Identification of important interactions between subchondral bone ...

2.3.2 The extracellular matrix of cartilage in OA
CHAPTER 2: Introduction
The health of normal cartilage is maintained by a balance between matrix synthesis and
degradation. This balance is disturbed in OA. In early OA, there is increased synthesis of the
principal matrix molecules of cartilage 82 , including collagen type II and aggrecan. However, the
increased levels of these matrix molecules may be exported to the synovial fluid rather than
incorporated into the tissue 56,83 . This is seen by an elevated rate of cartilage proteoglycan turnover
in emerging OA and observed in the serum as an increase of aggrecan fragments in the synovial
fluid and sulphate epitopes 84 . Thus, there is a decrease in total proteoglycan concentration, chain
length and aggregation in OA cartilage 85 .
Proteoglycans play an important role in keeping the water in
the matrix. Thus it is important to understand the
degradation processes of aggrecan in OA, to find the right
treatment for the right stages of OA. This thesis investigates
the different degradations processes for aggrecan (PAPER III)
The elevated matrix synthesis in OA is accompanied by increased synthesis of proteases and
other inflammatory factors, which may be related to elevated levels of interleukin-1 (IL-1) and
tumour necrosis factor α (TNF-α) 86,87 . Multiple proteases are involved in the degradation of
cartilage, including cysteine-, aspartic-, serine-, and metalloproteinases. Especially, the expression
of the zinc-dependent matrix metalloproteinase (MMP) family of enzymes is highly up-regulated
in OA cartilage 88,89 . Mainly, MMP-1, -2, -3, -8, -9, -13 and -14 play a major part in protein
degradation. MMP-1, -8 and -13 (collagenases) mainly cleave collagen type II in the triple
helix 81,90,91,92 , whereas MMP-2 and -9 (gelatinases) cleave in the N-teleopeptide end 93 . Most MMPs
are secreted by chondrocytes as latent proMMPs, which can be activated by other proteases
through cleavage. As an example, MMP-2, -3 and membrane bound MMP-14 cleave other
proenzymes (e.g. MMP-13) 94,95 . MMP-3 (stromelysin) also breaks down collagen type II and
proteoglycans 96,97 . The breakdown of proteoglycans is also mediated by the aggrecanases, a
disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), and this breakdown
is thought to be an early step in the loss of cartilage in OA 98 .
The activity of MMPs and ADAMTS are normally controlled by the endogenous
tissue inhibitors of metalloproteinases (TIMPs) 99 , which are also expressed by chondrocytes. An
imbalance between metalloproteinases and TIMPs, results in cartilage degradation 89,100 . The
expression of these TIMPs is down regulated by TNF-α in OA 101 , which furthermore contributes
to the imbalance between metalloproteinases and their inhibitors.
28