Volume 6 Supplement 3

Global Arthritis Research Network (GARN): 4th World Congress on Arthritis in Montreal

Open Access

Advanced glycation endproducts in the development of osteoarthritis

  • J DeGroot1,
  • RA Bank1,
  • JWJ Bijlsma2,
  • JM TeKoppele1,
  • N Verzijl1 and
  • FPJG Lafeber2
Arthritis Res Ther20046(Suppl 3):78

https://doi.org/10.1186/ar1414

Published: 13 September 2004

Background

Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly. The most prominent feature of OA is the progressive destruction of articular cartilage resulting in impaired joint motion, severe pain and, ultimately, disability. Age is identified as the main risk factor for the development of OA, but the mechanism by which aging is involved still remains largely unclear. Age-related changes in the articular cartilage could 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. The present studies were designed to investigate whether AGE accumulation in cartilage may predispose to the development of OA.

Methods

The role of AGEs in the development of OA was studied by a combination of in vitro, ex vivo and in vivo experiments. The type and quantity of AGEs in human articular cartilage were determined using HPLC and GC-MS methods. Effects of AGE accumulation on cartilage extracellular matrix turnover were assessed in human articular cartilage and bovine alginate cultures using radiolabel incorporation, colorimetric, enzyme activity and HPLC analyses. The in vivo role of AGEs in OA predisposition was studied in the canine ACLT model for OA.

Results

High levels of all well-characterized AGEs (pentosidine, carboxymethyllysine and carboxyethyllysine) accumulate with age in cartilage collagen. Furthermore, an age-related increase of general measures of AGEs (fluorescence at 370/440 nm, browning, and amino acid modification) was also observed [1]. Accumulation of AGEs was correlated with increased stiffness and brittleness of the cartilage, rendering it more prone to mechanical damage. In addition to affecting the mechanical properties of tissues, articular cartilage chondrocytes show decreased proteoglycan and collagen synthesis at increased AGE levels. Degradation of AGE-modified collagen by matrix metalloproteinases is impaired compared with unmodified collagen. 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 [2]. Moreover, in a cross-sectional study using human articular cartilage samples obtained at autopsy, the presence of cartilage degeneration was associated with higher AGE levels in the joint cartilage.

Conclusion

AGE accumulation in cartilage leads to decreased mechanical properties (increased stiffness and brittleness) and impaired extracellular matrix turnover (decreased synthesis and degradation). Together these data support the hypothesis presented in Fig. 1 that the age-related accumulation of AGEs changes the properties of articular cartilage and thereby renders the tissue more prone to the development of OA.
Figure 1

Hypothesis of how advanced glycation endproduct (AGE)-related accumulation of AGEs could predispose to the development of osteoarthritis (OA).

Authors’ Affiliations

(1)
Division of Biomedical Research, TNO Pharma
(2)
Department of Rheumatology and Clinical Immunology, University Medical Center

References

  1. Verzijl N, Bank RA, TeKoppele JM, DeGroot J: AGEing and osteoarthritis: a different perspective. Curr Opin Rheum. 2003, 15: 616-622. 10.1097/00002281-200309000-00016.View ArticleGoogle Scholar
  2. DeGroot J, Verzijl N, Wenting-van Wijk MJG, et al: Accumulation of advanced glycation endproducts as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum. 2004, 50: 1207-1215. 10.1002/art.20170.View ArticlePubMedGoogle Scholar

Copyright

© The Author(s) 2004

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