Identification of important interactions between subchondral bone ...

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