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Proteinases involved in matrix turnover during cartilage and bone breakdown

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Abstract

The joint is a discrete unit that consists of cartilage, bone, tendon and ligaments. These tissues are all composed of an extracellular matrix made of collagens, proteoglycans and specialised glycoproteins that are actively synthesised, precisely assembled and subsequently degraded by the resident connective tissue cells. A balance is maintained between matrix synthesis and degradation in healthy adult tissues. Different classes of proteinases play a part in connective tissue turnover in which active proteinases can cleave matrix protein during resorption, although the proteinase that predominates varies between different tissues and diseases. The metalloproteinases are potent enzymes that, once activated, degrade connective tissue and are inhibited by tissue inhibitors of metalloproteinases (TIMPs); the balance between active matrix metalloproteinases and TIMPs determines, in many tissues, the extent of extracellular matrix degradation. The serine proteinases are involved in the initiation of activation cascades and some, such as elastase, can directly degrade the matrix. Cysteine proteinases are responsible for the breakdown of collagen in bone following the removal of the osteoid layer and the attachment of osteoclasts to the exposed bone surface. Various growth factors increase the synthesis of matrix and proteinase inhibitors, whereas cytokines (alone or in combination) can inhibit matrix synthesis and stimulate proteinase production and matrix destruction.

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Abbreviations

ADAM:

a disintegrin and metalloproteinase

ADAMTS:

a disintegrin and metalloproteinase with thrombospondin motifs

BMP-1:

bone morphogenetic protein-1

ECM:

extracellular matrix

GPI:

glycosylphosphatidyl inositol

HDAC:

histone deacetylase

IGFBP:

insulin-like growth factor binding protein

IL:

interleukin

Jak-STAT:

Janus kinase-signal transducer and activator of transcription

MAPK:

mitogen-activated protein kinase

MMPs:

matrix metalloproteinases

NF-κB:

nuclear factor kappa B

OA:

osteoarthritis

OSM:

oncostatin M

RA:

rheumatoid arthritis

RANKL:

receptor activator of nuclear factor κB ligand

TNF:

tumour necrosis factor

TIMPs:

tissue inhibitors of metalloproteinases

TGF:

transforming growth factor

References

  • Ahrens D, Koch AE, Pope RM, Stein-Picarella M, Niedbala MJ (1996) Expression of matrix metalloproteinase 9 (96-kd gelatinase B) in human rheumatoid arthritis. Arthritis Rheum 39:1576–1587

    CAS  PubMed  Google Scholar 

  • Aimes RT, Quigley JP (1995) Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4 and 1/4-length fragments. J Biol Chem 270:5872–5876

    CAS  PubMed  Google Scholar 

  • Arner EC, Hughes CE, Decicco CP, Caterson B, Tortorella MD (1998) Cytokine-induced cartilage proteoglycan degradation is mediated by aggrecanase. Osteoarthritis Cartilage 6:214–228

    CAS  PubMed  Google Scholar 

  • Barrett AJ, Rawlings ND, Woessner JF Jr (1998) Handbook of proteolytic enzymes. Academic Press, New York

    Google Scholar 

  • Becherer JD, Blobel CP (2003) Biochemical properties and functions of membrane-anchored metalloprotease-disintegrin proteins (ADAMs). Curr Top Dev Biol 54:101–123

    CAS  PubMed  Google Scholar 

  • Berg WB van den (1999) The role of cytokines and growth factors in cartilage destruction in osteoarthritis and rheumatoid arthritis. Z Rheumatol 58:136–141

    PubMed  Google Scholar 

  • Berg WB van den (2000) Pathophysiology of osteoarthritis. Joint Bone Spine 67:555–556

    PubMed  Google Scholar 

  • Billington CJ, Clark IM, Cawston TE (1998) An aggrecan-degrading activity associated with chondrocyte membranes. Biochem J 336:207–212

    CAS  PubMed  Google Scholar 

  • Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385:729–733

    CAS  PubMed  Google Scholar 

  • Blanchard F, Chipoy C (2005) Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases? Drug Discov Today 10:197–204

    CAS  PubMed  Google Scholar 

  • Boldt HB, Overgaard MT, Laursen LS, Weyer K, Sottrup-Jensen L, Oxvig C (2001) Mutational analysis of the proteolytic domain of pregnancy-associated plasma protein-A (PAPP-A): classification as a metzincin. Biochem J 358:359–367

    CAS  PubMed  Google Scholar 

  • Borkakoti N (2004) Matrix metalloprotease inhibitors: design from structure. Biochem Soc Trans 32:17–20

    CAS  PubMed  Google Scholar 

  • Bossard MJ, Tomaszek TA, Thompson SK, Amegadzie BY, Hanning CR, Jones C, Kurdyla JT, McNulty DE, Drake FH, Gowen M, Levy MA (1996) Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem 271:12517–12524

    CAS  PubMed  Google Scholar 

  • Brew K, Dinakarpandian D, Nagase H (2000) Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 1477:267–283

    CAS  PubMed  Google Scholar 

  • Bri E de, Lei W, Svensson O, Chowdhury M, Moak SA, Greenwald RA (1998) Effect of an inhibitor of matrix metalloproteinases on spontaneous osteoarthritis in guinea pigs. Adv Dent Res 12:82–85

    PubMed  Google Scholar 

  • Bryson H, Bunning RAD, Feltell R, Kam CM, Kerrigan J, Powers JC, Buttle DJ (1998) A serine proteinase inactivator inhibits chondrocyte-mediated cartilage proteoglycan breakdown occurring in response to proinflammatory cytokines. Arch Biochem Biophys 355:15–25

    CAS  PubMed  Google Scholar 

  • Burleigh MC, Barrett AJ, Lazarus GS (1974) Cathepsin B1. A lysosomal enzyme that degrades native collagen. Biochem J 137:387–398

    CAS  PubMed  Google Scholar 

  • Butler GS, Will H, Atkinson SJ, Murphy G (1997) Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases. Eur J Biochem 244:653–657

    CAS  PubMed  Google Scholar 

  • Buttle DJ, Bramwell H, Hollander AP (1995) Proteolytic mechanisms of cartilage breakdown: a target for arthritis therapy? Clin Pathol Mol Pathol 48:M167–M177

    CAS  Google Scholar 

  • Campbell IK, Wojta J, Novak U, Hamilton JA (1994) Cytokine modulation of plasminogen activator inhibitor-1 (PAI-1) production by human articular cartilage and chondrocytes. Down-regulation by tumor necrosis factor α and up-regulation by transforming growth factor-β and basic fibroblast growth factor. Biochim Biophys Acta 1226:277–285

    CAS  PubMed  Google Scholar 

  • Caterson B, Flannery CR, Hughes CE, Little CB (2000) Mechanisms involved in cartilage proteoglycan catabolism. Matrix Biol 19:333–344

    CAS  PubMed  Google Scholar 

  • Cawston TE (1996) Metalloproteinases inhibitors and the prevention of connective tissue breakdown. Pharmacol Ther 70:163–182

    CAS  PubMed  Google Scholar 

  • Cawston TE, Curry VA, Summers CA, Clark IM, Riley GP, Life PF, Spaull JR, Goldring MB, Koshy PJ, Rowan AD, Shingleton WD (1998) The role of oncostatin M in animal and human connective tissue collagen turnover and its localization within the rheumatoid joint. Arthritis Rheum 41:1760–1771

    CAS  PubMed  Google Scholar 

  • Chau T, Jolly G, Plym MJ, McHugh M, Bortolon E, Wakefield J, Gianpaolo-Ostravage C, Maniglia C (1998) Inhibition of articular cartilage degradation in dog and guinea-pig models of osteoarthritis by the stromelysin inhibitor, BAY-12–9566. Arthritis Rheum 41:S300

    Google Scholar 

  • Chevrier A, Mort JS, Crine P, Hoemann CD, Buschmann MD (2001) Soluble recombinant neprilysin induces aggrecanase-mediated cleavage of aggrecan in cartilage explant cultures. Arch Biochem Biophys 396:178–186

    CAS  PubMed  Google Scholar 

  • Choo QY, Ho PC, Lin HS (2008) Histone deacetylase inhibitors: new hope for rheumatoid arthritis? Curr Pharm Des 14:803–820

    CAS  PubMed  Google Scholar 

  • Chung YL, Lee MY, Wang AJ, Yao LF (2003) A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis. Mol Ther 8:707–717

    CAS  PubMed  Google Scholar 

  • Clark IM, Parker AE (2003) Metalloproteinases: their role in arthritis and potential as therapeutic targets. Expert Opin Ther Targets 7:19–34

    CAS  PubMed  Google Scholar 

  • Clark IM, Swingler TE, Sampieri CL, Edwards DR (2008) The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol 40:1362–1378

    CAS  PubMed  Google Scholar 

  • Cohen SB, Cheng TT, Chindalore V, Damjanov N, Burgos-Vargas R, Delora P, Zimany K, Travers H, Caulfield JP (2009) Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthritis Rheum 60:335–344

    CAS  PubMed  Google Scholar 

  • Collins-Racie LA, Flannery CR, Zeng W, Corcoran C, Annis-Freeman B, Agostino MJ, Arai M, DiBlasio-Smith E, Dorner AJ, Georgiadis KE, Jin M, Tan XY, Morris EA, LaVallie ER (2004) ADAMTS-8 exhibits aggrecanase activity and is expressed in human articular cartilage. Matrix Biol 23:219–230

    CAS  PubMed  Google Scholar 

  • Delaisse JM, Eeckhout Y, Vaes G (1980) Inhibition of bone resorption in culture by inhibitors of thiol proteinases. Biochem J 192:365–368

    CAS  PubMed  Google Scholar 

  • Delaisse JM, Eeckhout Y, Vaes G (1984) In vivo and in vitro evidence for the involvement of cysteine proteinases in bone resorption. Biochem Biophys Res Commun 125:441–447

    CAS  PubMed  Google Scholar 

  • Dudler J, Renggli-Zulliger N, Busso N, Lotz M, So A (2000) Effect of interleukin 17 on proteoglycan degradation in murine knee joints. Ann Rheum Dis 59:529–532

    CAS  PubMed  Google Scholar 

  • Eeckhout Y, Vaes G (1977) Further studies on the activation of procollagenase, the latent precursor of bone collagenase. Effects of lysomal cathepsin B, plasmin and kallikrein and spontaneous activation. Biochem J 166:21–31

    CAS  PubMed  Google Scholar 

  • Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2:161–174

    CAS  PubMed  Google Scholar 

  • Ellis AJ, Curry VA, Powell EK, Cawston TE (1994) The prevention of collagen breakdown in bovine nasal cartilage by TIMP-1, TIMP-2 and a low molecular weight synthetic inhibitor. Biochem Biophys Res Commun 201:94–101

    CAS  PubMed  Google Scholar 

  • Etherington DJ (1972) The nature of the collagenolytic cathepsin of rat liver and its distribution in other rat tissues. Biochem J 127:685–692

    CAS  PubMed  Google Scholar 

  • Everts V, Beertsen W, Tigchelaar-Gutter W (1985) The digestion of phagocytosed collagen is inhibited by the proteinase inhibitors leupeptin and E-64. Collagen Relat Res 5:315–336

    CAS  Google Scholar 

  • Everts V, Delaisse JM, Korper W, Niehof A, Vaes G, Beertsen W (1992) Degradation of collagen in the bone-resorbing compartment underlying the osteoclast involves both cysteine-proteinases and matrix metalloproteinases. J Cell Physiol 150:221–231

    CAS  PubMed  Google Scholar 

  • Everts V, Van der Zee E, Creemers L, Beertsen W (1996) Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling. Histochem J 28:229–245

    CAS  PubMed  Google Scholar 

  • Felson DT, Lohmander LS (2009) Whither osteoarthritis biomarkers? Osteoarthritis Cartilage 17:419–422

    CAS  PubMed  Google Scholar 

  • Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361

    CAS  PubMed  Google Scholar 

  • Fosang AJ, Neame PJ, Last K, Hardingham TE, Murphy G, Hamilton JA (1992) The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B. J Biol Chem 267:19470–19474

    CAS  PubMed  Google Scholar 

  • Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, Flannery CR, Peluso D, Kanki K, Yang Z, Majumdar MK, Morris EA (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434:644–648

    CAS  PubMed  Google Scholar 

  • Goldring MB (2000) The role of the chondrocyte in osteoarthritis. Arthritis Rheum 43:1916–1926

    CAS  PubMed  Google Scholar 

  • Goldring MB, Otero M, Tsuchimochi K, Ijiri K, Li Y (2008) Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism. Ann Rheum Dis 67 (Suppl 3):iii75–iii82

    CAS  PubMed  Google Scholar 

  • Greene J, Wang M, Liu YE, Raymond LA, Rosen C, Shi YE (1996) Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem 271:30375–30380

    CAS  PubMed  Google Scholar 

  • Gruber BL, Sorbi D, French DL, Marchese MJ, Nuovo GJ, Kew RR, Arbeit LA (1996) Markedly elevated serum MMP-9 (gelatinase B) levels in rheumatoid arthritis: a potential useful laboratory marker. Clin Immunol Immunopathol 78:161–171

    CAS  PubMed  Google Scholar 

  • Guo H, Li R, Zucker S, Toole BP (2000) EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface. Cancer Res 60:888–891

    CAS  PubMed  Google Scholar 

  • Halili MA, Andrews MR, Sweet MJ, Fairlie DP (2009) Histone deacetylase inhibitors in inflammatory disease. Curr Top Med Chem 9:309–319

    CAS  PubMed  Google Scholar 

  • Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, Manning AM, Firestein GS (2001) c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 108:73–81

    CAS  PubMed  Google Scholar 

  • He C, Wilhelm SM, Pentland AP, Marmer BL, Grant GA, Eisen AZ, Goldberg GI (1989) Tissue cooperation in a proteolytic cascade activating human interstitial collagenase. Proc Natl Acad Sci USA 86:2632–2636

    CAS  PubMed  Google Scholar 

  • Hembry RM, Bagga MR, Reynolds JJ, Hamblen DL (1995) Immunolocalisation studies on six matrix metalloproteinases and their inhibitors, TIMP-1 and TIMP-2, in synovia from patients with osteo- and rheumatoid arthritis. Ann Rheum Dis 54:25–32

    CAS  PubMed  Google Scholar 

  • Hemmings FJ, Farhan M, Rowland J, Banken L, Jain R (2001) Tolerability and pharmacokinetics of the collagenase-selective inhibitor Trocade in patients with rheumatoid arthritis. Rheumatology (Oxford) 40:537–543

    CAS  Google Scholar 

  • Hou WS, Li Z, Gordon RE, Chan K, Klein MJ, Levy R, Keysser M, Keyszer G, Bromme D (2001) Cathepsin k is a critical protease in synovial fibroblast-mediated collagen degradation. Am J Pathol 159:2167–2177

    CAS  PubMed  Google Scholar 

  • Hou WS, Li W, Keyszer G, Weber E, Levy R, Klein MJ, Gravallese EM, Goldring SR, Bromme D (2002) Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum 46:663–674

    CAS  PubMed  Google Scholar 

  • Hui W, Barksby HE, Young DA, Cawston TE, McKie N, Rowan AD (2005) Oncostatin M in combination with tumour necrosis factor alpha induces a chondrocyte membrane-associated aggrecanase that is distinct from ADAMTS aggrecanase-1 or -2. Ann Rheum Dis 64:1624–1632

    CAS  PubMed  Google Scholar 

  • Hummel KM, Petrow PK, Franz JK, Muller-Ladner U, Aicher WK, Gay RE, Bromme D, Gay S (1998) Cysteine proteinase cathepsin K mRNA is expressed in synovium of patients with rheumatoid arthritis and is detected at sites of synovial bone destruction. J Rheumatol 25:1887–1894

    CAS  PubMed  Google Scholar 

  • Inaoka T, Bilbe G, Ishibashi O, Tezuka K, Kumegawa M, Kokubo T (1995) Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochem Biophys Res Commun 206:89–96

    CAS  PubMed  Google Scholar 

  • Iozzo RV (1998) Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem 67:609–652

    CAS  PubMed  Google Scholar 

  • Ishikawa H, Nakagawa Y, Shimizu K, Nishihara H, Matsusue Y, Nakamura T (1999) Inflammatory cytokines induced down-regulation of m-calpain mRNA expression in fibroblastic synoviocytes from patients with osteoarthritis and rheumatoid arthritis. Biochem Biophys Res Commun 266:341–346

    CAS  PubMed  Google Scholar 

  • Ishikawa T, Nishigaki F, Miyata S, Hirayama Y, Minoura K, Imanishi J, Neya M, Mizutani T, Imamura Y, Naritomi Y, Murai H, Ohkubo Y, Kagayama A, Mutoh S (2005a) Prevention of progressive joint destruction in collagen-induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR255031. Br J Pharmacol 144:133–143

    CAS  PubMed  Google Scholar 

  • Ishikawa T, Nishigaki F, Miyata S, Hirayama Y, Minoura K, Imanishi J, Neya M, Mizutani T, Imamura Y, Ohkubo Y, Mutoh S (2005b) Prevention of progressive joint destruction in adjuvant induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR217840. Eur J Pharmacol 508:239–247

    CAS  PubMed  Google Scholar 

  • Johnstone RW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287–299

    CAS  PubMed  Google Scholar 

  • Kafienah W, Bromme D, Buttle DJ, Croucher LJ, Hollander AP (1998) Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem J 331:727–732

    CAS  PubMed  Google Scholar 

  • Kashiwagi M, Tortorella M, Nagase H, Brew K (2001) TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). J Biol Chem 276:12501–12504

    CAS  PubMed  Google Scholar 

  • Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L, Porter S, Brockbank SM, Edwards DR, Parker AE, Clark IM (2004) Expression profiling of metalloproteinases and their inhibitors in cartilage. Arthritis Rheum 50:131–141

    CAS  PubMed  Google Scholar 

  • Kleiner DE Jr, Stetler-Stevenson WG (1993) Structural biochemistry and activation of matrix metalloproteases. Curr Opin Cell Biol 5:891–897

    CAS  PubMed  Google Scholar 

  • Knäuper V, Wilhelm SM, Seperack PK, DeClerck YA, Langley KE, Osthues A, Tschesche H (1993) Direct activation of human neutrophil procollagenase by recombinant stromelysin. Biochem J 295:581–586

    PubMed  Google Scholar 

  • Knäuper V, López-Otin C, Smith B, Knight G, Murphy G (1996a) Biochemical characterization of human collagenase-3. J Biol Chem 271:1544–1550

    PubMed  Google Scholar 

  • Knäuper V, Will H, López-Otin C, Smith B, Atkinson SJ, Stanton H, Hembry RM, Murphy G (1996b) Cellular mechanisms for human procollagenase-3 (MMP-13) activation. J Biol Chem 271:17124–17131

    PubMed  Google Scholar 

  • Konttinen YT, Ainola M, Valleala H, Ma J, Ida H, Mandelin J, Kinne RW, Santavirta S, Sorsa T, López-Otin C, Takagi M (1999) Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis. Ann Rheum Dis 58:691–697

    CAS  PubMed  Google Scholar 

  • Koshy PJ, Henderson N, Logan C, Life PF, Cawston TE, Rowan AD (2002a) Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines. Ann Rheum Dis 61:704–713

    CAS  PubMed  Google Scholar 

  • Koshy PJ, Lundy CJ, Rowan AD, Porter S, Edwards DR, Hogan A, Clark IM, Cawston TE (2002b) The modulation of matrix metalloproteinase and ADAM gene expression in human chondrocytes by interleukin-1 and oncostatin M: a time-course study using real-time quantitative reverse transcription-polymerase chain reaction. Arthritis Rheum 46:961–967

    CAS  PubMed  Google Scholar 

  • Kouzarides T (2000) Acetylation: a regulatory modification to rival phosphorylation? EMBO J 19:1176–1179

    CAS  PubMed  Google Scholar 

  • Laan W van der, Molenaar E, Ronday K, Verheijen J, Breedveld F, Greenwald R, Dijkmans B, TeKoppele J (2001) Lack of effect of doxycycline on disease activity and joint damage in patients with rheumatoid arthritis. A double blind, placebo controlled trial. J Rheumatol 28:1967–1974

    PubMed  Google Scholar 

  • Laan WH van der, Quax PH, Seemayer CA, Huisman LG, Pieterman EJ, Grimbergen JM, Verheijen JH, Breedveld FC, Gay RE, Gay S, Huizinga TW, Pap T (2003) Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3. Gene Ther 10:234–242

    PubMed  Google Scholar 

  • Lee MH, Rapti M, Knauper V, Murphy G (2004) Threonine 98, the pivotal residue of tissue inhibitor of metalloproteinases (TIMP)-1 in metalloproteinase recognition. J Biol Chem 279:17562–17569

    CAS  PubMed  Google Scholar 

  • Lee MH, Rapti M, Murphy G (2005) Total conversion of tissue inhibitor of metalloproteinase (TIMP) for specific metalloproteinase targeting: fine-tuning TIMP-4 for optimal inhibition of TNF-a converting enzyme (TACE). J Biol Chem 280:15967-15975

    CAS  PubMed  Google Scholar 

  • Leff RL, Elias I, Ionescu M, Reiner A, Poole AR (2003) Molecular changes in human osteoarthritic cartilage after 3 weeks of oral administration of BAY 12–9566, a matrix metalloproteinase inhibitor. J Rheumatol 30:544–549

    CAS  PubMed  Google Scholar 

  • Lewis EJ, Bishop J, Bottomley KM, Bradshaw D, Brewster M, Broadhurst MJ, Brown PA, Budd JM, Elliott L, Greenham AK, Johnson WH, Nixon JS, Rose F, Sutton B, Wilson K (1997) Ro 32–3555, an orally active collagenase inhibitor, prevents cartilage breakdown in vitro and in vivo. Br J Pharmacol 121:540–546

    CAS  PubMed  Google Scholar 

  • Li Z, Hou WS, Bromme D (2000) Collagenolytic activity of cathepsin K is specifically modulated by cartilage-resident chondroitin sulfates. Biochemistry 39:529–536

    CAS  PubMed  Google Scholar 

  • MacPherson LJ, Bayburt EK, Capparelli MP, Carroll BJ, Goldstein R, Justice MR, Zhu L, Hu S, Melton RA, Fryer L, Goldberg RL, Doughty JR, Spirito S, Blancuzzi V, Wilson D, O'Byrne EM, Ganu V, Parker DT (1997) Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits. J Med Chem 40:2525–2532

    CAS  PubMed  Google Scholar 

  • Mazzuca SA, Brandt KD, Lane KA, Katz BP (2003) Subject retention and adherence to dosing regimen in a 30-month clinical trial of doxycycline (doxy) as a disease-modifying osteoarthritis drug (DMOARD). Arthritis Rheum 48:294

    Google Scholar 

  • McKie N, Edwards T, Dallas DJ, Houghton A, Stringer B, Graham R, Russell G, Croucher PI (1997) Expression of members of a novel membrane linked metalloproteinase family (ADAM) in human articular chondrocytes. Biochem Biophys Res Comm 230:335–339

    CAS  PubMed  Google Scholar 

  • Medicherla S, Ma JY, Mangadu R, Jiang Y, Zhao JJ, Almirez R, Kerr I, Stebbins EG, O'Young G, Kapoun AM, Luedtke G, Chakravarty S, Dugar S, Genant HK, Protter AA (2006) A selective p38 alpha mitogen-activated protein kinase inhibitor reverses cartilage and bone destruction in mice with collagen-induced arthritis. J Pharmacol Exp Ther 318:132–141

    CAS  PubMed  Google Scholar 

  • Mihara K, Almansa C, Smeets RL, Loomans EE, Dulos J, Vink PM, Rooseboom M, Kreutzer H, Cavalcanti F, Boots AM, Nelissen RL (2008) A potent and selective p38 inhibitor protects against bone damage in murine collagen-induced arthritis: a comparison with neutralization of mouse TNFalpha. Br J Pharmacol 154:153–164

    CAS  PubMed  Google Scholar 

  • Milner JM, Elliott SF, Cawston TE (2001) Activation of procollagenases is a key control point in cartilage collagen degradation: interaction of serine and metalloproteinase pathways. Arthritis Rheum 44:2084–2096

    CAS  PubMed  Google Scholar 

  • Milner JM, Rowan AD, Elliott SF, Cawston TE (2003) Inhibition of furin-like enzymes blocks interleukin-1alpha/oncostatin M-stimulated cartilage degradation. Arthritis Rheum 48:1057–1066

    CAS  PubMed  Google Scholar 

  • Milner JM, Kevorkian L, Young DA, Jones D, Wait R, Donell ST, Barksby E, Patterson AM, Middleton J, Cravatt BF, Clark IM, Rowan AD, Cawston TE (2006) Fibroblast activation protein alpha is expressed by chondrocytes following a pro-inflammatory stimulus and is elevated in osteoarthritis. Arthritis Res Ther 8:R23

    PubMed  Google Scholar 

  • Milner JM, Patel A, Rowan AD (2008) Emerging roles of serine proteinases in tissue turnover in arthritis. Arthritis Rheum 58:3644–3656

    CAS  PubMed  Google Scholar 

  • Morgan K, Kalsheker NA (1997) Regulation of the serine proteinase inhibitor (SERPIN) gene α1-antitrypsin: a paradigm for other SERPINs. Int J Biochem Cell Biol 29:1501–1511

    CAS  PubMed  Google Scholar 

  • Morgan TG, Rowan AD, Dickinson SC, Jones D, Hollander AP, Deehan D, Cawston TE (2006) Human nasal cartilage responds to oncostatin M in combination with interleukin 1 or tumour necrosis factor alpha by the release of collagen fragments via collagenases. Ann Rheum Dis 65:184–190

    CAS  PubMed  Google Scholar 

  • Mori H, Abe F, Furukawa S, Sakai F, Hino M, Fujii T (2003) FR235222, a fungal metabolite, is a novel immunosuppressant that inhibits mammalian histone deacetylase (HDAC) II. Biological activities in animal models. J Antibiot (Tokyo) 56:80–86

    CAS  Google Scholar 

  • Mort JS, Billington CJ (2001) Articular cartilage and changes in arthritis: matrix degradation. Arthritis Res 3:337–341

    CAS  PubMed  Google Scholar 

  • Murphy G, Cockett MI, Stephens PE, Smith B, Docherty AJP (1987) Stromelysin is an activator of procollagenase. J Biochem 248:265–268

    CAS  Google Scholar 

  • Murphy G, Crabbe T (1995) Gelatinases A and B. Methods Enzymol 248:470–484

    CAS  PubMed  Google Scholar 

  • Nagase H (1995) Stromelysins 1 and 2. Methods Enzymol 248:449–470

    CAS  PubMed  Google Scholar 

  • Nagase H, Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274:21491–21494

    CAS  PubMed  Google Scholar 

  • Nagase H, Brew K (2003) Designing TIMP (tissue inhibitor of metalloproteinases) variants that are selective metalloproteinase inhibitors. Biochem Soc Symp 70:201–212

    CAS  PubMed  Google Scholar 

  • Nemunaitis J, Poole C, Primrose J, Rosemurgy A, Malfetano J, Brown P, Berrington A, Cornish A, Lynch K, Rasmussen H, Kerr D, Cox D, Millar A (1998) Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies. Clin Cancer Res 4:1101–1109

    CAS  PubMed  Google Scholar 

  • Nishida K, Komiyama T, Miyazawa S, Shen ZN, Furumatsu T, Doi H, Yoshida A, Yamana J, Yamamura M, Ninomiya Y, Inoue H, Asahara H (2004) Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum 50:3365–3376

    CAS  PubMed  Google Scholar 

  • Nishikawa M, Myoui A, Tomita T, Takahi K, Nampei A, Yoshikawa H (2003) Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum 48:2670–2681

    CAS  PubMed  Google Scholar 

  • O'Byrne EM, Blancuzzi V, Singh H, MacPherson LJ, Parker DT, Roberts ED (1999) Chondroprotective activity of a matrix metalloproteinase inhibitor, CGS 27023A in animal models of osteoarthritis. Springer, Tokyo

    Google Scholar 

  • Ogata Y, Enghild JJ, Nagase H (1992) Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9. J Biol Chem 267:3581–3584

    CAS  PubMed  Google Scholar 

  • Ohuchi E, Imai K, Fujii Y, Satio H, Seiki M, Okada Y (1997) Membrane type 1 matrix metalloproteinase digests interstitial collagenase and other extracellular macromolecules. J Biol Chem 272:2446–2451

    CAS  PubMed  Google Scholar 

  • Okada Y, Shinmei M, Tanaka O, Naka K, Kimura A, Nakanishi I, Bayliss MT, Iwata K, Nagase H (1992) Localization of matrix metalloproteinase 3 (stromelysin) in osteoarthritic cartilage and synovium. Lab Invest 66:680–690

    CAS  PubMed  Google Scholar 

  • Overgaard MT, Boldt HB, Laursen LS, Sottrup-Jensen L, Conover CA, Oxvig C (2001) Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase. J Biol Chem 276:21849–21853

    CAS  PubMed  Google Scholar 

  • Pavlaki M, Zucker S (2003) Matrix metalloproteinase inhibitors (MMPIs): the beginning of phase I or the termination of phase III clinical trials. Cancer Metastasis Rev 22:177–203

    CAS  PubMed  Google Scholar 

  • Pei D (1999) Identification and characterization of the fifth membrane-type matrix metalloproteinase MT5-MMP. J Biol Chem 274:8925–8932

    CAS  PubMed  Google Scholar 

  • Porter S, Clark IM, Kevorkian L, Edwards DR (2005) The ADAMTS metalloproteinases. Biochem J 386:15–27

    CAS  PubMed  Google Scholar 

  • Powell AJ, Little CB, Hughes CE (2007) Low molecular weight isoforms of the aggrecanases are responsible for the cytokine-induced proteolysis of aggrecan in a porcine chondrocyte culture system. Arthritis Rheum 56:3010–3019

    CAS  PubMed  Google Scholar 

  • Primakoff P, Myles DG (2000) The ADAM gene family: surface proteins with adhesion and protease activity. Trends Genet 16:83–87

    CAS  PubMed  Google Scholar 

  • Rodriguez-Manzaneque JC, Westling J, Thai SN, Luque A, Knauper V, Murphy G, Sandy JD, Iruela-Arispe ML (2002) ADAMTS1 cleaves aggrecan at multiple sites and is differentially inhibited by metalloproteinase inhibitors. Biochem Biophys Res Commun 293:501–508

    CAS  PubMed  Google Scholar 

  • Rogerson FM, Stanton H, East CJ, Golub SB, Tutolo L, Farmer PJ, Fosang AJ (2008) Evidence of a novel aggrecan-degrading activity in cartilage: studies of mice deficient in both ADAMTS-4 and ADAMTS-5. Arthritis Rheum 58:1664–1673

    CAS  PubMed  Google Scholar 

  • Ronday HK, Laan WH van der, Tak PP, Roos JA de, Bank RA, TeKoppele JM, Froelich CJ, Hack CE, Hogendoorn PC, Breedveld FC, Verheijen JH (2001) Human granzyme B mediates cartilage proteoglycan degradation and is expressed at the invasive front of the synovium in rheumatoid arthritis. Rheumatology (Oxford) 40:55–61

    CAS  Google Scholar 

  • Rowan AD, Hui W, Cawston TE, Richards CD (2003) Adenoviral gene transfer of interleukin-1 in combination with oncostatin M induces significant joint damage in a murine model. Am J Pathol 162:1975–1984

    CAS  PubMed  Google Scholar 

  • Roycik MD, Fang X, Sang QX (2009) A fresh prospect of extracellular matrix hydrolytic enzymes and their substrates. Curr Pharm Des 15:1295–1308

    CAS  PubMed  Google Scholar 

  • Ryan ME, Greenwald RA, Golub LM (1996) Potential of tetracyclines to modify cartilage breakdown in osteoarthritis. Curr Opin Rheumatol 8:238–247

    CAS  PubMed  Google Scholar 

  • Sabatini M, Lesur C, Thomas M, Chomel A, Anract P, Nanteuil G de, Pastoureau P (2005) Effect of inhibition of matrix metalloproteinases on cartilage loss in vitro and in a guinea pig model of osteoarthritis. Arthritis Rheum 52:171–180

    CAS  PubMed  Google Scholar 

  • Sandy JD, Flannery CR, Neame PJ, Lohmander LS (1992) 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. J Clin Invest 89:1512–1516

    CAS  PubMed  Google Scholar 

  • Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M (1994) A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370:61–65

    CAS  PubMed  Google Scholar 

  • Schett G, Redlich K, Hayer S, Zwerina J, Bolon B, Dunstan C, Gortz B, Schulz A, Bergmeister H, Kollias G, Steiner G, Smolen JS (2003) Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice. Arthritis Rheum 48:2042–2051

    CAS  PubMed  Google Scholar 

  • Shingleton WD, Ellis AJ, Rowan AD, Cawston TE (2000) Retinoic acid combines with interleukin-1 to promote the degradation of collagen from bovine nasal cartilage: matrix metalloproteinases-1 and - 13 are involved in cartilage collagen breakdown. J Cell Biochem 79:519–531

    CAS  PubMed  Google Scholar 

  • Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K, Yoshimura A (2001) Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 108:1781–1788

    CAS  PubMed  Google Scholar 

  • Skoumal M, Haberhauer G, Kolarz G, Hawa G, Woloszczuk W, Klingler A (2005) Serum cathepsin K levels of patients with longstanding rheumatoid arthritis: correlation with radiological destruction. Arthritis Res Ther 7:R65–R70

    CAS  PubMed  Google Scholar 

  • Song RH, Tortorella MD, Malfait AM, Alston JT, Yang Z, Arner EC, Griggs DW (2007) Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis Rheum 56:575–585

    CAS  PubMed  Google Scholar 

  • Springman EB, Angleton EL, Birkedal-Hansen H, Van Wart HE (1990) Multiple modes of activation of latent human fibroblast collagenase: evidence for the role of a Cys73 active-site zinc complex in latency and a "cysteine switch" mechanism for activation. Proc Natl Acad Sci USA 87:364–368

    CAS  PubMed  Google Scholar 

  • Stanton H, Ung L, Fosang AJ (2002) The 45 kDa collagen-binding fragment of fibronectin induces matrix metalloproteinase-13 synthesis by chondrocytes and aggrecan degradation by aggrecanases. Biochem J 364:181–190

    CAS  PubMed  Google Scholar 

  • Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, Little CB, Last K, Farmer PJ, Campbell IK, Fourie AM, Fosang AJ (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434:648–652

    CAS  PubMed  Google Scholar 

  • Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463–516

    CAS  PubMed  Google Scholar 

  • Stocker W, Grams F, Baumann U, Reinemer P, Gomis-Ruth FX, McKay DB, Bode W (1995) The metzincins–topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc-peptidases. Protein Sci 4:823–840

    CAS  PubMed  Google Scholar 

  • Stone M, Fortin PR, Pacheco-Tena C, Inman RD (2003) Should tetracycline treatment be used more extensively for rheumatoid arthritis? Metaanalysis demonstrates clinical benefit with reduction in disease activity. J Rheumatol 30:2112–2122

    CAS  PubMed  Google Scholar 

  • Suzuki K, Shimizu K, Hamamoto T, Nakagawa Y, Murachi T, Yamamuro T (1992) Characterization of proteoglycan degradation by calpain. Biochem J 285:857–862

    CAS  PubMed  Google Scholar 

  • Swingler TE, Waters JG, Davidson RK, Pennington CJ, Puente XS, Darrah C, Cooper A, Donell ST, Guile GR, Wang W, Clark IM (2009) Degradome expression profiling in human articular cartilage. Arthritis Res Ther 11:R96

    PubMed  Google Scholar 

  • Szomor Z, Shimizu K, Fujimori Y, Yamamoto S, Yamamuro T (1995) Appearance of calpain correlates with arthritis and cartilage destruction in collagen induced arthritic knee joints of mice. Ann Rheum Dis 54:477–483

    CAS  PubMed  Google Scholar 

  • Tak PP, Gerlag DM, Aupperle KR, Geest DA van de, Overbeek M, Bennett BL, Boyle DL, Manning AM, Firestein GS (2001) Inhibitor of nuclear factor kappaB kinase beta is a key regulator of synovial inflammation. Arthritis Rheum 44:1897–1907

    CAS  PubMed  Google Scholar 

  • Takaishi H, Kimura T, Dalal S, Okada Y, D'Armiento J (2008) Joint diseases and matrix metalloproteinases: a role for MMP-13. Curr Pharm Biotechnol 9:47–54

    CAS  PubMed  Google Scholar 

  • Takino T, Sato H, Shinagawa A, Seiki M (1995) Identification of the second membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library—MT-MMPs form a unique membrane-type subclass in the MMP family. J Biol Chem 270:23013–23020

    CAS  PubMed  Google Scholar 

  • Tallant C, Marrero A, Gomis-Ruth FX (2009) Matrix metalloproteinases: fold and function of their catalytic domains. Biochim Biophys Acta (in press)

  • Tanaka K, Kawakami T, Tateishi K, Yashiroda H, Chiba T (2001) Control of IkappaBalpha proteolysis by the ubiquitin-proteasome pathway. Biochimie 83:351–356

    CAS  PubMed  Google Scholar 

  • Tetlow LC, Adlam DJ, Woolley DE (2001) Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage. Arthritis Rheum 44:585–594

    CAS  PubMed  Google Scholar 

  • Tortorella MD, Malfait AM, Deccico C, Arner E (2001) The role of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) in a model of cartilage degradation. Osteoarthritis Cartilage 9:539–552

    CAS  PubMed  Google Scholar 

  • Tortorella MD, Liu RQ, Burn T, Newton RC, Arner E (2002) Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4). Matrix Biol 21:499–511

    CAS  PubMed  Google Scholar 

  • Turk V, Turk B, Turk D (2001) Lysosomal cysteine proteases: facts and opportunities. EMBO J 20:4629–4633

    CAS  PubMed  Google Scholar 

  • Van Wart HE, Birkedal-Hansen H (1990) The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci USA 87:5578–5582

    PubMed  Google Scholar 

  • Varga J, Rosenbloom J, Jimenez SA (1987) Transforming growth factor beta (TGF beta) causes a persistent increase in steady-state amounts of type I and type III collagen and fibronectin mRNAs in normal human dermal fibroblasts. Biochem J 247:597–604

    CAS  PubMed  Google Scholar 

  • Velasco G, Cal S, Merlos-Suárez A, Ferrando AA, Alvarez S, Nakano A, Arribas J, López-Otín C (2000) Human MT6-matrix metalloproteinase: identification, progelatinase A activation, and expression in brain tumors. Cancer Res 60:877–882

    CAS  PubMed  Google Scholar 

  • Vu TH, Werb Z (2000) Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev 14:2123–2133

    CAS  PubMed  Google Scholar 

  • Walsh NC, Crotti TN, Goldring SR, Gravallese EM (2005) Rheumatic diseases: the effects of inflammation on bone. Immunol Rev 208:228–251

    CAS  PubMed  Google Scholar 

  • Werb Z, Mainardi CL, Vater CA, Harris ED (1977) Endogenous activation of latent collagenase by rheumatoid synovial cells. Evidence for a role of plasminogen activator. N Engl J Med 296:1017–1023

    CAS  PubMed  Google Scholar 

  • Wlodawer A (1995) Proteasome: a complex protease with a new fold and a distinct mechanism. Structure 3:417–420

    CAS  PubMed  Google Scholar 

  • Wolfe GC, MacNaul KL, Buechel FF, McDonnell J, Hoerrner LA, Lark MW, Moore VL, Hutchinson NI (1993) Differential in vivo expression of collagenase messenger RNA in synovium and cartilage: quantitative comparison with stromelysin messenger RNA levels in human rheumatoid arthritis and osteoarthritis patients and in two animal models of acute inflammatory arthritis. Arthritis Rheum 36:1540–1547

    CAS  PubMed  Google Scholar 

  • Yamanishi Y, Boyle DL, Clark M, Maki RA, Tortorella MD, Arner EC, Firestein GS (2002) Expression and regulation of aggrecanase in arthritis: the role of TGF-beta. J Immunol 168:1405–1412

    CAS  PubMed  Google Scholar 

  • Yamanouchi-Pharmaceutical (2001) Patent WO0134785

  • Yan C, Boyd DD (2007) Regulation of matrix metalloproteinase gene expression. J Cell Physiol 211:19–26

    CAS  PubMed  Google Scholar 

  • Yoshihara Y, Nakamura H, Obata K, Yamada H, Hayakawa T, Fujikawa K, Okada Y (2000) Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis. Ann Rheum Dis 59:455–461

    CAS  PubMed  Google Scholar 

  • Young DA, Lakey RL, Pennington CJ, Kevorkian L, Edwards DR, Cawston TE, Clark IM (2005) Histone deacetylase inhibitors modulate metalloproteinase gene expression in chondrocytes and block cartilage resorption. Arthritis Res Ther 7:R503-R512

    CAS  PubMed  Google Scholar 

  • Yu WH, Woessner JF Jr (2000) Heparan sulfate proteoglycans as extracellular docking molecules for matrilysin (matrix metalloproteinase 7). J Biol Chem 275:4183–4191

    CAS  PubMed  Google Scholar 

  • Zeng W, Corcoran C, Collins-Racie LA, Lavallie ER, Morris EA, Flannery CR (2006) Glycosaminoglycan-binding properties and aggrecanase activities of truncated ADAMTSs: comparative analyses with ADAMTS-5, -9, -16 and -18. Biochim Biophys Acta 1760:517–524

    CAS  PubMed  Google Scholar 

  • Zhang Q, Hui W, Litherland GJ, Barter MJ, Davidson R, Darrah C, Donell ST, Clark IM, Cawston TE, Robinson JH, Rowan AD, Young DA (2008) Differential Toll-like receptor-dependent collagenase expression in chondrocytes. Ann Rheum Dis 67:1633–1641

    CAS  PubMed  Google Scholar 

  • Zucker S, Pei D, Cao J, Lopez-Otin C (2003) Membrane type-matrix metalloproteinases (MT-MMP). Curr Top Dev Biol 54:1–74

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Hospitals NHS Foundation Trust, Arthritis Research Campaign, the Wellcome Trust, FARNE, Dunhill Medical Trust, JGW Patterson Foundation and the Nuffield Foundation (Oliver Bird Fund) for financial support.

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  1. Musculoskeletal Research Group, Institute of Cellular Medicine, The Medical School, University of Newcastle upon Tyne, 4th Floor Cookson Building, Newcastle upon Tyne, NE2 4HH, UK

    Tim E. Cawston & David A. Young

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Correspondence to Tim E. Cawston.

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Cawston, T.E., Young, D.A. Proteinases involved in matrix turnover during cartilage and bone breakdown. Cell Tissue Res 339, 221–235 (2010). https://doi.org/10.1007/s00441-009-0887-6

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