Identification of important interactions between subchondral bone ...

CHAPTER 2: Introduction
Cysteine proteases are also essential players in the proteolytic cleavage of ECM in OA, which are
synthesized both by the chondrocytes and synovial cells in response to cytokines and growth
factors 102 . Cysteine proteases are normally responsible for the breakdown of collagen in bone,
especially collagen type I 89 . However, cysteine proteases, like cathepsins K, B and L, have also
been implicated as major participants in the degradation of collagen type II and
proteoglycans 103,104,105,106 . As an example, expression of cathepsin K is up regulated in articular
chondrocytes in a transgenic mouse model for OA 102 and urine concentrations of the cartilage
breakdown products of collagen type II (CTX-II) are reduced by chronic cathepsin K
inhibition 107 . Furthermore, expression of cathepsin B, H, L, and S are seen in hypertrophic
chondrocytes, which are a hallmark of OA 108 . Besides the above mentioned actions, the main role
of cathepsins is believed to be indirect degradation of matrix proteins through activation of
MMPs 109,110,111 .
2.3.3 The subchondral bone in OA
The subchondral bone turnover increases in OA 5,112 , which is demonstrated by the increase in
alkaline phosphatase, osteocalcin, MMP expression (MMP-2 and -3), cytokines (TNF-α, IL-1, IL-
8, IL-10), transforming growth factor beta (TGF-β) and TIMP-1 113,114 . Furthermore, the
thickening of the subchondral bone with an abnormally low mineralization pattern 115 supports a
greater proportion of osteoid in the diseased tissue with a higher turnover rate 112 . These changes
in mineralization and structural organization, of the subchondral bone compartment, result in
tissue stiffness. This stiffness impairs the ability of the subchondral bone to act as shock absorber
to the overlying cartilage 116 .
As described in section 2.1, the etiology of OA is unknown. An increasing line of
evidence suggests that both bone and cartilage, and not cartilage alone, contribute to the onset
and progression of the disease. Several studies have addressed the importance of subchondral
bone in the pathogenesis of OA. In a study with a primate model of spontaneous OA, the
progression of the disease severity of cartilage correlated with the increased thickness of the
subchondral bone. Moreover, the bone changes preceded the changes in cartilage 117 . Another
study showed a correlation between cartilage loss in OA patients and increased subchondral bone
turnover as measured by uptake of technetium-labelled bisphosphonate 118 . These studies confirm
the importance of subchondral bone, either as an initiator or as a “partner in crime” in the
pathogenesis of OA.
The knowledge of subchondral bone in OA is limited. Thus this area
needs to be investigated more thoroughly, as both tissues are involved in
the pathogenesis of OA. This thesis also focus on the communication
between the cartilage and subchondral bone (PAPER I and II)
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