Research Article: Recent Findings on the Role of Gelatinases (Matrix Metalloproteinase-2 and -9) in Osteoarthritis

Date Published: July 26, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Olimpio Galasso, Filippo Familiari, Marco De Gori, Giorgio Gasparini.

http://doi.org/10.1155/2012/834208

Abstract

Several studies dealing with the pathomechanisms of OA refer to MMP-1, -3, -7, -8, and -13 whereas a smaller number of investigations have pointed out the pathogenic role of gelatinases in OA. These gelatinases are best known for their involvement in pulmonary, myocardial, and neoplastic disease but they are emerging as important proteases implicated in the OA progression. This paper highlights the role of the gelatinases as emerging factors in OA pathogenesis through the regulation of subchondral bone resorption and microvascular invasion. The most significant new findings over the last year that add to our knowledge of the activity of these proteins in OA have been reported.

Partial Text

Hereditary, mechanical, and biological factors participate in the causation of osteoarthritis (OA) that is finally characterized by a net loss of the articular cartilage, resulting in pain, deformity, loss of motion, and decreased function [1]. Changes in the normal homeostasis of articular cartilage and subchondral bone during OA are caused by the combination of (1) chondrocyte death, (2) increased degradation, and (3) decreased production of extracellular matrix (ECM).

We performed a literature search of the MEDLINE/PubMed, Excerpta Medica/EMBASE databases for articles published during the past 30 years (1981–2011). Our purpose was to identify all English-language literature included under the key-words metalloproteinase-2, metalloproteinase-9, MMP-2, MMP-9, gelatinase A, and gelatinase B alone or combined with osteoarthritis. The contents of 166 pertinent abstracts or full-text articles were identified during our literature search. Then, abstracts, case reports, and letters to the editor were excluded thus leaving 101 articles to be finally considered for this paper.

MMP-2 (gelatinase A, 72 kDa type IV collagenase) is a matrix metalloproteinase which was first described and purified from highly metastatic murine tumors [17, 18] and cultured human melanoma cells [19]. MMP-2 is abundantly expressed in fibroblasts, endothelial, and epithelial cells [20–22] and it is secreted as proenzyme and activated at the cell surface. Its activation is mediated by the membrane-type metalloproteinase-1 (MT-MMP 1) [23, 24]. MMP-2 activation involves tissue inhibitor of MMP (TIMP)-2 as a bridging molecule between MT-MMP 1 and pro-MMP-2. Thus, net activity of MT-MMP 1 and MMP-2 depends on TIMP-2 concentration [25].

It was demonstrated that the expression of both MMP-2 and MMP-9 is enhanced in osteoarthritic cartilage (Figure 1) [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, 35]. 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.

Recent articles confirm that the gelatinases influence OA onset and progression regulating the subchondral bone remodeling (Table 2). In particular, a predominant role of MMP-9 emerged during, last year. Among various MMPs, the total MMP-9 level is positively correlated with the total MMP-13 levelin OA [58], and it has been hypothesized that this gelatinase might be involved in the activation of pro-MMP-13 through yet unknown mechanisms. Notably, MMP-13 has long been considered as the major enzyme involved in cartilage erosion during OA, thus MMP-9 might play a role, at least cooperatively, in joint degradation.

Collagenases have long been considered as the major enzymes involved in OA occurrence and progression. This paper highlights the role of the gelatinases as important factors in OA pathogenesis through the regulation of subchondral bone resorption. New intriguing regulatory mechanisms of gelatinases expression and further data about the relationship between these proteins and microvascular invasion commonly found in OA have been demonstrated over the last year. Experimental strategies that modify the expression and/or the activity of MMPs might consider the gelatinases as promising targets for the treatment of OA disease.

 

Source:

http://doi.org/10.1155/2012/834208

 

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