skeletal Biology and Engineering Research Center
Osteoporosis International | Year: 2014

New bone formation leading to progressive ankylosis of the sacroiliac joints and the spine is an important feature of spondyloarthritis and contributes to patient disability. Current evidence supports the view that biomechanical factors contribute to these pathological remodeling events and trigger both inflammation and new bone formation. © 2014 International Osteoporosis Foundation and National Osteoporosis Foundation.

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