Abstract
The extracellular matrix (ECM) is a complex and specialized three-dimensional macromolecular network, present in nearly all tissues, that also interacts with cell surface receptors on joint resident cells. Changes in the composition and physical properties of the ECM lead to the development of many diseases, including osteoarthritis (OA). OA is a chronic degenerative rheumatic disease characterized by a progressive loss of synovial joint function as a consequence of the degradation of articular cartilage, also associated with alterations in the synovial membrane and subchondral bone. During OA, ECM-degrading enzymes, including urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), cleave ECM components, such as fibronectin (Fn), generating fibronectin fragments (Fn-fs) with catabolic properties. In turn, Fn-fs promote activation of these proteinases, establishing a degradative and inflammatory feedback loop. Thus, the aim of this review is to update the contribution of ECM-degrading proteinases to the physiopathology of OA as well as their modulation by Fn-fs.
Highlights
Osteoarthritis (OA) is the most prevalent arthritic disease affecting the joints
This review focuses on the emerging issues related to the role of fibronectin fragments (Fn-fs) in the inflammatory cascade through the stimulation of urokinase-type plasminogen activator, matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) proteinases in OA
Fn is structured into four functional domains including a N-terminal domain (FnI1-9 plus FnII1-2), which binds Fn to heparin, collagen or fibrin; a central binding domain (FnII1-12) is responsible in part for Fn binding with the cells through the interaction with different integrins; and a C-terminal binding domain (FnIII12-14 plus III connecting segment (IIICS) plus FnI10-12) that has other cell-binding sites, heparin- or fibrin-binding sites and the disulfide bridges responsible for Fn dimerization
Summary
Osteoarthritis (OA) is the most prevalent arthritic disease affecting the joints. While mainly related to aging, it is associated with a diversity of risk factors including genetic predisposition, epigenetic factors, gender, obesity, exercise, work-related injury, and trauma. The ECM is a complex and specialized three-dimensional macromolecular network, present in most tissues, which interacts with cell surface receptors on joint resident cells It is secreted, assembled, and modeled by the surrounding cells, providing physical support and organization to tissues. This review focuses on the emerging issues related to the role of Fn-fs in the inflammatory cascade through the stimulation of urokinase-type plasminogen activator (uPA), matrix metalloproteinases (MMPs), and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) proteinases in OA. The mechanisms underlying these proteinases are discussed
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