Modern Rheumatology

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Matrix-degrading metalloproteinases and their roles in joint destruction Y. Okada To cite this article: Y. Okada (2000) Matrix-degrading metalloproteinases and their roles in joint destruction, Modern Rheumatology, 10:3, 121-128 To link to this article: http://dx.doi.org/10.3109/s101650070018

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Date: 05 November 2015, At: 18:19

Mod Rheumatol (2000) 10:121–128

© The Japan Rheumatism Association and Springer-Verlag Tokyo 2000

REVIEW ARTICLE

Yasunori Okada

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Matrix-degrading metalloproteinases and their roles in joint destruction

Received: March 14, 2000

Abstract Progressive degradation of the extracellular matrix (ECM) of articular cartilage and bone by enhanced activities of proteinases is an essential step for joint destruction in rheumatoid arthritis (RA) and osteoarthritis (OA). Among the proteinases, matrix-degrading metalloproteinases play a key role in joint destruction. Recent studies have indicated that these metalloproteinases comprise members of the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) gene families. The MMP family is composed of 19 different members and classified into five subgroups of collagenases, gelatinases, stromelysins, membrane-type MMPs, and other MMPs. They have the ability to digest almost all ECM components in human tissues when they act in concert. Their prospective roles in RA and OA joint destruction have been well established. On the other hand, the ADAM family members are classified into ADAM metalloproteinases and catalytically inactive nonproteolytic homologues. The ADAM metalloproteinases contain ADAM with a transmembrane domain (membrane-type ADAM) and ADAM with thrombospondin motifs (ADAMTS). Although members in both groups are known to degrade ECM components, ADAMTS species may be especially important for the aggrecan (cartilage proteoglycan) degradation of articular cartilage in RA and OA, since aggrecanases-1 and -2 are included in this group. This review outlines the characters of the MMP and ADAM gene family members and their roles in joint destruction in RA and OA. Key words Rheumatoid arthritis · Osteoarthritis · Matrix metalloproteinase · A disintegrin and metalloproteinase · Joint destruction · Matrix degradation

Y. Okada (*) Department of Pathology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan Tel. 181-3-5363-3763; Fax 181-3-3353-3290 e-mail: [email protected]

Introduction Extracellular matrix (ECM) is essential for maintaining the structural integrity of tissues, and plays an important role in many biological processes such as cell proliferation and differentiation, migration, apoptosis, and matricrine.1,2 Transient and well-controlled degradation of ECM components by proteinases is seen in other biological phenomena including fertilized egg implantation, embryogenesis, and wound healing.2 On the other hand, excessive ECM degradation causes tissue destruction under various pathological conditions. Joint destruction in rheumatoid arthritis (RA) and osteoarthritis (OA) is one of the typical pathological conditions in which ECM is progressively degraded by the elevated proteinase activities on the basis of an imbalance with endogenous inhibitors. Recent studies on matrix-degrading metalloproteinases have provided evidence suggesting the implication of the metalloproteinases in cartilage and bone destruction in RA and OA. This review focuses on the ECM components in joint tissues, the properties and regulation mechanisms of ECM-degrading metalloproteinases, and their roles in joint destruction.

Extracellular matrix of joint tissues Diarthrodial joints are joints in which two or more bones are connected to each other to allow smooth movement. Their principal structural components are articular cartilage, synovial membranes, and joint cavities. No blood vessels are present in normal articular cartilage, and thus the cartilage is nourished by serum components and substances generated by synovial membranes through the synovial fluid in joint cavities. Articular cartilage is composed of chondrocytes and ECM components. Although the character of chondrocytes in the superficial zone seems to be different from those in the deeper zones, they are basically a single cell type. On the other hand, cartilage contains various ECM components,

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which comprise mainly collagens and proteoglycans. Collagens are a large gene family consisting of 19 different molecules in eight subgroups: fibrillar collagens (type I, II, III, V, and XI collagens), basement membrane collagen (type IV collagen), microfibrillar collagen (type VI collagen), long-chain collagen (type VII collagen), shortchain collagens (type VIII and X collagens), fibrilassociated collagens with interrupted triple-helices (FACIT) collagens (type IX, XII, XIV, and XIX collagens), membrane-type collagens (type XIII and XVII collagens), and other collagens (type XV, XVI, and XVIII collagens). Although type II, V, VI, IX, X, and XI collagens are present in cartilage,3 the major collagen is type II collagen, which forms collagen fibrils in the cartilage. Type IX collagen is an essential component for maintaining the structural integrity of cartilage, since it aligns along the surface of type II collagen fibrils and interacts with the polyanionic glycosaminoglycan chains of cartilage proteoglycan (aggrecan) through the basic noncollagenous 4 domain, which projects out from the surface of the fibrils.3 Proteoglycans are classified into five major subgroups: large proteoglycans (aggrecan, versican, neurocan, and brevican), leucin-rich small proteoglycans (decorin, biglycan, and fibromodulin), heparan sulfate proteoglycan in basement membranes (perlecan), storage granule proteoglycan (serglycin), and cell-surface heparan sulfate proteoglycans (syndecans and glypican).4 Aggrecan, the major proteoglycan species in cartilage, contains three globular domains in the core protein (G1, G2, and G3 from the NH2-terminus) and binds to hyaluronan through the G1 domain.4 This interaction is strengthened by a link protein that binds to both the G1 domain of the core protein and hyaluronan. Synovial membranes are composed of the lining cell layer and the sublining cell layer, which has many capillaries lined by fenestrated endothelial cells.5 The ECM component in the lining cell layer comprises mainly type VI collagen with a small amount of type III collagen.6 Type VI collagen is special in that it has only 30% of collagenous triple helical domain in the molecule, and functions as an adhesive molecule for synovial lining cells. Type I and III collagens are present in the interstitium, and type IV collagen is in basement membranes of blood vessels in the sublining cell layer.6 Synovial cavities contain hyaluronic acid without collagen fibrils, and serum proteins and other metabolites derived from joint tissues permeate freely. Thus, a synovial cavity is thought to be a special ECM itself.5 The major ECM component in bone is type I collagen, with type III and V collagens as minor components. The most important character of bone ECM is that it is mineralized. Thus, water cannot get into the bone matrix prior to decalcification.

Extracellular matrix-degrading metalloproteinases Proteinases are generally classified according to their catalytic mechanism into aspartic proteinases, cysteine

proteinases, serine proteinases, and metalloproteinases. Among the proteinases, metalloproteinases are considered to play a key role in ECM degradation because of their actions at neutral pH and their broad substrate specificity against ECM components. Matrix-degrading metalloproteinases comprise members of the matrix metalloproteinase (MMP)7 and a disintegrin and metalloproteinase (ADAM) gene families.8 The activities of MMPs in tissues are regulated by multiple steps, including the gene expression of the proteinases and inhibitors, i.e., tissue inhibitors of metalloproteinases (TIMP-1, 2, 3, and 4), the activation of proenzymes (proMMPs), and the balance between the proteinases and their inhibitors. On the other hand, the regulation mechanisms of the activities of ADAMs are not well known.

Matrix metalloproteinase family The human MMP family contains 19 different members and can be classified into five subgroups based on structural similarity and substrate specificity: collagenases (tissue collagenase 5 MMP-1, neutrophil collagenase 5 MMP-8, and collagenase-3 5 MMP-13), gelatinases (gelatinase A 5 MMP-2 and gelatinase B 5 MMP-9), stromelysins (stromelysin-1 5 MMP-3 and stromelysin-2 5 MMP-10), membrane-type MMPs (MT1-MMP 5 MMP-14,9 MT2MMP 5 MMP-15,10 MT3-MMP 5 MMP-16,11 MT4-MMP 5 MMP-17,12 MT5-MMP 5 MMP-24,13 and MT6-MMP 5 MMP-2514), and others (matrilysin 5 MMP-7, stromelysin-3 5 MMP11, metalloelastase 5 MMP-12, novel MMP 5 MMP-19, enamelysin 5 MMP-20, and novel MMP 5 MMP2315) (Table 1). The majority of MMPs possess three common domains, i.e., the propeptide, catalytic, and hemopexin-like domains, which are preceded by hydrophobic signal peptides. The NH2-terminal propeptide domain has the conserved sequence of PRCG(V/N)PD, the cysteine residue of which interacts with the zinc atom to maintain the proenzyme in an inactive state. The catalytic domain has the zinc-binding motif HEXGHXXGXXH, in which three histidines bind to the catalytic zinc atom. The COOH-terminal hemopexin-like domain interacts with other molecules such as ECM components and plays a role in determining the substrate specificity. Gelatinases (MMP2 and MMP-9) contain a single insertion of three tandem repeats of fibronectin type II modules in the catalytic domain, which provide them with gelatin-binding properties. MMP-7, the smallest among the MMP members, lacks the hemopexin-like domain. MT-MMPs have a transmembrane domain in the COOH-terminal region, and the catalytic domain is exposed to the cell surfaces.9 However, MT4-MMP is different from other MT-MMPs in that it is a glycosylphosphatidylinositol-anchored MMP and is readily shed from cell surfaces.16 MMP-19 is also unique in that the second proline in the cysteine-switch motif (PRCG(V/N)PD) is replaced by glutamic acid, and it has a special oligoglutamic acid stretch and threonine-rich region in the hinge region and the COOH-terminus, respectively.17 Among all the MMP members, MMP-23 is an extreme,

123 Table 1. Human matrix metalloproteinases Enzymes

Molecular mass (kD) Precursor

Active

MMP-1

52 56a

41 45a

MMP-8

75a

65a

MMP-13

65

55

Gelatinases Gelatinase A

MMP-2

72

67

Gelatinase B

MMP-9

92a

84a 67a

Stromelysins Stromelysin 1

MMP-3

57 59a

45 28

MMP-10

56

47 24

MT-MMPs MT1-MMP

MMP-14

66

60

MT2-MMP

MMP-15

68

62

MT3-MMP MT4-MMP MT5-MMP MT6-MMP

MMP-16 MMP-17 MMP-24 MMP-25

64 Unknown Unknown Unknown

55 Unknown Unknown Unknown

MMP-7

28

19

Stromelysin 3 Metalloelastase

MMP-11 MMP-12

58 54

Novel MMP Enamelysin Novel MMP

MMP-19 MMP-20 MMP-23

Unknown Unknown Unknown

28 45 22 Unknown Unknown Unknown

Collagenases Interstitial collagenase Neutrophil collagenase Collagenase 3

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MMP No.

Stromelysin 2

Others Matrilysin

Matrix substrates

Cell source

Collagens I, II, III, VII, and X; gelatins; proteoglycan; link protein; entactin; tenascin Collagens, I, II, and III; gelatins; proteoglycan; link protein Collagens I, II, III, IV, IX, X, and XIV; proteoglycan; fibronectin; tenascin

Fibroblasts, synovial cells, chondrocytes, macrophages, endothelial cells, cancer cells Neutrophils Chondrocytes, breast carcinoma cells

Gelatins; collagens IV, V, VII, and XI; laminin; fibronectin; elastin; proteoglycan; link protein Gelatins; collagens III, IV, and V; proteoglycan; elastin; entactin; link protein

Fibroblasts, chondrocytes, mesangial cells, macrophages, endothelial cells Neutrophils, macrophages, osteoclasts, trophoblasts, T lymphocytes, cancer cells

Proteoglycan; gelatins; fibronectin; laminin; collagens III, IV, IX, and X; tenascin; link protein Proteoglycan; fibronectin; laminin; collagens III, IV, and V; link protein

Synovial cells, chondrocytes, fibroblasts

Collagens I, II, and III; gelatins; proteoglycan; fibronectin; laminin Fibronectin; tenascin; nidogen; aggrecan; perlecan; laminin Collagen III; fibronectin; gelatin Unknown Proteoglycans Gelatin

Cancer cells, chondrocytes, fibroblasts Cancer cells Glioma cells Unknown Brain, brain tumors Leukocytes

Proteoglycan; gelatins; fibronectin; laminin; elastin; entactin; collagen IV; tenascin; link protein Fibronectin; laminin; proteoglycan; gelatins Elastin

Cancer cells, chondrocytes, macrophages, mesangial cells Cancer stromal cells Macrophages

Tenascin, gelatin, aggrecan Enamel; gelatin Unknown

Synovial cells, ovary Enameloblasts Ovary, uterus, testis, prostate

Cancer cells, T lymphocytes

MMP-4, MMP-5, and MMP-6 are missing MMPs. MMP-18 (Xenopus collagenase 482), MMP-21 (Xenopus MMP83), and MMP-22 (chick MMP84) are not mammalian and are thus omitted from this list a Glycosylated form

since it lacks the signal peptide, the cysteine-switch motif, and the hemopexin-like domain, but a transmembrane region is present in the propeptide.15 MMPs are active to many ECM macromolecules present in human tissues (Table 1) and almost all components are readily degraded if two or more MMPs act in concert. Collagenases (MMP-1, MMP-8, and MMP-13) commonly degrade triple helical regions of interstitial collagen types I, II, and III at a specific single site located at about threequarters of the distance from the NH2-terminus, generating fragments approximately three-quarters and one-quarter the size of the original molecules. However, MMP-13 attacks α chains of type II collagen at two sites, the Gly906Leu and Gly909-Gln bonds.18 Although these three MMPs degrade the fibrillar collagens, MMP-1, 8, and 13 preferen-

tially digest collagen types III, I, and II, respectively.19 MMP-1 also digests entactin, collagen X, gelatins, aggrecan, and cartilage link protein (Table 1). MMP-8 cleaves aggrecan, gelatins, and cartilage link protein (Table 1). MMP-13 preferentially hydrolyzes aggrecan,20 type IV, IX, X, and XIV collagens, fibronectin and tenascin.21 Gelatinases (MMP-2 and MMP-9) digest type IV and V collagens.22–24 Elastin, aggrecan,25 and cartilage link protein26 are also cleaved by the gelatinases. Although MMP-2 digests fibronectin and laminin,22 MMP-9 is not active to such substrates, but digests type III collagen and α2 chains of type I collagen.23 Stromelysins (MMP-3 and MMP-10) have similar enzymatic properties27,28 and hydrolyze a number of ECM macromolecules including aggrecan, fibronectin, laminin, and collagen IV.28,29 Collagen types

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III, IX, and X, and telopeptides of collagens I, II, and XI are also digested by MMP-3.30 They are also activators of many proMMPs including proMMP-1, 7, 8, and 9.31 Among six different MT-MMPs, all except for MT4-MMP and MT6MMP can activate proMMP-2, and MT1-MMP is thought to play a major role in the activation of proMMP-2 in various tissues. In addition to its activator function, however, MT1MMP digests the triple helical portions of interstitial collagen types I, II, and III32 as well as other ECM components including fibronectin, laminin, aggrecan, and gelatin.32–34 MT2-MMP also digests fibronectin, tenascin, nidogen, aggrecan, perlecan, and laminin,35 and MT3-MMP cleaves collagen type III, fibronectin, and gelatins.36 MT5MMP37 and MT6-MMP14 also digest proteoglycans and gelatin, respectively, but ECM substrates of MT4-MMP are unknown. MMP-7 digests a wide range of substrates such as aggrecan, cartilage link protein, fibronectin, laminin, collagen IV, and elastin.25,26,28,38 MMP-11 shows only weak proteolytic activity on fibronectin, laminin, proteoglycan, and gelatin.39 MMP-12 digests elastin40 and α1-proteinase inhibitor. MMP-19,17 which is identical to MMP-1841 in protein sequence, digests aggrecan and gelatin. MMP-20 is called enamelysin since it degrades enamel, but its detailed biochemical properties are not reported.42 MMP-23 hydrolyzes a synthetic substrate of MMPs, but its ECM substrates are not known.15 Since MMPs are synthesized as proMMPs, their activation is essential to their functioning in vivo. ProMMPs are activated by three different pathways depending on the MMP members: extracellular, intracellular, and pericelluar activation. ProMMP-1, 3, 7, 8, 9, 10, 12, and 13 are activated extracellularly by nonproteolytic agents and proteinases. Nonproteolytic activators include thiol-modifying reagents (e.g., mercurial compounds, iodoacetamide, Nethylmaleimide, and oxidized glutathione), hypochlorous acid, sodium dodecyl sulfate, chaotropic agents, and physical factors (heat and acid exposure).31 Although many proteinases are involved in the activation, plasmin may play a major role in the activation of proMMP-3 and proMMP10 in vivo.27 However, since other proMMPs cannot be fully activated by serine proteinases such as plasmin, but are activated by active MMP-3 or MMP-10,31,43 this intermolecular activation cascade of MMPs may be important to in vivo activation of proMMPs. ProMMP-11 and MT1MMP are activated intracellularly by removal of propeptides by furin in the trans-Golgi network.44–46 Thus, MMP-11 is secreted as an active enzyme and active MT1MMP is expressed on the cell membranes. Since other MTMMPs also have the furin recognition motif of RXKR,10–14 furin is supposed to be responsible for the intracellular activation of the MT-MMPs. ProMMP-2 can be activated by MT1-MMP, MT2-MMP, MT3-MMP, and MT5-MMP on the cell membranes, although it is resistant to extracellular activation by most endopeptidases.22 Interestingly, TIMP-2 is required for the efficient activation of proMMP-2 by MT1-MMP on the cell membranes. Binding of proMMP-2 to MT1-MMP via TIMP-2 on the cell membranes facilitates its activation by increasing a local concentration of proMMP-2 and presenting it to the near free MT1-MMP.47,48

However, an excess amount of TIMP-2 inhibits the binding and activation of proMMP-2.48 It seems likely that the local concentration of TIMP-2 is a critical factor controlling the proMMP-2 activation. After activation of proMMPs, their activities are strictly regulated by TIMPs (TIMP-1, 2, 3, and 4), which share approximately 40%–50% sequence identity with each other.49–51 Although TIMP-1 is not an efficient inhibitor to the activities of MT-MMPs,35,36,52 TIMPs inhibit all the other MMPs by binding in a 1 : 1 molar ratio.49 In addition to the direct inhibition of activity by TIMPs, TIMP-1 and TIMP2 bind to the C-terminal domains of proMMP-9 and proMMP-2 (proMMP-9/TIMP-1 and proMMP-2/TIMP-2 complexes), respectively,23,49 and the activation of these proMMPs is suppressed in the complex forms. TIMP-3 is different from others in that it binds to ECM components and is thus deposited in the ECM. The production levels are selectively enhanced with calcium pentosan polysulfate by the posttranscriptional mechanism.53

ADAM family The ADAM family comprises at least 23 members of various animal species, and is still growing. According to their differences in the active-site sequence, they are classified into ADAM metalloproteinases and catalytically inactive nonproteolytic homologues. ADAM metalloproteinases have two subgroups: ADAM metalloproteinases with a transmembrane domain (ADAM-1, 8, 9, 10, 12, 13, 15, 17, 19, and 20) and ADAMs with thrombospondin motifs (ADAMTS1, 2, 3, 4, and 5) (Table 2). Their active sites contain a common sequence of HEXGHXXGXXHD including D. Among membrane-type ADAMs, only ADAM-10 and ADAM-17 are known to have proteinase activity. ADAM-10 cleaves not only myelin basic protein but also type IV collagen,54 and processes proform of tumor necrosis factor-α (TNF-α).55 ADAM-17 cleaves proform of TNF-α at the physiological processing site into the soluble form of TNF-α, and is called TNFα-conversing enzyme (TACE).56,57 Recent studies on ADAM-17-deficient mice indicate that it is also involved in release of L-selectin, transforming growth factor-α, and p75 TNF receptor.58 On the other hand, ADAMTS2, also called procollagen Nproteinase,59 cleaves specifically the NH2-terminal propeptides of type I and II collagens. ADAMTS4 and ADAMTS5 are called aggrecanase-1 and aggrecanase-2, respectively,60,61 since they can cleave the Glu373–Ala374 bond of aggrecan (the aggrecanase site).34 Most members of membrane-type ADAMs and ADAMTS contain the furin recognition site in the molecules. Thus, they may be activated intracellularly by furin, although data for this hypothesis are available only with ADAMTS1.62 Among TIMP-1, 2, and 3, TIMP-3 specifically inhibits the activity of TACE (ADAM-17).63 ADAMTS4 is also reported to be weakly inhibited by TIMP-1.64 However, neither the inhibitor activity of these TIMPs against other ADAM family members nor the presence of ADAM-specific inhibitors is known.

125 Table 2. ADAM metalloproteinases ADAM No.

Other names

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ADAM metalloproteinases with transmembrane domain ADAM 1 Fertilin α, PH-30α ADAM 8 MS2 (CD156) ADAM 9 MDC9, meltrin γ ADAM 10

MADM

ADAM 12

(Human homologue of kuzbanian Meltrin α

ADAM 13 ADAM 15

Metargidin, MDC15

ADAM 17

TACE, cSVP

ADAM 19 ADAM 20

Meltrin β

ADAM metalloproteinases with thrombospondin motifs ADAMTS1 – ADAMTS2

Procollagen N-proteinase

ADAMTS3 ADAMTS4 ADAMTS5

KIAA0366 KIAA0688, aggrecanase-1 ADAMTS11, aggrecanase-2

Functions of properties

Species or expression sites

Egg–sperm fusion, spermatogenesis Neutrophil infiltration Shedding of heparin-binding EGF-like growth factor Release of TNF-α, digestion of collagen IV and myelin basic protein, presence of RRKR sequence Processing of Delta Myotube formation, presence of RRKR sequence Migration of neural crest Increase in arteriosclerosis, binding to αvβ3 integrin Release of TNF-α, TGF-α, L-selectin and p75 TNF receptor, presence of RXKR Neural formation? Spermatogenesis

Sperm Macrophages; neutrophils Many tissues

Binding to heparin, presence of RXKR and thrombospondin motifs Processing of N-propeptides of type I and II collagens Unknown Digestion of aggrecan Digestion of aggrecan

Chondrocytes, microglia, kidney, brain Drosophila) Osteoblasts, myoblasts, chondrocytes Xenopus Smooth muscle cells, endothelial cells, osteoclasts, chondrocytes Macrophages and many tissues Osteoblasts, myoblasts Testis Kidney, heart Skin, tendon Brain Brain, heart Uterus, placenta

ADAM family members can be divided into ADAM metalloproteinases and nonproteolytic homologues based on the structural differences of the metalloproteinase domain. ADAM metalloproteinases comprise two subgroups of membrane type ADAM and ADAMTS, as shown in this table. EGF, epidermal growth factor; TNF, tumor necrosis factor; TGF, transforming growth factor

Expression of metalloproteinases and joint destruction Articular cartilage is the major target for joint destruction in both RA and OA. During the cartilage destruction processes, depletion of aggrecan from the cartilage ECM is the initial event, followed by collagen degradation, leading to fibrillation and laceration of the cartilage. In RA, synovium shows hyperplasia of the lining cells and inflammatory cell infiltration and angiogenesis in the sublining cell layer. MMP-1 and MMP-3 are produced by the lining cells,65,66 MMP-2 by the sublining cells,67 and MMP-9 by both lining and sublining inflammatory cells.68 TIMP-1, 2, and 3 are also expressed in the synovial tissues.53,67 T lymphocytes in the synovium synthesize MMP-9, which may be important for their infiltration into the synovium. Polymorphonuclear leukocytes contain MMP-8 in their specific granules. These proteinases and inhibitors are secreted into the synovial fluids. In fact, MMP-1, 2, 3, 8, and 9 and TIMP-1 are detectable in RA synovial fluids, and their steady-state levels are significantly higher in RA than in OA.69 The molar ratios of the MMPs to TIMP-1 and TIMP-2 are ~44, and the metalloproteinase activity can be detected after activation of proMMPs. Thus, the MMPs are considered to be in favor of proteinases in RA synovial fluids69 and attack the articular cartilage on the basis of imbalance in favor of proteinases. This may explain the proteolytic damage of the central part of the articular surface without pannus tissue. At the margins of the articular surface, the cartilage may be

attacked by proteinases in synovial fluid and/or by a direct contact with the highly proteolytic synovial tissue. Our recent studies have demonstrated that proMMP-2 is efficiently activated by MT1-MMP expressed by the lining cells of RA synovium, and the lining cell layer has gelatinolytic activity.70 This synovium may be ascribed to the destruction of the marginal part of articular cartilage facing synovium in the early stage of RA. The damaged cartilage is commonly covered with pannus tissue at the margin, but it is not known whether pannus tissue is actively involved in the destruction or repair of the articular cartilage. In RA, cytokines derived from synovium stimulate articular chondrocytes to produce MMPs, which may cause cartilage destruction. However, information about this pathway is still limited. Bone is progressively resorbed by osteoclasts in RA. This is commonly observed at the bare zone, where pannuslike granulation tissue invades the subchondral bone. Osteoclastic bone resorption occurs under acidic (pH 4–5) and hypercalcemic (40–50 mM Ca11) conditions.71 Because of collagenolytic activity with a broad pH optimum and selective expression in osteoclasts and giant cell tumors, cathepsin K, a collagenolytic cysteine proteinase, is believed to play a key role in the bone resorption. However, inhibition of bone resorption by cysteine proteinase inhibitors is partial, and similar levels of inhibition are also observed with MMP inhibitors.71 MMP-9 is strongly expressed in osteoclasts in normal and rheumatoid bones72 and in giant cells of giant cell tumors.73 It has telopeptidase

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activity against soluble and insoluble type I collagen, and strong gelatinolytic activity.72 ProMMP-9 is activated by acid exposure followed by neutralization, and once activated it is proteolytically active under acidic and hypercalcemic conditions.72 Thus, MMP-9 as well as cathepsin K may play an important role in bone resorption in RA. Destruction of articular cartilage in OA is ascribed mainly to an elevated production of enzymes from the chondrocytes themselves. MMP-3 and MMP-7 are immunolocalized in chondrocytes in the proteoglycandepleted zone of OA cartilage, and the levels of their staining correlate directly with the histological scores.74,75 MMP-1, MMP-8, and MMP-13 are also expressed in OA cartilage.18,76,77 Among them, MMP-13 may be most important in the degradation of cartilage collagen, i.e., type II collagen, since it preferentially degrades type II collagen over type I and III collagens.18,19 Elevated expression of MMP-9 protein and mRNA is observed in OA cartilage.78 Activation of proMMP-2 mediated by MT1-MMP is also demonstrated in OA cartilage.79 In addition to these MMPs, ADAMs-10, 12, and 17 are expressed in OA cartilage,80,81 although the functions of these ADAMs in cartilage degradation are not clear at the moment. ADAMTS4 and ADAMTS5 (aggrecanase-1, 2) are isolated from cartilage,60,61 but their expression and relation to cartilage destruction in OA remains to be elucidated.64

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