ADVANCED GLYCATION ENDPRODUCTS IN THE DEVELOPMENT OF OSTEOARTHRITIS

J. DeGrootBiomedical Research, TNO Prevention and Health, Leiden, NetherlandsOsteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly and poses a significant public health problem, especially in view of the aging western society. The most prominent feature of OA is the progressive destruction of articular cartilage resulting in impaired joint motion, severe pain and ultimately disability. As yet, the etiology of OA is still for a large part unknown. The incidence of OA increases strongly with age: >50% of the population over 60 years of age is affected. Although age is identified as the main risk factor for the development of OA, the mechanism by which aging is involved still remains largely unclear. Age-related changes in the articular cartilage are expected to play an important role in the susceptibility of cartilage to OA.One of the major age-related changes in articular cartilage is the accumulation of advanced glycation endproducts (AGEs), resulting from the spontaneous reaction of reducing sugars with proteins: so-called nonenzymatic glycation The initial step in this reaction is the condensation of a sugar aldehyde with an epsilon-amino group of lysine, hydroxylysine or arginine residues in proteins. Subsequently, the initially formed Schiff base is stabilized by Amadori rearrangement. The Amadori product is further stabilized by oxidation and molecular rearrangements, ultimately generating a range of fluorophores and chromophores, collectively known as advanced glycation endproducts (AGEs). Most of these AGEs are not yet isolated nor characterized. Therefore, a few well-characterized AGEs are routinely used as marker for the process of nonenzymatic glycation. Pentosidine, a fluorescent AGE formed between lysine and arginine residues, is often used for this purpose. AGEs are formed in all proteins, and since they can only be removed from the body when the protein is removed, AGEs accumulate in long-lived proteins such as collagens. In human articular cartilage – a tissue with extremely slow turnover (half-life of type II collagen >100 yr.) – pentosidine levels increase 50-fold from age 20 to 80 years.AGEs are known to affect physical and chemical properties of proteins. In particular tissue strength is dependent upon the amount of crosslinks present. Accumulation of AGEs is correlated with increased tissue stiffness in arteries, lens, skin, tendon and also in articular cartilage. Moreover, an increase in AGE renders tissues increasingly brittle, and thus more prone to mechanical damage. This effect has been shown for human lens capsules, cortical bone and again, also for articular cartilage. In addition to affecting the mechanical properties of tissues, AGEs interfere with cellular processes such as adhesion of cells to the extracellular matrix, proliferation and gene expression. Articular cartilage chondrocytes show decreased proteoglycan and collagen synthesis at increased AGE levels. Degradation of AGE-modified collagen by matrix metalloproteinases is impaired compared to unmodified collagen.Altogether, the age-related accumulation of AGEs in articular cartilage increases tissue stiffness and decreases the capacity of the chondrocytes to remodel their extracellular matrix. In combination, these effects render the tissue more prone to damage and provide the molecular mechanism by which age-related accumulation of AGEs may eventually lead to the development of OA. Indeed, in a canine study of experimentally induced OA by anterior cruciate ligament transection, animals with elevated AGE levels suffered from more severe OA than those with normal AGE levels. Moreover, in a cross-sectional study using human articular cartilage samples obtained at autopsy, cartilage AGE levels were higher in the visually intact cartilage of subjects with cartilage degeneration elsewhere in the joint, than in the cartilage of subjects without any form of degeneration.Together these data support the hyppothesis that the age related accumulation of advanced glycation endproducts changes the properties of articular cartilage and thereby renders the tissue more prone to the development of OA.References: 1. DeGroot et al (2004) Arthritis Rheum. In press2. Verzijl et al (2003) Current Opin. Rheum. 15(5):616-6223. Verzijl et al. (2002) Arthritis Rheum. 46:114-1234. Chen et al (2002) Arthritis Rheum. 46:3212-32175. DeGroot et al. (2001) Arthritis Rheum. 44:2562-25716. Verzijl et al. (2001) Matrix Biol. 20:409-4177. DeGroot et al. (2001) Osteoarthritis Cartilage. 9:720-7268. DeGroot et al. (2001) Exp. Cell Res. 266:303-3109. Verzijl et al. (2000) Biochem. J. 350:381-38710. Verzijl et al. (2000) J. Biol. Chem. 275:39027-3903111. DeGroot et al. (1999) Arthritis Rheum. 42:1003-1009Citation: , volume , supplement , year 2004, page Session: Osteoarthritis, from the bench to the clinic