It was demonstrated that the expression of both MMP-2 and MMP-9 is enhanced in osteoarthritic cartilage () [36
]. Also the MT-MMP 1, which activates the MMP-2, was found highly expressed in the chondrocytes during OA [37
]. Duerr et al.
evaluated the quantitative expression levels and the distribution of MMP-2 and MMP-9 both in normal and osteoarthritic cartilage and in cultured articular chondrocytes [29
]. They found that in osteoarthritic cartilage degradation, MMP-9 is expressed at a very much lower level than MMP-2. Accordingly, Wang et al. reported minimal changes in the cartilage expression of MMP-9 in an experimental model of secondary OA [38
]. Indeed, this study showed that the experimentally induced cartilage damage led to OA-like lesions with disarrangement of cellular disposition, cell-free areas, coagulation necrosis, pyknotic nuclei, and local loss of extracellular matrix accompanied by absent immunopositive expression of MMP-3, MMP-9, TIMP-1, and aggrecan.
The activation of gelatinases and their activity during osteoarthritis. Normal (left) and osteoarthritic (right) cartilage and subchondral bone.
Current data suggest that during OA, the activity of gelatinases is higher on the subchondral bone rather than on cartilage ECM [39
]. Indeed, MMP-2 is capable of cleaving type I and other fibrillar collagens [40
] that are uncommon in the ECM of articular cartilage but are present in the ECM of subchondral bone. Using a specific gelatinase inhibitor, Hill et al.
showed that both the gelatinases participate in the degradation of the organic matrix of bone [41
]. Mansell and Bailey investigating the cancellous bone metabolism during OA, reported an increased potential for collagen degradation in presence of increased levels of both pro- and active MMP-2 [42
]. What is evident from this study is that OA cancellous bone is metabolically active compared with normal tissue. Such differences in turnover might result in altered joint morphology, which in turn might exacerbate the osteoarthritic process (). Osteoclasts constitutively express MMP-2, and synthesize MMP-9, MMP-3, and TIMP-1 in response to IL-1α
stimulation, and during OA the increased levels of osteoclast-derived MMPs might contribute to osteoclast lacunar resorption [43
]. This hypothesis concurs with the demonstration of higher plasma levels of MMP-9 in patients with rapidly destructive hip OA in comparison patients with OA or normal controls [44
]. The higher detected amount of MMP-9 could be explained by the wide number of osteoclasts, which are one source of MMP-9, observed around necrotic bone in subchondral areas in rapidly destructive hip OA [45
]. Nor should be excluded the enhanced production of MMP-9 by synovial cells of patients with this kind of OA [47
]. A direct route into the bloodstream via the subchondral microcirculatory system and an indirect route from synovial fluid into circulation could explain the higher plasma levels of MMP-9 in OA [48
The work of Bellido et al.
strengthens the role of the subchondral bone as a key player in the puzzle of OA development [49
]. They found raised subchondral MMP-9 levels in patient suffering from OA demonstrating a clear increase in local bone resorption with a decreased thickness of the subchondral plate. The subchondral plate that separates articular noncalcified cartilage from the bone marrow cavity consists of calcified cartilage and subchondral lamellar bone layers [50
]. Any impairment in subchondral bone quality makes this organ not able to receive and properly distribute loads from and/or to the articular cartilage. Thus, changes at subchondral bone may aggravate cartilage damage. Indeed, the authors observed a direct correlation between subchondral structural parameters and cartilage damage evaluated with the Mankin's scale. The presence of subchondral bone resorption pits composed by MMP-producing cells derived from bone marrow has been previously evidenced together with their contribution to cartilage degradation through the invasion of this tissue [51
The type II collagen, the most abundant collagen expressed in articular cartilage, is natively degraded by MMP-1, -8, -13, and -14 producing fragments. However, denatured and partially degraded collagen II is further degraded by gelatinases and stromelysins thus obtaining a C-terminal peptide fragment, named CTX-II. This fragment is used as an urinary marker of cartilage degradation because it was found to correlate with cartilage loss in animal models of OA [52
] and increased CTX-II levels in patients with OA compared with controls were reported [53
]. Correlations of CTX-II with clinical assessment [54
] and X-rays [55
] or MRI [56
] evaluation of human OA have been found.