Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
ReviewProteases involved in cartilage matrix degradation in osteoarthritis☆
Highlights
► Osteoarthritis is characterised by degradation of cartilage extracellular matrix. ► Collagen is degraded by matrix metalloproteinases such as MMP-13. ► Aggrecan is degraded by related ADAMTS metalloproteinases. ► Less abundant cartilage components are degraded by a variety of proteinases. ► Factors such as inflammation and mechanical damage stimulate enzyme expression.
Introduction
Osteoarthritis (OA) is a chronic degenerative joint disease affecting millions of people worldwide [1]. The disease is a leading cause of disability in the elderly, causing pain, stiffness and loss of function in articulating joints. OA is characterised by changes in the anatomy of load-bearing joints that lead to degradation of articular cartilage, inflammation of the synovium (synovitis), changes to subchondral bone and growth of new bone and cartilage (osteophytes) at the joint edge (see Fig. 1) [2], [3]. The causes of OA are not fully understood, but mechanical factors such as joint injury and obesity are thought to be primary initiators of disease, with other risk factors such as age, gender and genetics contributing to disease development and progression [3], [4]. There are currently no disease-modifying OA drugs available, and treatment is limited to symptomatic relief or surgical replacement of affected joints. There is thus considerable interest in developing effective treatments that can halt or reverse the progression of the disease.
Loss of cartilage is central to the aetiology of OA. Cartilage is composed of one cell type, the chondrocytes, which are surrounded by a large volume of extracellular matrix (ECM). The matrix can be divided into zones based on their distance from the chondrocyte and matrix composition (see [4] for review). The pericellular matrix is localised immediately adjacent to the cell and is enriched with perlecan, type VI collagen and various regulatory molecules and growth factors that modulate chondrocyte function. The zone next to the pericellular matrix is the territorial matrix and further removed is the interterritorial matrix whose major components are collagen II and aggrecan. Collagen provides the tissue with tensile strength, whilst aggrecan is the major cartilage proteoglycan, drawing water into the matrix and allowing it to resist compression. Degradation of collagen and aggrecan is central to OA pathology, although degradation of less abundant molecules that participate in matrix organisation is also likely to contribute to disease progression [4]. This review describes the current understanding of which proteinases are responsible for aggrecan and collagen degradation in OA, and discusses recent advances in understanding the factors regulating their expression and activity. Other proteinases with potential roles in OA pathology are also highlighted.
Section snippets
Aggrecan-degrading enzymes
Aggrecan is a large proteoglycan containing numerous chondroitin sulphate and keratan sulphate glycosaminoglycan moieties, which are central to the function of the molecule as they draw water into the cartilage matrix, giving it the ability to withstand compression. Aggrecan is sensitive to proteolysis at numerous sites along its length. Cleavage of aggrecan in the interglobular domain (IGD) between the N-terminal G1 and G2 globular domains is thought to be of greatest pathological importance,
Collagenases
The primary collagen found in the cartilage ECM is type II collagen, which forms a fibrillar network and provides the cartilage matrix with tensile strength. Along with aggrecan breakdown, degradation of collagen is a central feature of OA [51], [52]. The exact order in which cartilage matrix components are degraded during the development of OA is difficult to ascertain, but a number of in vitro studies on cartilage explants suggest that collagen degradation occurs only after aggrecan is lost
Other MMPs and ADAMs
In addition to MMP13, ADAMTS4 and ADAMTS5, mRNA expression of various other MMPs (e.g. MMP28), adamalysins (e.g. ADAM12, ADAM15) and ADAMTSs (e.g. ADAMTS16, ADAMTS17) is reportedly increased in OA [61], [71], [72]. ADAM-8 has been suggested to contribute to OA pathogenesis by cleaving fibronectin, generating fragments that stimulate further cartilage catabolism [73]. Single nucleotide polymorphisms in ADAM12 [72] and ADAMTS14 [74] has reported associations with knee OA. The effects of numerous
Transcriptional regulation of MMPs and ADAMTSs in OA
Studies on transgenic mice have confirmed the importance of MMP-13 and ADAMTS-5 in the development of OA. As described above, inhibitors targeting these enzymes are in development as potential OA therapies. Additionally, there is considerable interest in understanding the factors that lead to increased activity of these enzymes in OA, with the hope of uncovering therapeutic targets upstream of the effector proteinases. Some of these newly described networks and regulatory mechanisms are
Inhibitors of MMPs and ADAMTSs
The tissue inhibitors of metalloproteinases (TIMPs) are the endogenous inhibitors of the MMPs and some members of the ADAM and ADAMTS families (see [177] for review). The MMPs are strongly inhibited by all four of the mammalian TIMPs (TIMP-1, -2, -3 and -4), with the exception of some of the membrane-type MMPs that are poorly inhibited by TIMP-1. Conversely, ADAMTS-4 and ADAMTS-5 are effectively inhibited only by TIMP-3 [178], [179]. As TIMP-3 can inhibit both MMPs and ADAMTSs, it is a central
Collagenase activators
The collagenases MMP-1 and MMP-13 are known to be activated by a number of other proteinases, including MMP-3 and the serine proteinase plasmin, which is in turn generated from plasminogen by urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) [77], [78]. Increased expression of MMP-3 [60], [76], tPA [188] and uPA [188] have all been reported in OA. As discussed above (Section 3), degradation of aggrecan in cytokine-stimulated bovine and porcine cartilage
Cathepsins
The papain-like cysteine proteinase cathepsin K is the only enzyme other than the collagenolytic MMPs that can hydrolyse native triple helical type I and type II collagen [206]. Chondrocyte expression of cathepsin K is increased in OA [207], [208] and the enzyme has been proposed to play a role in degradation of collagen in the cartilage matrix and in subchondral bone [209], [210].
Cathepsin K is highly expressed in osteoclasts, and studies on null mice and patients with genetic mutations
Conclusions and future prospects
OA remains a disease with insufficient disease-modifying treatments. With an increasing number of people suffering from the disease, the identification of novel therapeutic targets is a priority. The central role of aggrecanases and collagenases in cartilage degradation has been verified in recent years by studies on transgenic mice. Whilst these enzymes are also thought to play pivotal roles in human OA, there are likely to be some differences in the roles of individual enzymes between the two
Acknowledgments
Linda Troeberg is the recipient of an Arthritis Research UK Career Development Fellowship (grant number 19466). Hideaki Nagase is supported by Arthritis Research UK Core Grant to the Kennedy Institute of Rheumatology, and grant AR40994 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIAMS or NIH.
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This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.