Dirk Elewaut

Publications of Dirk Elewaut

• The transition of acute to chronic bowel inflammation in spondyloarthritis.

  Authors: Liesbet Van Praet, Peggy Jacques, Filip Van den Bosch, Dirk Elewaut

  Nature reviews. Rheumatology. 04/2012;

  That gut and joint inflammation are linked in spondyloarthritis (SpA) has been recognized for almost three decades. Intriguingly, microscopic gut inflammation, which occurs frequently in patientsThat gut and joint inflammation are linked in spondyloarthritis (SpA) has been recognized for almost three decades. Intriguingly, microscopic gut inflammation, which occurs frequently in patients with SpA, is an important risk factor for clinically overt Crohn's disease and ankylosing spondylitis. This Review describes current insights into the underlying mechanisms that lead to chronic gut inflammation in patients with SpA. We propose that the development of chronic bowel inflammation in these individuals occurs through a transition phase, in which inflammation evolves from an acute into a chronic state. Our transition model implies that different cell types are involved at different stages during disease progression, with stromal cells having an important role in chronicity. In addition, deficient regulatory feedback mechanisms or genetically determined alterations in antigen presentation, endoplasmic reticulum stress, autophagy or cytokine signaling might also favor a transition from self-limiting acute inflammation to chronic inflammation. We anticipate that this transition phase might be an important window for therapeutic intervention.

• First Insights into Human Acetabular Labrum Cell Metabolism.

  Authors: Aad A M Dhollander, Stijn Lambrecht, Peter C M Verdonk, Emmanuel A Audenaert, Karl F Almqvist, Christophe Pattyn, René Verdonk, Dirk Elewaut, Gust Verbruggen

  Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 04/2012;

  OBJECTIVE: Hip labrum pathology has only begun to emerge as a significant source of groin pain in the last decade since the development of hip arthroscopy. Few data are available on the anatomy,OBJECTIVE: Hip labrum pathology has only begun to emerge as a significant source of groin pain in the last decade since the development of hip arthroscopy. Few data are available on the anatomy, histology and function of this structure. Moreover, no metabolic data exist at cellular level. The aim of this study was to characterize extracellular matrix (ECM) genes and pro-inflammatory mediators expressed by these cells. METHODS: Isolated human acetabular labrum cells were cultured in alginate beads for 10 days and additionally stimulated with IL-1 for 24 hours. Gene expression levels and secretion of different ECM genes, enzymes and cytokines were examined by quantitative PCR and ELISA to assess the metabolic characteristics of labrum cells. Articular chondrocytes and meniscus cells served as controls. RESULTS: Labrum cells expressed high levels of COL1A1 and low levels of COL2A1, aggrecan and SOX-9 compared to chondrocytes. However, COL2A1 was more expressed by labrum cells than by meniscus cells. The expression of MMP-1/-2/-9, ADAMTS-4 and IL-6 was significantly higher in labrum cells than in chondrocytes. IL-1 suppressed the ECM gene expression levels of labrum cells, but increased the expression levels and release of MMP-1/-3/-9/-13 and ADAMTS-4 and IL-6 by these cells. Remarkably, MMP-9 was only significantly upregulated in acetabular labrum cells. CONCLUSIONS: The findings in this study demonstrated that the acetabular labrum is populated with unique highly active fibrochondrocyte-like cells. These cells are capable of expressing and releasing pro-inflammatory enzymes and cytokines and react to a pro-inflammatory stimulus. In this way, they contribute obviously to disturbed tissue function in hip labrum pathology.

• A pilot study of the use of an osteochondral scaffold plug for cartilage repair in the knee and how to deal with early clinical failures.

  Authors: Aad A M Dhollander, Koen Liekens, Karl F Almqvist, René Verdonk, Stijn Lambrecht, Dirk Elewaut, Gust Verbruggen, Peter C M Verdonk

  Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association. 02/2012; 28(2):225-33.

  To present our short-term experience with an osteochondral scaffold plug (TruFit plug; Smith & Nephew, Andover, MA) for cartilage repair in the knee and, more importantly, to discuss our approach toTo present our short-term experience with an osteochondral scaffold plug (TruFit plug; Smith & Nephew, Andover, MA) for cartilage repair in the knee and, more importantly, to discuss our approach to treat early clinical failures. Twenty patients were consecutively treated for their cartilage lesions with the plug technique. These patients were prospectively clinically evaluated at 6 and 12 months of follow-up. Magnetic resonance imaging (MRI) was used for morphologic analysis of the cartilage repair. Biopsy samples were taken from 3 cases during revision surgery, allowing histologic assessment of the repair tissue. The short-term clinical and MRI outcome of this pilot study are modest. No signs of deterioration of the repair tissue were observed. Of the 15 patients followed up during 1 year, 3 (20.0%) showed persistent clinical symptoms or even more clinical symptoms after insertion of the plug. These patients were considered as failures and therefore eligible for revision surgery. During revision surgery, the repair tissue was carefully removed. The remaining osteochondral defect was filled with autologous bone grafts. Immediate and persistent relief of symptoms was observed in all 3 patients. Histologic assessment of biopsy specimens taken during revision surgery showed fibrous vascularized repair tissue with the presence of foreign-body giant cells. The overall short-term clinical and MRI outcome of the osteochondral scaffold plug for cartilage repair in the knee is modest. In this pilot study a modest clinical improvement became apparent at 12 months of follow-up. MRI data showed no deterioration of the repair tissue. Of the 15 patients, 3 (20%) had persistent clinical symptoms after surgery. These patients were successfully treated with removal of the osteochondral plug remnants and the application of autologous bone grafts. Level IV, therapeutic case series.

• Divergent synthetic approach to 6''-modified α-GalCer analogues.

  Authors: Nora Pauwels, Sandrine Aspeslagh, Gerd Vanhoenacker, Koen Sandra, Esther D Yu, Dirk M Zajonc, Dirk Elewaut, Bruno Linclau, Serge Van Calenbergh

  Organic & biomolecular chemistry. 12/2011; 9(24):8413-21.

  A synthetic approach is presented for the synthesis of galacturonic acid and D-fucosyl modified KRN7000. The approach allows for late-stage functionalisation of both the sugar 6''-OH and theA synthetic approach is presented for the synthesis of galacturonic acid and D-fucosyl modified KRN7000. The approach allows for late-stage functionalisation of both the sugar 6''-OH and the sphingosine amino groups, which enables convenient synthesis of promising 6''-modified KRN7000 analogues.

• Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification.

  Authors: Gust Verbruggen, Ruth Wittoek, Bert Vander Cruyssen, Dirk Elewaut

  Annals of the rheumatic diseases. 11/2011;

  BACKGROUND: Adalimumab blocks the action of tumor necrosis factor-α and reduces disease progression in rheumatoid arthritis and psoriatic arthritis. The effects of adalimumab in controllingBACKGROUND: Adalimumab blocks the action of tumor necrosis factor-α and reduces disease progression in rheumatoid arthritis and psoriatic arthritis. The effects of adalimumab in controlling progression of structural damage in erosive hand osteoarthritis (HOA) were assessed.METHODS: Sixty patients with erosive HOA on radiology received 40 mg adalimumab or placebo subcutaneously every two weeks during a 12-month randomized double-blind trial. Response was defined as the reduction in progression of structural damage according to the categorical anatomic phase scoring system. Furthermore, subchondral bone, bone plate erosion, and joint-space narrowing were scored according to the continuous Ghent University Score System (GUSSTM).RESULTS: The disease appeared to be active since 40.0% and 26,7% of patients out of the placebo and adalimumab group, respectively, showed at least one new interphalangeal (IP) joint that became erosive during the 12 months follow-up. These differences were not significant and the overall results showed no effect of adalimumab.Risk factors for progression were then identified and the presence of palpable soft tissue swelling at baseline was recognized as the strongest predictor for erosive progression. In this subpopulation at risk, statistically significant less erosive evolution on the radiological image (3.7%) was seen in the adalimumab treated group compared to the placebo group (14.5%) (P = 0.009). GUSSTM scoring confirmed a less rapid rate of mean increase in the erosion scores during the first 6 months of treatment in patients in adalimumab-treated patients.CONCLUSION: Palpable soft tissue swelling in IP joints in patients with erosive HOA is a strong predictor for erosive progression. In these joints adalimumab significantly halted the progression of joint damage compared to placebo.

• Midterm results of the treatment of cartilage defects in the knee using alginate beads containing human mature allogenic chondrocytes.

  Authors: Aad A M Dhollander, Peter C M Verdonk, Stijn Lambrecht, René Verdonk, Dirk Elewaut, Gust Verbruggen, Karl Fredrik Almqvist

  The American journal of sports medicine. 09/2011; 40(1):75-82.

  The treatment of chondral lesions is still an important challenge for the orthopaedic surgeon. Attempts have been made to restore cartilage lesions by filling the defects with a temporaryThe treatment of chondral lesions is still an important challenge for the orthopaedic surgeon. Attempts have been made to restore cartilage lesions by filling the defects with a temporary biocompatible matrix. The authors present their midterm experience with the implantation of alginate beads containing human mature allogenic chondrocytes for the treatment of cartilage lesions in the knee. Case series; Level of evidence, 4. A biodegradable, alginate-based biocompatible scaffold containing human mature allogenic chondrocytes was used for the treatment of cartilage lesions in the knee. Twenty-one patients were clinically prospectively evaluated with use of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and a visual analog scale (VAS). The mean follow-up time was 6.3 years (range, 5-8 years). Magnetic resonance imaging (MRI) data were analyzed based on the MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) system, allowing morphologic assessment of the repair tissue. Magnetic resonance images were taken at 1 year of follow-up and at a mean follow-up of 6.1 years (range, 5-7 years). During the follow-up period, the WOMAC and VAS scores improved significantly. No signs of clinical deterioration or adverse reactions to the alginate beads/allogenic chondrocyte implantation were observed. Four failures occurred during the follow-up period in this study (19.05%). The MOCART scores were moderate and remained stable in time. This investigation provided useful information on the efficacy of the implantation of alginate beads containing human mature allogenic chondrocytes for the treatment of cartilage lesions in the knee. The midterm clinical outcome of the presented technique was satisfactory. However, these results were not confirmed by the MRI findings.

• Regulating the regulators: SOCS3 joins the dance.

  Authors: Michael Drennan, Dirk Elewaut

  Annals of the rheumatic diseases. 09/2011; 70(12):2061-2.

• Selection of non-competitive leptin antagonists using a random nanobody-based approach.

  Authors: Lennart Zabeau, Annick Verhee, Dominiek Catteeuw, Liesbeth Faes, Sylvie Seeuws, Tine Decruy, Dirk Elewaut, Frank Peelman, Jan Tavernier

  The Biochemical journal. 08/2011; 441(1):425-34.

  The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. Accumulating evidenceThe adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. Accumulating evidence suggests that leptin plays a role in human pathologies, such as autoimmune diseases and cancer, thus providing a rationale for the development of leptin antagonists. In the present study, we generated and evaluated a panel of neutralizing nanobodies targeting the LR (leptin receptor). A nanobody comprises the variable domain of the naturally occurring single-chain antibodies found in members of the Camelidae family. We identified three classes of neutralizing nanobodies targeting different LR subdomains: i.e. the CRH2 (cytokine receptor homology 2), Ig-like and FNIII (fibronectin type III) domains. Only nanobodies directed against the CRH2 domain inhibited leptin binding. We could show that a nanobody that targets the Ig-like domain potently interfered with leptin-dependent regulation of hypothalamic NPY (neuropeptide Y) expression. As a consequence, daily intraperitoneal injection increased body weight, body fat content, food intake, liver size and serum insulin levels. All of these characteristics resemble the phenotype of leptin and LR-deficient animals. The results of the present study support proposed models of the activated LR complex, and demonstrate that it is possible to block LR signalling without affecting ligand binding. These nanobodies form new tools to study the mechanisms of BBB (blood-brain barrier) leptin transport and the effect of LR inhibition in disease models.

• A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis.

  Authors: Mourad Matmati, Peggy Jacques, Jonathan Maelfait, Eveline Verheugen, Mirjam Kool, Mozes Sze, Lies Geboes, Els Louagie, Conor Mc Guire, Lars Vereecke, Yuanyuan Chu, Louis Boon, Steven Staelens, Patrick Matthys, Bart N Lambrecht, Marc Schmidt-Supprian, Manolis Pasparakis, Dirk Elewaut, Rudi Beyaert, Geert van Loo

  Nature genetics. 08/2011; 43(9):908-12.

  A20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-κB signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as aA20 (TNFAIP3) is a protein that is involved in the negative feedback regulation of NF-κB signaling in response to specific proinflammatory stimuli in different cell types and has been suggested as a susceptibility gene for rheumatoid arthritis. To define the contribution of A20 to rheumatoid arthritis pathology, we generated myeloid-specific A20-deficient mice and show that specific ablation of Tnfaip3 in myeloid cells results in spontaneous development of a severe destructive polyarthritis with many features of rheumatoid arthritis. Myeloid-A20-deficient mice have high levels of inflammatory cytokines in their serum, consistent with a sustained NF-κB activation and higher TNF production by macrophages. Destructive polyarthritis in myeloid A20 knockout mice was TLR4-MyD88 and IL-6 dependent but was TNF independent. Myeloid A20 deficiency also promoted osteoclastogenesis in mice. Together, these observations indicate a critical and cell-specific function for A20 in the etiology of rheumatoid arthritis, supporting the idea of developing A20 modulatory drugs as cell-targeted therapies.

• Mucosal inflammation in spondylarthritides: past, present, and future.

  Authors: Liesbet Van Praet, Filip Van den Bosch, Herman Mielants, Dirk Elewaut

  Current rheumatology reports. 07/2011; 13(5):409-15.

  Spondylarthritides (SpA) and inflammatory bowel disease (IBD) are idiopathic, chronic inflammatory disorders. Although they are very distinct and well-defined entities, there is clinical and geneticSpondylarthritides (SpA) and inflammatory bowel disease (IBD) are idiopathic, chronic inflammatory disorders. Although they are very distinct and well-defined entities, there is clinical and genetic evidence supporting some degree of overlap between the pathogenesis of the two. Subclinical gut inflammation is present in up to two thirds of all SpA patients and can evolve into IBD. This subclinical gut inflammation has been shown to be strongly associated with joint inflammation, providing a clue for a common pathophysiologic background. Despite extensive research progress in the field over the past few years, many questions remain unanswered. In this paper, we focus on the clinical, genetic, and pathophysiologic overlap of SpA and IBD. Furthermore, we discuss some of the targets that may influence therapeutic decision making.

• The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity.

  Authors: Mirjam Kool, Geert van Loo, Wim Waelput, Sofie De Prijck, Femke Muskens, Mozes Sze, Jens van Praet, Filipe Branco-Madeira, Sophie Janssens, Boris Reizis, Dirk Elewaut, Rudi Beyaert, Hamida Hammad, Bart N Lambrecht

  Immunity. 06/2011; 35(1):82-96.

  Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (Tnfaip3) determines the activation threshold of DCs, via control of canonicalDendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (Tnfaip3) determines the activation threshold of DCs, via control of canonical NF-κB activation. Tnfaip3(fl/fl)Cd11c-cre(+) mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative T cells, their conversion to interferon-γ (IFN-γ)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly-features of systemic lupus erythematosus-and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorphisms in TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity.

• Galactose-modified iNKT cell agonists stabilized by an induced fit of CD1d prevent tumour metastasis.

  Authors: Sandrine Aspeslagh, Yali Li, Esther Dawen Yu, Nora Pauwels, Matthias Trappeniers, Enrico Girardi, Tine Decruy, Katrien Van Beneden, Koen Venken, Michael Drennan, Luc Leybaert, Jing Wang, Richard W Franck, Serge Van Calenbergh, Dirk M Zajonc, Dirk Elewaut

  The EMBO journal. 06/2011; 30(11):2294-305.

  Invariant natural killer T (iNKT) cells are known to have marked immunomodulatory capacity due to their ability to produce copious amounts of effector cytokines. Here, we report the structure andInvariant natural killer T (iNKT) cells are known to have marked immunomodulatory capacity due to their ability to produce copious amounts of effector cytokines. Here, we report the structure and function of a novel class of aromatic α-galactosylceramide structurally related glycolipids with marked Th1 bias in both mice and men, leading to superior tumour protection in vivo. The strength of the Th1 response correlates well with enhanced lipid binding to CD1d as a result of an induced fit mechanism that binds the aromatic substitution as a third anchor, in addition to the two lipid chains. This induced fit is in contrast to another Th1-biasing glycolipid, α-C-GalCer, whose CD1d binding follows a conventional key-lock principle. These findings highlight the previously unexploited flexibility of CD1d in accommodating galactose-modified glycolipids and broaden the range of glycolipids that can stimulate iNKT cells. We speculate that glycolipids can be designed that induce a similar fit, thereby leading to superior and more sustained iNKT cell responses in vivo.

• Systematic candidate gene investigations in the SPA2 locus (9q32) show an association between TNFSF8 and susceptibility to spondylarthritis.

  Authors: Elena Zinovieva, Amir Kadi, Franck Letourneur, Nicolas Cagnard, Brigitte Izac, Agathe Vigier, Roula Said-Nahal, Dirk Elewaut, Kurt de Vlam, Fernando Pimentel-Santos, Gilles Chiocchia, Maxime Breban

  Arthritis and rheumatism. 04/2011; 63(7):1853-9.

  Our group previously identified a new susceptibility region linked to spondylarthritis (SpA) on chromosome 9q31-34. Fine mapping of this SPA2 locus allowed us to refine the peak of linkage to aOur group previously identified a new susceptibility region linked to spondylarthritis (SpA) on chromosome 9q31-34. Fine mapping of this SPA2 locus allowed us to refine the peak of linkage to a 1.3-Mb interval. The objective of this study was to resequence most positional candidate genes lying in that region, to identify polymorphisms, and to examine their association with SpA. Variants screening was performed in 30 independent patients with SpA from families with a high linkage score to the SPA2 locus and 30 control subjects. The coding regions, intron-exon boundaries, and 5'- and 3'-flanking regions of ZNF618, A1L4R1_HUMAN (AF495724), AMBP, KIF12, ORM1, ORM2, C9ORF91, ENSESTG000000230601, and TNFSF8 were resequenced to identify polymorphisms. Selected variants were genotyped in an extended French cohort (442 patients and 268 control subjects overall). Replication was performed in a combined Belgian and Portuguese cohort (433 patients and 299 control subjects). Variants screening allowed us to identify 98 polymorphisms, 5 of which were selected for further studies, based on statistical significance. The rare intronic single-nucleotide polymorphism (SNP) rs3181357, located in TNFSF8, was significantly associated with SpA in the French and the replication cohorts (odds ratio [OR] 2.03, P = 0.009 and OR 2.26, P = 0.0014, respectively) and in the pooled analysis (OR 2.14, P = 0.0001). Positional candidate gene screening in the SPA2 locus allowed us to identify and replicate an association between a rare SNP located in TNFSF8 and SpA. This new finding appears to be independent of an association with a haplotype near TNFSF15, which we recently reported.

• Specific anti-nuclear antibodies in systemic sclerosis patients with and without skin involvement: an extended methodological approach.

  Authors: Jens T Van Praet, Katleen Van Steendam, Vanessa Smith, Georges De Bruyne, Tsuneyo Mimori, Carolien Bonroy, Dirk Elewaut, Dieter Deforce, Filip De Keyser

  Rheumatology (Oxford, England). 02/2011; 50(7):1302-9.

  To determine how sensitively SSc-associated ANAs are detected by a standard identification algorithm compared with an extensive panel of ANA identification assays, and to assess the distribution ofTo determine how sensitively SSc-associated ANAs are detected by a standard identification algorithm compared with an extensive panel of ANA identification assays, and to assess the distribution of SSc-associated ANAs and SSc organ system involvement in patients without skin involvement (limited SSc). Serum samples from 145 consecutive monocentric SSc patients fulfilling LeRoy and Medgser's criteria for early SSc were studied. ANAs were detected by IIF on HEp-2000 cells and identified by western blotting, protein radio-immunoprecipitation, RNA immunoprecipitation and line immunoassay (LIA). SSc organ involvement was assessed according to a modification of Medsger's disease severity scale. At least one specific ANA reactivity was present in 88% of the patients. The standard algorithm (IIF and LIA) found at least one specific ANA in 74% of the patients. The main reactivities missed by this algorithm were anti-RNA polymerase III, anti-PM/Scl and anti-Th/To. Eighty-three percent of the patients with limited SSc had at least one ANA. ACAs and anti-Th/To antibodies were significantly associated with limited SSc, whereas anti-topoisomerase I and anti-RNA polymerase III were observed less frequently. SSc organ system involvement was present in 63% of the patients with limited SSc, most of whom had lung involvement. Standard algorithms for ANA identification lack sensitivity for the detection of SSc-associated ANA and should be supplemented with additional assays, especially in a clinical environment that has particular interest in SSc. The spectrum of SSc-associated ANA differs according to the presence or absence of skin involvement.

• Optimized alkylated cyclodextrin polysulphates with reduced risks on thromboembolic accidents improve osteoarthritic chondrocyte metabolism.

  Authors: Sara Groeneboer, Stijn Lambrecht, Aad Dhollander, Peggy Jacques, Bert Vander Cruyssen, Rik J Lories, Katrien Devreese, Koen Chiers, Dirk Elewaut, Gust Verbruggen

  Rheumatology (Oxford, England). 02/2011; 50(7):1226-35.

  To compare the ability of different cyclodextrin polysulphate (CDPS) derivatives to affect human articular cartilage cell metabolism in vitro. OA chondrocytes were cultured in alginate and exposed toTo compare the ability of different cyclodextrin polysulphate (CDPS) derivatives to affect human articular cartilage cell metabolism in vitro. OA chondrocytes were cultured in alginate and exposed to 5 µg/ml of 2,3,6-tri-O-methyl-β-cyclodextrin (ME-CD), 2,3-di-O-methyl-6-sulphate-β-cyclodextrin (ME-CD-6-S), 2,6-di-O-methyl-3-sulphate-β-cyclodextrin (ME-CD-3-S), (2-carboxyethyl)-β-CDPS (CE-CDPS), (2-hydroxypropyl)-β-CDPS (HP-CDPS), 6-monoamino-6-monodeoxy-β-CDPS (MA-CDPS) or β-CDPS for 5 days. Effects on IL-1-driven chondrocyte extracellular matrix (ECM) metabolism were assayed by analysis of the accumulation of aggrecan in the interterritorial matrix, IL-6 secretion and qPCR. MA-CDPS, HP-CDPS, CE-CDPS and CDPS were analysed for their in vitro effect on coagulation and their ability to activate platelets in an in vitro assay to detect possible cross-reactivity with heparin-induced thrombocytopenia (HIT) antibodies. The monosulphated cyclodextrins ME-CD-6-S and -3-S failed to affect aggrecan synthesis and IL-6 secretion by the OA chondrocytes. Polysulphated cyclodextrins MA-CDPS, HP-CDPS, CE-CDPS and CDPS at 5 µg/ml concentrations, on the other hand, significantly induced aggrecan production and repressed IL-6 release by the chondrocytes in culture. aPTT and PT for all derivatives were lengthened for polysaccharide concentrations >50 µg/ml. Five micrograms per millilitre of β-CDPS concentrations that significantly modulated ECM ground substance production in vitro did not affect aPTT or PT. Furthermore, CE-CDPS, in contrast to MA-CDPS, HP-CDPS and CDPS, did not significantly activate platelets, suggesting a minimal potential to induce HIT thromboembolic accidents in vivo. CE-CDPS is a new, structurally adjusted, sulphated β-cyclodextrin derivative with preserved chondroprotective capacity and a promising safety profile.

• Histopathological cutaneous alterations in systemic sclerosis: a clinicopathological study.

  Authors: Jens T Van Praet, Vanessa Smith, Marc Haspeslagh, Nele Degryse, Dirk Elewaut, Filip De Keyser

  Arthritis research & therapy. 02/2011; 13(1):R35.

  The aims of the present study were to identify histopathological parameters which are linked to local clinical skin disease at two distinct anatomical sites in systemic sclerosis (SSc) patients withThe aims of the present study were to identify histopathological parameters which are linked to local clinical skin disease at two distinct anatomical sites in systemic sclerosis (SSc) patients with skin involvement (limited cutaneous systemic sclerosis (lcSSc) or diffuse cutaneous systemic sclerosis (dcSSc)) and to determine the sensitivity of SSc specific histological alterations, focusing on SSc patients without clinical skin involvement (limited SSc (lSSc)). Histopathological alterations were systematically scored in skin biopsies of 53 consecutive SSc patients (dorsal forearm and upper inner arm) and 18 controls (upper inner arm). Clinical skin involvement was evaluated using the modified Rodnan skin score. In patients with lcSSc or dcSSc, associations of histopathological parameters with local clinical skin involvement were determined by generalised estimation equation modelling. The hyalinised collagen score, the myofibroblast score, the mean epidermal thickness, the mononuclear cellular infiltration and the frequency of focal exocytosis differed significantly between biopsies with and without local clinical skin involvement. Except for mononuclear cellular infiltration, all of the continuous parameters correlated with the local clinical skin score at the dorsal forearm. Parakeratosis, myofibroblasts and intima proliferation were present in a minority of the SSc biopsies, but not in controls. No differences were found between lSSc and controls. Several histopathological parameters are linked to local clinical skin disease. SSc-specific histological alterations have a low diagnostic sensitivity.

• Mechanisms regulating TNF-driven gut and joint inflammation.

  Authors: Dirk Elewaut, Peggy Jacques, Lode Melis, Koen Venken

  Advances in experimental medicine and biology. 01/2011; 691:403-8.

• An anti-inflammatory selective glucocorticoid receptor modulator preserves osteoblast differentiation.

  Authors: Alexander Rauch, Valerie Gossye, Debby Bracke, Elien Gevaert, Peggy Jacques, Katrien Van Beneden, Bernard Vandooren, Martina Rauner, Lorenz C Hofbauer, Guy Haegeman, Dirk Elewaut, Jan P Tuckermann, Karolien De Bosscher

  FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 01/2011; 25(4):1323-32.

  Glucocorticoids (GCs) are in widespread use to treat inflammatory bone diseases, such as rheumatoid arthritis (RA). Their anti-inflammatory efficacy, however, is accompanied by deleterious effects onGlucocorticoids (GCs) are in widespread use to treat inflammatory bone diseases, such as rheumatoid arthritis (RA). Their anti-inflammatory efficacy, however, is accompanied by deleterious effects on bone, leading to GC-induced osteoporosis (GIO). These effects include up-regulation of the receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratio to promote bone-resorbing osteoclasts and include inhibition of bone-forming osteoblasts. We previously identified suppression of osteoblast differentiation by the monomer glucocorticoid receptor (GR) via the inhibition of Il11 expression as a crucial mechanism for GIO. Here we show that the GR-modulating substance compound A (CpdA), which does not induce GR dimerization, still suppresses proinflammatory cytokines in fibroblast-like synovial cells from patients with RA and in osteoblasts. In contrast to the full GR agonist dexamethasone, it does not unfavorably alter the RANKL/OPG ratio and does not affect Il11 expression and subsequent STAT3 phosphorylation in these cells. Notably, while dexamethasone inhibits osteoblast differentiation, CpdA does not affect osteoblast differentiation in vitro and in vivo. We describe here for the first time that selective GR modulators can act against inflammation, while not impairing osteoblast differentiation.

• Disruption of the SapM locus in Mycobacterium bovis BCG improves its protective efficacy as a vaccine against M. tuberculosis.

  Authors: Nele Festjens, Pieter Bogaert, Anjana Batni, Erica Houthuys, Evelyn Plets, Dieter Vanderschaeghe, Bram Laukens, Bob Asselbergh, Eef Parthoens, Riet De Rycke, Monique A Willart, Peggy Jacques, Dirk Elewaut, Peter Brouckaert, Bart N Lambrecht, Kris Huygen, Nico Callewaert

  EMBO molecular medicine. 01/2011; 3(4):222-34.

  Mycobacterium bovis bacille Calmette-Guerin (BCG) provides only limited protection against pulmonary tuberculosis. We tested the hypothesis that BCG might have retained immunomodulatory propertiesMycobacterium bovis bacille Calmette-Guerin (BCG) provides only limited protection against pulmonary tuberculosis. We tested the hypothesis that BCG might have retained immunomodulatory properties from its pathogenic parent that limit its protective immunogenicity. Mutation of the molecules involved in immunomodulation might then improve its vaccine potential. We studied the vaccine potential of BCG mutants deficient in the secreted acid phosphatase, SapM, or in the capping of the immunomodulatory ManLAM cell wall component with α-1,2-oligomannoside. Both systemic and intratracheal challenge of mice with Mycobacterium tuberculosis following vaccination showed that the SapM mutant, compared to the parental BCG vaccine, provided better protection: it led to longer-term survival. Persistence of the SapM-mutated BCG in vivo resembled that of the parental BCG indicating that this mutation will likely not compromise the safety of the BCG vaccine. The SapM mutant BCG vaccine was more effective than the parental vaccine in inducing recruitment and activation of CD11c(+) MHC-II(int) CD40(int) dendritic cells (DCs) to the draining lymph nodes. Thus, SapM acts by inhibiting recruitment of DCs and their activation at the site of vaccination.

• Involvement of endoplasmic reticulum stress in inflammatory bowel disease: a different implication for colonic and ileal disease?

  Authors: Sara Bogaert, Martine De Vos, Kim Olievier, Harald Peeters, Dirk Elewaut, Bart Lambrecht, Philippe Pouliot, Debby Laukens

  PloS one. 01/2011; 6(10):e25589.

  Endoplasmic reticulum (ER) stress has been suggested to play a role in inflammatory bowel disease (IBD). The three branches (ATF6, IRE1 and PERK) of the unfolded protein response (UPR) have differentEndoplasmic reticulum (ER) stress has been suggested to play a role in inflammatory bowel disease (IBD). The three branches (ATF6, IRE1 and PERK) of the unfolded protein response (UPR) have different roles and are not necessarily activated simultaneously. Expression of UPR-related genes was investigated in colonic and ileal biopsies of 23 controls, 15 ulcerative colitis (UC) and 54 Crohn's disease (CD) patients. This expression was confirmed at protein level in colonic and ileal samples of five controls, UC and CD patients. HSPA5, PDIA4 and XBP1s were significantly increased in colonic IBD at mRNA and/or protein levels, indicating activation of the ATF6 and IRE1 branch. Colonic IBD was associated with increased phosphorylation of EIF2A suggesting the activation of the PERK branch, but subsequent induction of GADD34 was not observed. In ileal CD, no differential expression of the UPR-related genes was observed, but our data suggested a higher basal activation of the UPR in the ileal mucosa of controls. This was confirmed by the increased expression of 16 UPR-related genes as 12 of them were significantly more expressed in ileal controls compared to colonic controls. Tunicamycin stimulation of colonic and ileal samples of healthy individuals revealed that although the ileal mucosa is exhibiting this higher basal UPR activation, it is still responsive to ER stress, even more than colonic mucosa. Activation of the three UPR-related arms is seen in colonic IBD-associated inflammation. However, despite EIF2A activation, inflamed colonic tissue did not increase GADD34 expression, which is usually involved in re-establishment of ER homeostasis. This study also implies the presence of a constitutive UPR activation in healthy ileal mucosa, with no further activation during inflammation. Therefore, engagement of the UPR differs between colon and ileum and this could be a factor in the development of ileal or colonic disease.