Profile of Matrix-Remodeling Proteinases in Osteoarthritis: Impact of Fibronectin

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.

Keywords: ADAMTS; MMP; fibronectin; osteoarthritis; proteinases; uPA.

Figure 1

Fibronectin (Fn) and Fn fragments (Fn-fs) primary structure. (A) the schematic shows a representation of an Fn dimer and its interactions with different cell–surface receptors or other extracellular matrix (ECM) components such as heparin, collagen, and proteoglycans. Twelve Fn type I (FnI), two Fn type II (FnII) and fifteen constitutively expressed and two alternatively spliced Fn type III (FnIII) are indicated. The extra domains A and B (EIIIA and EIIIB) and the segment connecting two other FnIII repeats called the type III connecting segment (IIICS) or V domain are also shown. The scissors symbolize protease-sensitive regions of Fn and corresponding enzymes most commonly responsible for cleavage at these regions; (B) structural differences between plasma Fn and cellular Fn are shown; (C) the figure shows the different fragments of Fn and the structural domains that remain in each of them after breakage with proteolytic enzymes, adapted from [9,15,16,17].

Scheme 1

Classification of proteases. Families of proteases involved in osteoarthritis (OA) development are highlighted in red, adapted from [55,56].

Figure 2

Schematic representation of proteinases involved in OA. (A) the serine proteinase uPA contains an N-terminal signal peptide (SP) followed by an epidermal growth factor (EGF)-like domain, a Kringle domain, and a catalytic domain. (B,C) the matrix metalloproteinase (MMP) and A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) families have an N-terminal signal peptide, a pro-domain and a zinc-dependent catalytic domain. (B) In MMPs, the catalytic domain is followed by an hemopexin like-domain, (C) whereas, in the ADAMTS family, it is followed by a disintegrin domain and an auxiliary domain composed of a variable number of Thrombospondin type 1 (TSP-1), a cysteine-rich region (Cys R) and a spacer region, adapted from [54].

Figure 3

Function and regulation of a urokinase-type plasminogen activator (uPA) system. Plasmin cleaves pro-uPA generating active uPA, which, in turn, mediates the cleavage from the zymogen plasminogen to plasmin. Plasmin as well as uPA cleave pro-MMPs, generating activated MMPs, and promoting ECM degradation. In addition, uPA-urokinase-type plasminogen activator receptor (uPAR) binding interacts with integrins inducing different intracellular signaling pathways. On the other hand, plasminogen activator inhibitor (PAI) antagonizes uPA, inhibiting its activity, adapted from [56,57].

Figure 4

Schematic representation of the interaction of Fn with proteinases in the context of OA pathology. In a situation of inflammation and cartilage damage, Fn cleavage from the cartilage ECM promotes the release of Fn-fs to the joint microenvironment. Binding of Fn-fs to their receptors (integrins and TLRs) activates different signaling pathways increasing the expression of proteinases (uPA, MMPs, and ADAMTSs). In turn, active proteinases degrade the cartilage ECM inducing a feed-back loop of inflammation and cartilage degradation.