Identification of important interactions between subchondral bone ...
Identification of important interactions between subchondral bone ...
Identification of important interactions between subchondral bone ...
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3.3 Ex vivo controls<br />
CHAPTER 3: Overview <strong>of</strong> OA models<br />
In order to design an ex vivo model for experimentation, it is critical to acquire appropriate<br />
controls, which induce an anabolic or catabolic system that represents regenerative or damaged<br />
tissue. The acknowledged cartilage explants model has established the best controls for cartilage:<br />
1) insulin-like growth factor-I (IGF-I) as an anabolic control, and 2) a combination <strong>of</strong> tumour<br />
necrosis factor-α (TNF-α) and oncostatin M (OSM) as a catabolic control 9,10,18 . In the early stages<br />
<strong>of</strong> OA, an increased amount <strong>of</strong> degrading enzymes is produced by the chondrocytes 27 . When<br />
articular cartilage explants are stimulated with TNF-α and OSM, the chondrocytes also produce<br />
these degrading enzymes 9 . OSM only induces a mild catabolic response in chondrocytes, but it<br />
act synergistically with TNF-α 10,28,29 . Thus, articular cartilage explants cultured in the presence <strong>of</strong><br />
OSM and TNF-α are shown to be a useful ex vivo model <strong>of</strong> OA 29 . Next is a short description <strong>of</strong><br />
the three key factors used in the cartilage explants model:<br />
IGF-I is <strong>important</strong> in skeletal development 30 , although this factor is primarily synthesized in the<br />
liver under the influence <strong>of</strong> growth hormones. IGF-I is essential for <strong>bone</strong> formation and it<br />
accounts for most <strong>of</strong> the chondrocyte-stimulating activity found in serum 30 . Several reports have<br />
described IGF-I to be the major anabolic factor <strong>of</strong> cartilage 31 . The ability <strong>of</strong> IGF-I to enhance<br />
matrix synthesis in normal cartilage is well established in vivo and in vitro 28,32 . For example, in<br />
cultures <strong>of</strong> human articular chondrocytes, IGF-I induces the production <strong>of</strong> GAGs and collagen<br />
type II 31 . Besides the chondroanabolic effects, it has been shown that IGF-I opposes the<br />
activities <strong>of</strong> catabolic cytokines in articular cartilage. Tyler showed in 1989 32 that IGF-I reduces<br />
proteoglycan degradation, probably by inhibiting the production and release <strong>of</strong> proteinases 28,33 .<br />
TNF-α is mainly produced by macrophages, but also by a broad variety <strong>of</strong> other cell types.<br />
TNF-α induces apoptosis, cellular proliferation, differentiation and inflammation. TNF-α has<br />
been shown to be an <strong>important</strong> mediator <strong>of</strong> cartilage destruction in vivo 28,32 . Besides mediating<br />
destruction <strong>of</strong> cartilage, TNF-α also inhibits synthesis <strong>of</strong> proteoglycan and collagen type II 27 .<br />
OSM is a member <strong>of</strong> the IL-6 family and is synthesized by stimulated T-cells and macrophages.<br />
Besides inhibition <strong>of</strong> proteoglycan synthesis, OSM also stimulates chondrocytes to produce<br />
proteinases, which induce proteoglycan degradation 27 . However, Wahl & Wallace indicated in<br />
2001 that OSM is anabolic; promoting wound healing, <strong>bone</strong> formation and anti-inflammatory<br />
effects 34 .<br />
The controls from the cartilage explants model<br />
were evaluated and used in the femur head<br />
explants model (PAPER I)<br />
47