The role of proteases in pathologies of the synovial joint

Abstract

Synovial (diarthrodial) joints are employed within the body to provide skeletal mobility and have a characteristic structure adapted to provide a smooth almost frictionless surface for articulation. Pathologies of the synovial joint are an important cause of patient morbidity and can affect each of the constituent tissues. A common feature of these pathologies is degenerative changes in the structure of the tissue which is mediated, at least in part, by proteolytic activity. Most tissues of the synovial joint are composed primarily of extracellular matrix and key pathological roles in the degeneration of this matrix are performed by metalloproteinases such as matrix metallproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). However, other proteases such as cathepsin K are likely to play an important role, especially in bone turnover. In addition to the cleavage of structural proteins, proteolytic activities are employed to regulate the activity of other proteases, growth factors, cytokines and other inflammatory mediators. Proteases combine to form complex regulatory networks, the correct functioning of which is required for tissue homeostasis and the imbalance of which may be a feature of pathology. A precise understanding of the proteases involved in these networks is required for a true understanding of the associated pathology.

Higher levels of matrix metalloproteinase-3 in patients with RA reflect disease activity and structural damage

“…It is now generally accepted that the activity of cells within synovium and, in particular, the cytokine and enzyme products which they generate are involved in the destruction of underlying matrix components 2,3 . The destruction of connective tissue is also driven by the action of matrix metalloproteinase enzymes (MMPs) released by synovial fibroblasts, chondrocytes and monocytes in response to IL-1β, TNF-α, interferon gamma, as well as by serum amyloid A (SAA) and epidermal growth factor and platelet-derived growth factor [4][5][6][7][8] . MMPs participate in the maintenance and remodeling of extracellular matrix (ECM) that is important for creating cellular environments.…”

Looking at the proteases from a simple perspective

“…These enzymes also act on other substrates such as cytokines, growth factor receptors, cell-cell and cell-matrix adhesion molecules (Chambers and Matrisian, 1997). Interestingly, the degradation of ECM and cell adhesion molecules may release cryptic sites that modulate the cell behavior (Polette et al, 2004;Jones et al, 2008). Thus, MMPs are secreted in a latent form and require previous activation for proteolytic activity (Liotta and Stetler-Stevenson, 1990;Chambers and Matrisian, 1997;Pender and MacDonald, 2004).…”

“…MMPs are important in both normal and abnormal biological conditions such as proliferation, invasion, and metastasis of tumor cells (Liotta and Stetler-Stevenson, 1990;Chambers and Matrisian, 1997;Nagase and Woessner, 1999;Hidalgo and Eckhardt, 2001;Sternlicht and Werb, 2001;Seiki, 2003;Pender and MacDonald, 2004;Garcia-Touchard et al, 2005;Roy et al, 2006;Jones et al, 2008). These enzymes also act on other substrates such as cytokines, growth factor receptors, cell-cell and cell-matrix adhesion molecules (Chambers and Matrisian, 1997).…”

Serum Matrix Metalloproteinase-3 Predicts Radiographic Joint Damage and Functional Disability in Rheumatoid Arthritis

“…Its production is upregulated by the proinflammatory cytokines IL-1β, TNF, IFNγ, and IL-17A, as well as by serum amyloid A (SAA) in RA (Galliera, et al 2010;Hueber et al 2010). It also contributes to the progression of RA by promoting the recruitment of many other inflammatory cells ie neutrophils, monocytes and T cells (Jones et al 2008). Since MMP-3 is produced in the inflamed joint, and subsequently circulated in the blood stream, it is a potential biomarker which may indicate the disease activity in RA (Zucker et al 1994).…”