http://repub.eur.nl/res/aut/15694/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/18147/ 2010-02-17T00:00:00Z With the ongoing aging of the population worldwide, osteoarthritis (OA) is a disease that will affect increasing numbers of people. In the last decades ‘disease-modifying osteoarthritis drugs’ have received considerable interest. Glucosamine (GlcN) is one of the compounds which is claimed to slow down OA progression and to have a beneficial effect on OA-related symptoms when compared to placebo treatment. The general aim of this thesis was to gain more insight into the working mechanism of GlcN in OA. In the first part of the thesis in vitro experiments with different OA models, using the tissue types that can be involved in OA, were performed. In osteoarthritic cartilage it was found that GlcN was able to interfere with mechanisms leading to further cartilage degradation. Restoration of already damaged cartilage by GlcN is not to be expected. It was also shown that adding GlcN to cultures with human OA synovium, led to more hyaluronic acid in vitro. In the second part of the thesis GlcN was administered orally to patients using placebo-controlled methodology, to establish its effects on OA symptoms, and to examine the effects on joint tissue in vivo after a period of GlcN ingestion. It was found that GlcN was not significantly better than placebo in reducing symptoms and progression of hip OA. Considering the effects of oral GlcN on joint tissues in vivo, it appeared that administration of GlcN may have primed the cartilage such, that its sensitivity to adding GlcN in vitro increased. http://repub.eur.nl/res/pub/18275/ 2009-04-01T00:00:00Z Objective: Recently we reported that glucosamine sulphate (GS) did not have an effect on the symptoms and progression of primary care patients with hip osteoarthritis (OA). The aim of this present study was to investigate whether there are subgroups of patients with hip OA for whom GS might be an effective therapy. Method: We randomized 222 patients with hip OA that met one of the American College of Rheumatology criteria to either 1500 mg of oral GS or placebo once daily for 2 years. Subgroup analyses were predefined for radiographic severity (Kellgren & Lawrence (KL) = 1 vs ≥2) and for type of OA (localised vs generalised). Additional exploratory subgroup analyses focused on groups based on pain level, pain medication use, baseline joint space width (JSW), and concomitant knee OA at baseline. Primary outcome measures were Western Ontario MacMaster Universities (WOMAC) pain and function scores over 24 months, and joint space narrowing (JSN) after 24 months. Results: In the predefined subgroups based on radiographic severity and type of OA, the outcomes WOMAC pain, function and JSN were similar for the GS and placebo group. Conclusion: GS was not significantly better than placebo in reducing symptoms and progression of hip OA in subgroups of patients. http://repub.eur.nl/res/pub/14701/ 2008-10-08T00:00:00Z Background. Glucosamine (GlcN) used by patients with osteoarthritis was demonstrated to reduce pain, but the working mechanism is still not clear. Viscosupplementation with hyaluronic acid (HA) is also described to reduce pain in osteoarthritis. The synthesis of HA requires GlcN as one of its main building blocks. We therefore hypothesized that addition of GlcN might increase HA production by synovium tissue. Methods. Human osteoarthritic synovium explants were obtained at total knee surgery and pre-cultured for 1 day. The experimental conditions consisted of a 2 days continuation of the culture with addition of N-Acetyl-glucosamine (GlcN-Ac; 5 mM), glucosamine-hydrochloride (GlcN-HCl; 0.5 and 5 mM), glucose (Gluc; 0.5 and 5 mM). Hereafter HA production was measured in culture medium supernatant using an enzyme-linked binding protein assay. Real time RT-PCR was performed for hyaluronic acid synthase (HAS) 1, 2 and 3 on RNA isolated from the explants. Results. 0.5 mM and 5 mM GlcN-HCl significantly increased HA production compared to control (approximately 2 - 4-fold), whereas GlcN-Ac had no significant effect. Addition of 5 mM Gluc also increased HA production (approximately 2-fold), but 0.5 mM Gluc did not. Gene expression of the HA forming enzymes HAS 1, 2 and 3 was not altered by the addition of GlcN or Gluc. Conclusion. Our data suggest that exogenous GlcN can increase HA production by synovium tissue and is more effective at lower concentrations than Gluc. This might indicate that GlcN exerts its potential analgesic properties through stimulation of synovial HA production. http://repub.eur.nl/res/pub/15728/ 2008-10-01T00:00:00Z Introduction: Het effect van glucosaminesulfaat bij de behandeling van artrose is omstreden. Een systematische review uit 2005 met twintig onderzoeken kon geen definitieve conclusie trekken.1 Van de vijftien onderzoeken die glucosamine vergeleken met een placebo was het algehele effect op pijn gemiddeld weliswaar in het voordeel van glucosamine, maar meer dan de helft van deze onderzoeken vond geen verschil tussen glucosamine en een placebo. Ook recente onderzoeken gaven geen duidelijkheid.2-4 Uit eerdere onderzoeken kon men concluderen dat patiënten met milde radiologische artrose meer baat zouden hebben bij glucosamine dan patiënten met een ernstiger ziektebeeld.5,6 We vonden slechts twee onderzoeken over het effect van glucosaminesulfaat op radiologische progressie,10,11 waarbij bovendien discussie ontstond over het radiologisch protocol.12-14 Daarom is verder onderzoek nodig. Tot nu toe is vooral het effect van glucosamine op knieartrose onderzocht, slechts drie onderzoeken includeerden ook patiënten met andere aangedane gewrichten.7-9 Wij vonden geen onderzoeken bij patiënten met heupartrose. En hoewel knieartrose meer voorkomt, komt heupartrose voldoende voor om het effect van glucosamine bij deze groep te testen. Al met al genoeg aanleiding voor een tweejarig, geblindeerd, gerandomiseerd, placebo-gecontroleerd onderzoek naar het effect van glucosaminesulfaat op de symptomatische en radiologische progressie van eerstelijns patiënten met heupartrose. http://repub.eur.nl/res/pub/15163/ 2007-11-01T00:00:00Z OBJECTIVE: To investigate the working mechanism of glucosamine (GlcN) by studying the effect of different GlcN derivatives on bovine chondrocytes in alginate beads under anabolic and catabolic culture conditions. METHODS: Bovine chondrocytes seeded in alginate beads were treated with different concentrations of glucosamine-sulfate (GlcN-S), glucosamine-hydrochloride (GlcN-HCl) or N-acetyl-glucosamine (GlcN-Ac). Culture conditions were anabolic, 3 day pre-culture followed by 14 days' treatment; catabolic, extracellular matrix (ECM) breakdown induced by 10ng/ml interleukin-1beta (IL-1beta); or a situation with balance between ECM breakdown and synthesis, 24 days' pre-culture followed by 14 days' treatment. The outcome measurements were total glycosaminoglycan (GAG) and DNA content per bead. RESULTS: In the situation with balance between ECM breakdown and synthesis, GlcN-Ac had a small stimulatory effect on total GAG content. GlcN-S and GlcN-HCl had no effect. Under anabolic condition 5mM GlcN-S and GlcN-HCl significantly reduced total GAG content. GlcN-Ac did not show this effect. IL-1beta induced catabolic effects were prevented by adding 5mM GlcN-HCl. Interference of GlcN with glucose (Gluc) was demonstrated by adding extra Gluc to the medium in the anabolic culture conditions. Increasing extracellular Gluc concentrations diminished the effect of GlcN. CONCLUSION: GlcN-S and GlcN-HCl, but not GlcN-Ac, reduce anabolic and catabolic processes. For anabolic processes this was demonstrated by decreased ECM synthesis, for catabolic processes by protection against IL-1beta mediated ECM breakdown. This might be due to interference of GlcN with Gluc utilization. We suggest that the claimed structure modifying effects of GlcN are more likely based on protection against ECM degradation than new ECM production. http://repub.eur.nl/res/pub/15678/ 2006-03-01T00:00:00Z OBJECTIVE: To investigate the effect of glucosamine (GlcN) in a human osteoarthritic explant model on expression of genes involved in anabolic and catabolic activities of chondrocytes. METHODS: Human osteoarthritic explants, obtained during knee arthroplasty surgery, were pre-cultured (3 days) and treated with glucosamine-hydrochloride (GlcN-HCl) or glucosamine-3-sulphate (GlcN-S) at 0.5mM and 5mM (4 days). RNA was isolated from the explants and real time RT-PCR was performed. Additionally, total matrix metalloproteinase (MMP) activity was measured in culture medium. RESULTS: Addition of 5mM GlcN led to significant down-regulation of aggrecan (2.65-7.73-fold) and collagen type II (7.75-22.17-fold) gene expression, indicating inhibited anabolic activity. Considering catabolic activities, 5mM GlcN significantly down-regulated aggrecanase-1 and MMP3 and 5mM GlcN-S additionally down-regulated aggrecanase-2 and tissue inhibitor of MMP gene expression significantly. Gene expression was not significantly altered by 0.5mM GlcN. Total MMP activity in culture medium was only significantly reduced after addition of 5mM GlcN-HCl. CONCLUSION: The effects of GlcN on gene expression in a human osteoarthritic explant model suggest that enzymatic breakdown of the extra-cellular matrix might be reduced by the addition of 5mM GlcN. Additionally, restoration of already damaged cartilage is not to be expected, because gene expression of anabolic genes is also down-regulated. We suggest that chondroprotective properties of GlcN in vivo may be based on inhibiting further degradation due to catabolic activities, rather than on the ability to rebuild cartilage. http://repub.eur.nl/res/pub/13787/ 2005-04-26T00:00:00Z BACKGROUND: Pharmacological treatment for osteoarthritis (OA) can be divided into two groups: symptom-modifying drugs and disease-modifying drugs. Symptom-modifying drugs are currently the prescription of choice for patients with OA, as disease-modifying drugs are not yet available in usual care. However, there has recently been a lot of debate about glucosamine sulphate (GS), a biological agent that is thought to have both symptom-modifying and disease-modifying properties. This assumption has yet to be proved. The objective of this article is to present the design of a blind randomised clinical trial that examines the long-term symptom-modifying and disease-modifying effectiveness of GS in patients with hip OA. This trial is ongoing and will finish in March 2006. METHODS/DESIGN: Patients with hip OA meeting the ACR-criteria are randomly allocated to either 1500 mg of oral GS or placebo for the duration of two years. The primary outcome measures, which are joint space narrowing (JSN), and change in the pain and function score of the Western Ontario McMaster Universities Osteoarthritis index (WOMAC), are determined at baseline and after two years of follow-up during the final assessment. Intermediate measures at three-month intervals throughout the trial are used to study secondary outcome measures. Secondary outcome measures are changes in WOMAC stiffness score, quality of life, medical consumption, side effects and differences in biomarker CTX-II.