Proteases involved in cartilage matrix degradation in osteoarthritis

doi:10.1016/j.bbapap.2011.06.020

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

Volume 1824, Issue 1, January 2012, Pages 133-145

https://doi.org/10.1016/j.bbapap.2011.06.020 Get rights and content

Abstract

Osteoarthritis is a common joint disease for which there are currently no disease-modifying drugs available. Degradation of the cartilage extracellular matrix is a central feature of the disease and is widely thought to be mediated by proteinases that degrade structural components of the matrix, primarily aggrecan and collagen. Studies on transgenic mice have confirmed the central role of Adamalysin with Thrombospondin Motifs 5 (ADAMTS-5) in aggrecan degradation, and the collagenolytic matrix metalloproteinase MMP-13 in collagen degradation. This review discusses recent advances in current understanding of the mechanisms regulating expression of these key enzymes, as well as reviewing the roles of other proteinases in cartilage destruction. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

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.

View full text

ReviewProteases involved in cartilage matrix degradation in osteoarthritis☆

Abstract

Highlights

Introduction

Section snippets

Aggrecan-degrading enzymes

Collagenases

Other MMPs and ADAMs

Transcriptional regulation of MMPs and ADAMTSs in OA

Inhibitors of MMPs and ADAMTSs

Collagenase activators

Cathepsins

Conclusions and future prospects

Acknowledgments

Osteoarthritis — an untreatable disease?

Nat. Rev. Drug Discov.

Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis

Ann. N. Y. Acad. Sci.

Developments in the clinical understanding of osteoarthritis

Arthritis Res. Ther.

The role of the cartilage matrix in osteoarthritis

Nat. Rev. Rheumatol.

Reversible collapse of rabbit ears after intravenous papain, and prevention of recovery by cortisone

J. Exp. Med.

Comparison of the effects of papain and vitamin A on cartilage. I. The effects in rabbits

J. Exp. Med.

Studies on the mode of action of excess of vitamin A. 2. A possible role of intracellular proteases in the degradation of cartilage matrix

Biochem. J.

Characterization of cathepsins in cartilage

Biochem. J.

Purification of cathepsin D from cartilage and uterus and its action on the protein–polysaccharide complex of cartilage

J. Biol. Chem.

The action of cathepsin D in human articular cartilage on proteoglycans

J. Clin. Invest.

Cathepsin D. Characteristics of immunoinhibition and the confirmation of a role in cartilage breakdown

Biochem. J.

Further characterization of a neutral metalloprotease isolated from human articular cartilage

Arthritis Rheum.

Purification and characterization of a rabbit bone metalloproteinase that degrades proteoglycan and other connective-tissue components

Biochem. J.

Purification of the neutral proteoglycan-degrading metalloproteinase from human articular cartilage tissue and its identification as stromelysin matrix metalloproteinase-3

Biochem. J.

Cleavage of cartilage proteoglycan between G1 and G2 domains by stromelysins

J. Biol. Chem.

The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B

J. Biol. Chem.

Fibroblast and neutrophil collagenases cleave at two sites in the cartilage aggrecan interglobular domain

Biochem. J.

Degradation of cartilage aggrecan by collagenase-3 (MMP-13)

FEBS Lett.

The structure of aggrecan fragments in human synovial fluid. Evidence for the involvement in osteoarthritis of a novel proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain

J. Clin. Invest.

Catabolism of aggrecan in cartilage explants. Identification of a major cleavage site within the interglobular domain

J. Biol. Chem.

Cell-mediated catabolism of aggrecan. Evidence that cleavage at the “aggrecanase” site (Glu373–Ala374) is a primary event in proteolysis of the interglobular domain

J. Biol. Chem.

Differential expression of aggrecanase and matrix metalloproteinase activity in chondrocytes isolated from bovine and porcine articular cartilage

J. Biol. Chem.

Matrix metalloproteinases are involved in C-terminal and interglobular domain processing of cartilage aggrecan in late stage cartilage degradation

Matrix Biol.

Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins

Science

Molecular cloning of a gene encoding a new type of metalloproteinase-disintegrin family protein with thrombospondin motifs as an inflammation associated gene

J. Biol. Chem.

ADAM-TS5, ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases. General features and genomic distribution of the ADAM-TS family

J. Biol. Chem.

Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family

J. Biol. Chem.

ADAMTS-5: the story so far

Eur. Cell. Mater.

Altered proteolytic activities of ADAMTS-4 expressed by C-terminal processing

J. Biol. Chem.

Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4

J. Biol. Chem.

ADAMTS-1 cleaves a cartilage proteoglycan, aggrecan

FEBS Lett.

Characterization of ADAMTS-9 and ADAMTS-20 as a distinct ADAMTS subfamily related to Caenorhabditis elegans GON-1

J. Biol. Chem.

ADAMTS-8 exhibits aggrecanase activity and is expressed in human articular cartilage

Matrix Biol.

Review
Proteases involved in cartilage matrix degradation in osteoarthritis☆

Cell-mediated catabolism of aggrecan. Evidence that cleavage at the “aggrecanase” site (Glu³⁷³–Ala³⁷⁴) is a primary event in proteolysis of the interglobular domain