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  • Biological Evaluation of Nutraceuticals Affecting Cartilage Metabolism

    and Inflammation

    Anita Hartog - te Kortschot

    anita01.indd 1 21-4-10 13:39

  • ISBN

    978-90-79488-08-7

    Cover design and thesis lay-out

    www.muskunst.nl (Karin Kuiper, Arnhem)

    Cover

    Illustration of the walking pattern of a healthy (brown) and an arthritic (white) subject

    Printed by

    Print Service Ede

    The printing of this thesis was financially supported by

    Danone Research Centre for Specialized Nutrition, Reumafonds, J.E. Jurriaanse Stichting

    The research described in this thesis was performed at Danone Research Centre for

    Specialized Nutrition, Wageningen, The Netherlands. The research of chapter 2, 3, 4 and 6

    was supported by SenterNovem, TSIN 1055. Chapter 7 and 8 were performed within the

    framework of TI Pharma project T1-103.

    2010 Anita Hartog - te Kortschot

    All rights are reserved. No part of this thesis may be reproduced or transmitted in any form

    or by any means, without permission from the author or the copyright owning journal.

    anita01.indd 2 21-4-10 13:39

  • Biological Evaluation of Nutraceuticals Affecting Cartilage Metabolism and Inflammation

    Bestudering van de effecten van nutraceuticals op het kraakbeen

    metabolisme en ontstekingsreacties

    (met een samenvatting in het Nederlands)

    Proefschrift

    ter verkrijging van de graad van doctor aan de Universiteit Utrecht

    op gezag van de rector magnificus, prof.dr. J.C. Stoof, ingevolge het besluit van het

    college voor promoties in het openbaar te verdedigen op donderdag 3 juni

    2010 des middags te 12.45 uur

    door

    Anita Hartog - te Kortschot

    geboren op 5 februari 1964 te Angerlo

    anita01.indd 3 21-4-10 13:39

  • Promotor

    Prof. dr. J. Garssen

    Co-promotoren

    Dr. P.M. van der Kraan

    Dr. H.F. Smit

    anita01.indd 4 21-4-10 13:39

  • Contents

    9 Chapter 1

    Introduction

    33 Chapter 2

    Identification of Grifola frondosa as a new cartilage supportive lead using a validated

    functional screening assay

    51 Chapter 3

    In vitro and in vivo modulation of cartilage degradation by a standardized Centella asia-

    tica fraction

    69 Chapter 4

    The multicomponent phytopharmaceutical SKI306X inhibits in vitro cartilage degrada-

    tion and the production of inflammatory mediators

    87 Chapter 5

    Oral administration of the NADPH-oxidase inhibitor apocynin partially restores dimini-

    shed cartilage proteoglycan synthesis and reduces inflammation in mice

    103 Chapter 6

    Anti-inflammatory effects of orally ingested lactoferrin and glycine in different zymosan-

    induced inflammation models: evidence for synergetic activity

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  • 6

    123 Chapter 7

    The combination of orally ingested lactoferrin and glycine inhibits arthritis development

    in a murine model of collagen-induced arthritis

    135 Chapter 8

    Locomotion and muscle mass measures in a murine model of collagen-induced arthritis

    149 Chapter 9

    Summary and remarks

    165 Chapter 10

    Samenvatting

    Affiliations of co-authors

    Curriculum Vitae

    List of Publications

    Dankwoord

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  • anita01.indd 7 21-4-10 13:39

  • anita01.indd 8 21-4-10 13:39

  • Chapter 1

    General introduction

    Musculoskeletal disorders, including osteoarthritis, rheumatoid arthritis and osteoporosis, are the most frequent cause of

    disability in the modern world, and the prevalence of these diseases is rising at an alarming rate [WHO, 1].

    anita01.indd 9 21-4-10 13:39

  • 10

    anita01.indd 10 21-4-10 13:39

  • 11

    chapter 1

    Arthritis

    The word arthritis is formed by two Greek words arthon (joint) and itis (inflammation). It

    means joint inflammation literally. The term arthritis holds no clear boundary; it refers to

    a group of more than 100 rheumatic diseases and other joint related disease conditions.

    Degenerative joint changes can be detected in different ancient animals including a case of

    post-traumatic arthritis in dinosaurs [2]. The first known human arthritis dates back as far as

    4500 B.C. [3]. In the fourth century B.C., Hippocrates, the father of western medicine, was

    the first to recognize and record the clinical signs of a number of these rheumatic conditions

    including gout and rheumatic fever [4]. Although rheumatic diseases can affect people at

    all ages, the two most common and important forms, osteoarthritis (OA) and rheumatoid

    arthritis (RA) have a relative high prevalence in elderly [5]. The prevalence rates of arthritis

    are expected to increase in the coming years due to the increasing proportion of the elderly

    in the population.

    Osteoarthritis

    OA is the most common joint disease and an important cause of physical disability [6]. More

    than 10% of the adult population is affected [5]. Noteworthy, more than 80% of the people

    older than 75 do have clinical signs while more than 80% of the people older than only 50

    years of age show radiological evidence of OA [7]. Clinical symptoms are frequently asso-

    ciated with a significant functional impairment and signs and symptoms of inflammation,

    including pain, stiffness and loss of mobility [8]. The etiology of OA is suggested to be multi-

    factorial. Risk factors can be separated into systemic factors as well as local factors. Systemic

    factors include: genetic susceptibility, dietary intake, race, gender, age, and bone density.

    Local factors include biomechanical (such as traumatic lesions and abrasion) and inflamma-

    anita01.indd 11 21-4-10 13:39

  • 12

    tory conditions [9]. The main characteristics of OA comprise involvement of multiple pro-

    cesses and tissues including cartilage loss, bone remodeling, synovial fibrosis, osteophyte

    formation at the joint margins and synovial inflammation (figure 1).

    Rheumatoid arthritis

    RA is a chronic, inflammatory, systemic autoimmune disease that affects about 1% of the

    general population in the western countries [10]. It is two to three times more common in

    females compared to males and it can start at any age, with a peak incidence between the

    fourth and sixth decade of life [10, 11]. The joints most commonly involved are those of

    the hands, feet and knees. However, almost all peripheral joints can be affected. RA is a so-

    called multifactor disease in which both genetic [12] as well as environmental factors are

    involved. External factors associated with increased risk of RA include smoking, low socio-

    economic status and a higher birth weight [13]. The inflamed synovium consists of diverse

    cell populations including B cells, T cells, macrophages and synovial fibroblasts. Synovial

    fibroblasts are key players in the destruction of the joint by secreting matrix degrading en-

    zymes en pro-inflammatory cytokines [14]. The cartilage and bone destruction are directly

    linked to the exacerbation of inflammatory processes (Figure 1).

    Fig. 1 Schematic representation of osteoarthritis and rheumatoid arthritis in a joint. The left figure represents a

    normal healthy joint whereas in the middle figure an osteoarthritic joint is depicted. The right figure shows a joint

    heavily affected by rheumatoid arthritis. Pictures are adapted from the Arthritis Research Campaign.

    Tissues involved in the pathogeneses of OA and RA

    Both OA and RA are diseases in which not only the articular cartilage of the synovial joint is

    affected but also the adjacent bone, ligaments, capsule and synovial membrane, and even

    peri-articular muscles.

    anita01.indd 12 21-4-10 13:39

  • 13

    chapter 1

    Articular cartilage

    Articular cartilage is an avascular, aneural, very smooth and highly compressible and re-

    silient connective tissue covering the joint surfaces. It is critical to normal joint function

    by distributing forces over the joint surface, acting as a shock absorber and aiding in joint

    lubrication for nearly frictionless articulation. Articular cartilage consists of a highly or-

    ganized extracellular matrix containing water (60-80%), collagen (10-20%), proteoglycans

    (PGs) (5-15%), other matrix proteins, lipids and chondrocytes. It can be divided in sev-

    eral different zones according to chondrocyte morphology and/or collagen organization

    [15-17]. The superficial zone is composed of flattened ellipsoid chondrocytes. The colla-

    gen fibers are aligned along the surface. The transitional/middle zone contains predom-

    inantly spheroid shaped cells. In this middle zone the large diameter collagen fibers are

    randomly arranged. The proteoglycan concentrations increases from the superficial zone

    to the deeper zone. The deep zone contains spherical cells. The cells and collagens in this

    deep zone have a perpendicular orientation. In the calcified zone a small number of cells

    are embedded in a calcified matrix (Figure 2). The cells in this zone express a hypertrophic

    phenotype and show very low metabolic activity. The collagen network defines the form

    and strength of the articular cartilage, while the highly hydrophilic PGs (a core protein with

    linked glycosaminoglycans) are responsible for the resilience of the cartilage. The largely

    negat

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