Anti-Arthritic Activity

  • Hans Gerhard Vogel
  • Martin Braddock
Living reference work entry


Multifactorial causes can lead to osteoarthritis (OA), and its pathogenesis is not clearly understood yet (Berenbaum 2013; Santos et al. 2014; Liu-Bryan and Terkeltaub 2015). The main characteristics of OA are the slowly progressing deterioration of the articular cartilage, accompanied by intermitted painful inflammatory episodes, and a continuous subchondral bone remodeling, often resulting in osteophyte formation in non-weight-bearing joint areas. Because of the lack of innervation and vascularization of the cartilage, the destruction of this specific tissue remains unnoticed until other joint compartments are involved such as the synovial membranes, answering with reactive synovitis to cartilage debris, or mechanoreception changes in the underlying bone, or until the diminution of the articular cartilage results in a radiographically detectable joint space narrowing.


Anterior Cruciate Ligament Articular Cartilage Hyaluronic Acid Articular Chondrocytes Cartilage Degradation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References and Further Reading

In Vitro Methods for Anti-Osteoarthritic Activity: General Considerations

  1. Akatsuka M, Yamamoto Y, Tobetto K, Yasui T, Ando T (1993) In vitro effects of hyaluronan on prostaglandin E2 induction by interleukin-1 in rabbit articular chondrocytes. Agents Actions 38:122–125PubMedGoogle Scholar
  2. Berenbaum F (2013) Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis). Osteoarthritis Cartilage 21:16–21PubMedGoogle Scholar
  3. Bulstra SK, Kuijer R, Buurman WA, Terwindt-Rouwenhorst E, Guelen PJM, van der Linden AJ (1992) The effect of piroxicam on the metabolism of isolated human chondrocytes. Clin Orthop 277:289–296PubMedGoogle Scholar
  4. Chu CR, Izzo NJ, Coyle CH, Papas NE, Logar A (2008) The in vitro effects of bupivacaine on articular chondrocytes. J Bone Joint Surg 90-B:814–820Google Scholar
  5. Currain MP (2010) Hyaluronic acid (Supartz) a review of its use in osteoarthritis of the knee. Drugs Aging 27:925–941Google Scholar
  6. Collier S, Ghosh P (1991) Comparison of the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on proteoglycan synthesis by articular cartilage explant and chondrocyte monolayer cultures. Biochem Pharmacol 41:1375–1384PubMedGoogle Scholar
  7. De Campos G (2014) Chondroprotective agents: are we being too dogmatic? Med Express 1:211–213Google Scholar
  8. De Isla N, Huselstein C, Mainard D, Stoltz J-F (2012) Validation of an in vitro model to study human cartilage responses to compression. Engineering 5:61–64Google Scholar
  9. Green GD, Chipman SD, Birkhead JR, Troubetskoy OV, Goldring MB (1995) Interleukin-1 modulation of matrix metalloprotease and proteoglycan expression in human chondrocytes immortalized by simian virus 40. Trans Orthop Res Soc 20:334Google Scholar
  10. Grenier S, Bhargava MM, Torzilli (2014) An in vitro model for the pathological degradation of articular cartilage in osteoarthritis. J Biomech 47:645–652PubMedCentralPubMedGoogle Scholar
  11. Ishijima M, Nakamura T, Shimizu K, Hayashi K, Kikuchi K, Soen S, Omori G, Yamashita T, Uchio Y, Chiba J, Ideno Y, Kubota M, Kurosawa H, Kaneko K (2014) Intra-articular hyaluronic acid injections versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-centre, randomized, open label, non-inferiority trial. Arthritis Res Ther 16:R18PubMedCentralPubMedGoogle Scholar
  12. Ismaiel S, Hollander AP, Atkins RM, Elson CJ (1991) Differential responses of human and rat cartilage to degrading stimuli in vitro. J Pharm Pharmacol 43:207–209PubMedGoogle Scholar
  13. Jerosch J (2011) Effects of glucosamine and chondroitin sulphate on cartilage metabolism in OA: outlook on other nutrient partners especially Omega-3 fatty acids. Int J Rheum. doi:10.1155/2011/969012Google Scholar
  14. Junior OVL, Indacio AM (2013) Use of glucosamine and chondroitin to treat osteoarthritis: a review of the literature. Rev Bras Ortop 48:300–306Google Scholar
  15. Korver GHV, van de Stadt RJ, van Kampen GPJ, Kiljan E, van der Korst JK (1989) Bovine sesamoid bones: a culture system for anatomically intact articular cartilage. In Vitro Cell Dev Biol 25:1099–1106PubMedGoogle Scholar
  16. Lee CM, Kisiday JD, McIlwraith W, Grodzinsky AJ, Frisbie DD (2013) Development of an in vitro model of injury-induced osteoarthritis in cartilage explants from adult horses through application of single-impact compressive overload. Am J Vet Res 74:40–47PubMedGoogle Scholar
  17. Leong DJ, Choudhury M, Hirsch DM, Hardin JA, Cobelli NJ, Sun HB (2013) Nutraceuticals: potential for chondroprotection and molecular targeting of osteoarthritis. Int J Mol Sci 14:23063–23085PubMedCentralPubMedGoogle Scholar
  18. Liu-Bryan R, Terkeltaub R (2015) Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Immunol 11:35–44Google Scholar
  19. Lozito TP, Alexander PG, Lin H, Gottardi R, Cheng AW-M, Tuan RS (2013) Three-dimensional osteochondral microtissue to model pathogenesis of osteoarthritis. Stem Cell Res Ther 4(Suppl 1):56Google Scholar
  20. Mangone G, Orioli A, Pinna A, Pasquetti P (2014) Infiltrative treatment with platelet rich plasma (PRP) in gonarthrosis. Clin Cases Miner Bone Metab 11:67–72PubMedCentralPubMedGoogle Scholar
  21. Mohamed-Ali H (1992) Influence of synovial cells on cartilage in vitro: induction of breakdown and inhibition of synthesis. Virchows Arch B Cell Pathol Incl Mol Pathol 62:227–236PubMedGoogle Scholar
  22. Mladenovic Z, Saurel A-S, Berenbaum F, Jacques C (2014) Potential role of hyaluronic acid on bone osteoarthritis: matrix metalloproteinases, aggrecanases and RANKL expression are partially prevented by hyaluronic acid in interleukin-1 stimulated osteoblasts. J Rheumatol 41:5. doi:10.3899/jrheum.I30378Google Scholar
  23. Ono Y, Ishizuka S, Knudson CB, Knudson W (2014) Chondroprotective effect of kartogenin on CD44-mediated functions in articular cartilage and chondrocytes. Cartilage doi:10.1177/1947603514528354Google Scholar
  24. Petrella RJ (2005) Hyaluronic acid for the treatment of knee osteoarthritis: long-term outcomes from a naturalistic primary care experience. Am J Phys Med Rehabil 84:278–283PubMedGoogle Scholar
  25. Santos ALG, Demange MK, Prado MP, Fernandes TD, Giglio PN, Hintermann B (2014) Cartilage lesions and ankle osteoarthroses: review of the literature and treatment algorithm. Rev Bras Ortop 49:565–572Google Scholar
  26. Seed MP, Ismaiel S, Cheung CY, Thomson TA, Gardner CR, Atkins RM, Elson CJ (1993) Inhibition of interleukin 1β induced rat and human cartilage degradation in vitro by the metalloproteinase inhibitor U27391. Ann Rheum Dis 52:37–43PubMedCentralPubMedGoogle Scholar
  27. Schlichtling N, Dehne T, Mans K, Endres M, Stuhlmuller B, Sittinger M, Kaps C, Ringe J (2014) Suitability of porcine chondrocyte micromass culture to model osteoarthritis in vivo. Mol Pharm 11:2092–2105Google Scholar
  28. Seong SC, Matsumura T, Lee FY, Whelan MC, Li XQ, Trippel SB (1994) Insulin-like growth factor I regulation of swarm rat chondrosarcoma chondrocytes in culture. Exp Cell Res 211:238–244PubMedGoogle Scholar
  29. Shimazu A, Jikko A, Iwamoto M et al (1993) Effects of hyaluronic acid on the release of proteoglycan from the cell matrix in rabbit chondrocyte cultures in the presence and absence of cytokines. Arthritis Rheum 36:247–253PubMedGoogle Scholar
  30. Srinivas GR, Chichester CO, Barrach HJ, Matoney AL (1994) Effects of certain antiarthritic agents on the synthesis of type II collagen and glycosaminoglycans in rat chondrosarcoma cultures. Agents Actions 41:193–199PubMedGoogle Scholar
  31. Stanos S (2013) Osteoarthritis guidelines: a progressive role for topical NSAIDs. J Am Osteopath Assoc 113:123–127PubMedGoogle Scholar
  32. Tashiro T, Seino S, Sato T, Matsuoka R, Masuda Y, Fukui N (2012) Oral administration of polymer hyaluronic acid alleviates symptoms of knee osteoarthritis: a double blind, placebo-controlled study over a 12-month period. Sci World J doi:10.1100/2012/167928Google Scholar
  33. Van Vijen JPJ, Luijsterburg PAJ, Verhagen AP, van Osch GJVM, Kloppenburg M, Bierma-Zeinstra SMA (2012) Osteoarthritis and Cartilage Symptomatic and chondroprotective treatment with collagen derivatives in osteoarthritis: a systematic overview. Osteoarthritis and Cartilage 20:809–821Google Scholar
  34. Venn G, Lauder RM, Hardingham TE, Muir H (1990) Effects of catabolic and anabolic cytokines on proteoglycan biosynthesis in young, old and osteoarthritic canine cartilage. Biochem Soc Trans 18:973–974PubMedGoogle Scholar
  35. Verbruggen G (2006) Chondroprotective drugs in degenerative joint diseases. Rheumatology (Oxford) 45:129–138Google Scholar
  36. Verschure PJ, van der Kraan PM, Vitters EL, van den Berg WB (1994) Stimulation of proteoglycan synthesis by triamcinolone acetonide and insulin-like growth factor 1 in normal and arthritic murine articular cartilage. J Rheumatol 21:920–926PubMedGoogle Scholar
  37. Vignon E, Mathieu P, Louisot P, Richard M (1991) In vitro effect of nonsteroidal antiinflammatory drugs on proteoglycanase and collagenase activity in human osteoarthritic cartilage. Arthritis Rheum 34:1332–1335PubMedGoogle Scholar
  38. Wang C-T, Lin J, Chang C-J, Lin Y-T, Hou S-M (2004) Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials. J Bone Joint Surg Am 86:538–545PubMedGoogle Scholar
  39. Yu LP Jr, Smith GN Jr, Hasty KA, Brandt KD (1991) Doxycycline inhibits type XI collagenolytic activity of extracts from human osteoarthritic cartilage and of gelatinase. J Rheumatol 18:1450–1452PubMedGoogle Scholar
  40. Zafarullah M, Martel-Pelletier J, Cloutier JM, Gedamu L, Pelletier JP (1992) Expression of c-fos, c-jun, jun-B, metallothionein and metalloproteinase genes in human chondrocyte. FEBS Lett 306:169–172PubMedGoogle Scholar

Modulation of Cellular Proteoglycan Metabolism

  1. Archer CW, McDowell J, Bayliss MT, Stephens MD, Bentley G (1990) Phenotypic modulation in sub-populations of human articular chondrocytes in vitro. J Cell Sci 97:361–371PubMedGoogle Scholar
  2. Aydelotte MB, Kuettner KE (1988) Differences between sub-populations of cultured bovine articular chondrocytes. I. Morphology and cartilage matrix production. Connect Tissue Res 18:205–222PubMedGoogle Scholar
  3. Aydelotte MB, Greenhill RR, Kuettner KE (1988) Differences between sub-populations of cultured bovine articular chondrocytes. II. Proteoglycan metabolism. Connect Tissue Res 18:223–234PubMedGoogle Scholar
  4. Aydelotte MB, Raiss RX, Caterson B, Kuettner KE (1992) Influence of interleukin-1 on the morphology and proteoglycan metabolism of cultured bovine articular chondrocytes. Connect Tissue Res 28:143–159PubMedGoogle Scholar
  5. Bassleer C, Henrotin Y, Franchimont P (1990) In vitro assays of chondrocyte functions: the influence of drugs and hormones. Scand J Rheumatol Suppl 81:13–20PubMedGoogle Scholar
  6. Bassleer CT, Henrotin YE, Reginster JYL, Franchimont PP (1992) Effects of tiaprofenic acid and acetylsalicylic acid on human articular chondrocytes in 3-dimensional culture. J Rheumatol 19:1433–1438PubMedGoogle Scholar
  7. Benya PD, Schaffer JD (1982) Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell 30:215–224PubMedGoogle Scholar
  8. Bonaventure J, Kadhom N, Cohen-Solal L, Ng KH, Bourguignon J, Lasselin C, Freisinger P (1994) Reexpression of cartilage-specific genes by dedifferentiated human articular chondrocytes cultured in alginate beads. Exp Cell Res 212:97–104PubMedGoogle Scholar
  9. Greiling H, Gressner AM, Stuhlsatz HW (1977) Influence of anti-inflammatory drugs on connective tissue metabolism. In: Glynn LE, Schlumberger HD (eds) Experimental models of chronic inflammatory diseases. Springer, Berlin/Heidelberg/New York, pp 406–420Google Scholar
  10. Guo J, Jourdian GW, MacCallum DK (1989) Culture and growth characteristics of chondrocytes encapsulated in alginate beads. Connect Tissue Res 19:277–297PubMedGoogle Scholar
  11. Häuselmann HJ, Fernandes RJ, Mok SS, Schmid TM, Block JA, Aydelotte MB, Kuettner KE, Thonar EJMA (1994) Phenotypic stability of bovine articular chondrocytes after long-term culture in alginate beads. J Cell Sci 107:17–27PubMedGoogle Scholar
  12. Henrotin Y, Bassleer C, Franchimont P (1992) In vitro effects of etodolac and acetylsalicylic acid on human chondrocyte metabolism. Agents Actions 36:317–323PubMedGoogle Scholar
  13. Jortikka M, Lammi MJ, Parkkinen JJ, Lahtinen R, Tammi MI (1993) A high sensitivity dot-blot assay for proteoglycans by cuprolinic blue precipitation. Connect Tissue Res 29:263–272PubMedGoogle Scholar
  14. Kolibas LM, Goldberg RL (1989) Effect of cytokines and anti-arthritic drugs on glycosaminoglycan synthesis by bovine articular chondrocytes. Agents Actions 27:245–249PubMedGoogle Scholar
  15. Lane NE, Williams RJ III, Schurman DJ, Smith RL (1992) Inhibition of interleukin 1 induced chondrocyte protease activity by a corticosteroid and a nonsteroidal antiinflammatory drug. J Rheumatol 19:135–139PubMedGoogle Scholar
  16. Malemud CJ, Stevenson S, Mehraban F, Papay RS, Purchio AF, Goldberg VM (1994) The proteoglycan synthesis repertoire of rabbit chondrocytes maintained in type II collagen gels. Osteoarthritis Cartilage 2:29–42PubMedGoogle Scholar
  17. McCollum R, Martel-Pelletier J, DiBattista J, Pelletier JP (1991) Regulation of interleukin 1 receptors in human articular chondrocytes. J Rheumatol (Suppl 27) 18:85–88Google Scholar
  18. Parkinson J, Samiric T, Ilic MZ, Cook J, Feller JA, Handley CJ (2010a) Change in proteoglycan metabolism is a characteristic of human patellar tendinopathy. Arthritis Rheum 10:3028–3035Google Scholar
  19. Parkinson J, Samiric T, Ilic MZ, Cook J, Feller JA, Handley CJ (2010b) Involvement of proteoglycans in tendinopathy. J Musculoskelet Neuronal Interact 11:86–93Google Scholar
  20. Sauerland K, Raiss RX, Steinmeyer J (2003) Proteoglycan metabolism and viability of articular cartilage explants as modulated by the frequency of intermittent loading. Osteoarthritis Cartilage 11:343–350PubMedGoogle Scholar
  21. Seid JM, Rahman S, Graveley R, Bunning RAD, Nordmann R, Wishart W, Russel RG (1993) The effect of interleukin-1 on cytokine gene expression in cultured human articular chondrocytes analyzed by messenger RNA phenotyping. Arthritis Rheum 36:35–43PubMedGoogle Scholar
  22. van der Kraan P, Vitters E, van den Berg W (1992) Differential effect of transforming growth factor β on freshly isolated and cultured articular chondrocytes. J Rheumatol 19:140–145PubMedGoogle Scholar
  23. Verbruggen G, Veys EM, Wieme N, Malfait AM, Gijselbrecht L, Nimmegeers J, Almquist KF, Broddelez C (1990) The synthesis and immobilisation of cartilage-specific proteoglycan by human chondrocytes in different concentrations of agarose. Clin Exp Rheumatol 8:371–378Google Scholar

Cellular Chondrocytic Chondrolysis

  1. Aydelotte MB, Schleyerbach R, Zeck BJ, Kuettner KE (1986) Articular chondrocytes cultured in agarose gel for study of chondrocytic chondrolysis. In: Kuettner (ed) Articular cartilage biochemistry. Raven, New York, pp 235–256Google Scholar
  2. Chu CR, Izzo NJ, Coyle CH, Papas NE, Logar A (2008) The in vitro effects of bupivacaine on articular chondrocytes. J Bone Joint Surg 90-B:814–820Google Scholar
  3. Homandberg GA, Davis G, Manigkia C, Shrikhande A (1997) Cartilage chondrolysis by fibronectin fragments causes cleavage of aggrecan at the same site as found in osteoarthritic cartilage. Osteoarthritis Cartilage 5:450–453PubMedGoogle Scholar
  4. Liu S, Zhang Q-S, Hester W, O’Brien MJ, Savoie FH, You Z (2012) Hyaluronan protects bovine articular chondrocytes against cell death induce by bupivacaine at supraphysiologic temperatures. Am J Sports Med 40:1375–1383PubMedCentralPubMedGoogle Scholar
  5. Oestensen M, Veiby OP, Raiss R, Hagen A, Pahle J (1991) Responses of normal and rheumatic human articular chondrocytes cultured under various experimental conditions in agarose. Scand J Rheumatol 20:172–182Google Scholar
  6. Parker E, Vessilier S, Pingguan-Murphy B, Abas WABW, Bader DL, Chowdhury TT (2013) Low oxygen tension increased fibronectin fragment induced catabolic activities – response prevented with biochemical signals. Arthritis Res Ther 15:R163PubMedCentralPubMedGoogle Scholar
  7. Raiss RX, Oestensen M, Aydelotte MB (1992) Drug evaluation on isolated articular chondrocytes. In: Kuettner K et al (eds) Articular cartilage and osteoarthritis. Raven Press, New York, pp 569–582Google Scholar
  8. Raiss RX, Karbowski A, Aigner T, Schleyerbach R (1995) Chondrocytes and antirheumatic drugs. J Rheumatol 22(Suppl 43):152–154Google Scholar
  9. Verbruggen G, Veys EM, Malfait AM, Schatteman L, Wieme N, Heynen G, Vanhoutte V, Broddelez C (1989) Proteoglycan metabolism in isolated chondrocytes from human cartilage and in short-term tissue-cultured human articular cartilage. Clin Exp Rheumatol 7:13–17Google Scholar

Cartilage Explant Chondrolysis

  1. Assirelli E, Pulsatelli L, Dolzani P, Platano D, Olivotto E, Filardo G, Trisolino G, Facchini A, Borzi RM, Meliconi R (2014) Human osteoarthritic cartilage shows reduced in vivo expression of IL-4, a chondroprotective cytokine that differentially modulates IL-1b –stimulated production of chemokines and matrix-degrading enzymes in vitro. PLoS One 9:e96925PubMedCentralPubMedGoogle Scholar
  2. Bondeson J, Wainwright SD, Lauder S, Amos N, Hughes CE (2006) The role of synovial macrophages and macrophage-produced cytokines in driving aggrecanases, matrix metalloproteinases, and other destructive and inflammatory responses in osteoarthritis. Arthritis Res Ther 8:R187PubMedCentralPubMedGoogle Scholar
  3. Bordji K, Grillasca JP, Gouze JN, Magdalou J, Schohn H, Keller JM, Bianchi A, Dauça M, Netter P, Terlain B (2000) Evidence for the presence of peroxisome proliferator-activated receptor (PPAR) α and γ and retinoid Z receptor in cartilage. J Biol Chem 275:12243–12250PubMedGoogle Scholar
  4. Chayen J, Bitensky L, Mehdizadeh S, Dunham J, Older J (1994) Testing drugs on human osteoarthritic articular cartilage. Cell Biochem Funct 12:63–68PubMedGoogle Scholar
  5. Culley KL, Hui W, Barter MJ, Davidson RK, Swingler TE, Destrument APM, Scott JL, Donell ST, Fenwick S, Rowan AD, Young DA, Clark IM (2013) Class I histone deacetylase inhibition modulates metalloproteinase expression and blocks cytokine-induced cartilage degradation. Arthritis Rheum 65:1822–1830PubMedGoogle Scholar
  6. Lafeber FPG, van Roy H, Wilbrink B, Huber-Bruning O, Bijlsma JWJ (1992) Human osteoarthritic cartilage is synthetically more active but in culture less vital than normal cartilage. J Rheumatol 19:123–129PubMedGoogle Scholar
  7. Lafeber FPJG, van der Kraan PM, van Roy JLAM, Huber-Bruning O, Bijlsma JWJ (1993) Articular cartilage explant culture; an appropriate in vitro system to compare osteoarthritic and normal human cartilage. Connect Tissue Res 29:287–299PubMedGoogle Scholar
  8. McQuillan DJ, Handley CJ, Robinson HC (1986) Control of proteoglycan biosynthesis. Biochem J 237:741–747PubMedCentralPubMedGoogle Scholar
  9. Nixon JS, Bottomley KMK, Broadhust MJ et al (1991) Potent collagenase inhibitors prevent interleukin-1-induced cartilage degradation in vitro. Int J Tissue React 13:237–243PubMedGoogle Scholar
  10. Ono Y, Ishizuka S, Knudson CB, Knudson W (2014) Chondroprotective effect of kartogenin on CD44-mediated functions in articular cartilage and chondrocytes. Cartilage doi:10.1177/1947603514528354Google Scholar
  11. Pelletier JP, Martel-Pelletier J (1989) Evidence for the involvement of interleukin 1 in human osteoarthritic cartilage degradation: protective effect of NSAID. J Rheumatol 16(Suppl 18):19–27Google Scholar
  12. Pelletier JP, Cloutier JM, Martel-Pelletier J (1989) In vitro effects of tiaprofenic acid, sodium salicylate and hydrocortisone on the proteoglycan metabolism of human osteoarthritic cartilage. J Rheumatol 16:646–655PubMedGoogle Scholar
  13. Sabatini M, Bardiot A, Lesur C, Moulharat N, Thomas M, Richard I, Fradin A (2002) Effects of agonists of peroxisome proliferator-activated receptor γ on proteoglycan degradation and matrix metalloproteinase production in rat cartilage in vitro. Osteoarthritis Cartilage 10:673–679Google Scholar
  14. Verbruggen G, Veys EM, Malfait AM et al (1989) Proteoglycan metabolism in tissue cultured human articular cartilage. Influence of piroxicam. J Rheumatol 16:355–362Google Scholar
  15. Verbruggen G, Veys EM, Malfait AM et al (1990) Proteoglycan metabolism in tissue-cultured human articular cartilage. Scand J Rheumatology 19:257–268Google Scholar
  16. Yang XH, Zhang ZX (1991) Effects of DMSO and glycerol in 35S incorporation of articular cartilage. Cryo-Letters 12:53–58Google Scholar

Influence on Matrix Metalloproteinases

  1. Aranapakam V, Grosu GT, Davis JM, Hu B, Ellingboe J, Baker JL, Skotnitcki JS, Zask A, DiJoseph JF, Sung A, Sharr MA, Killar LM, Walter T, Jin G, Cowling R (2003) Synthesis and structure-activity relationship of α-sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis. J Med Chem 46:2361–2375Google Scholar
  2. Barr AJ, Conaghan PG (2013) Disease-modifying osteoarthritis drugs (DMOADs): what are they and when can we expect them? Medicographia 35:189–196Google Scholar
  3. Beck G, Bottomley G, Bradshaw D, Brewster M, Broadhurst M, Devos R, Hill C, Johnson W, Kim HJ, Kirtland S, Kneer J, Lad N, Mackenzie R, Martin R, Nixon J, Price G, Rodwell A, Rose F, Tang JP, Walter DS, Wilson K, Worth E (2002) (E)-2(R-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-(methanesulfonyl)-4-methylvalerohydrazide (Ro 32–7315), a selective and orally active inhibitor of tumor necrosis factor-α convertase. J Pharmacol Exp Ther 302:390–396PubMedGoogle Scholar
  4. Berton A, Rigot V, Huett E, Decarme M, Eeckhout Y, Patthy L, Godeau G, Hornebeck W, Bellon G, Emonard H (2001) Involvement of fibronectin type II repeats in the efficient inhibition of gelatinases A and B by long-chained unsaturated fatty acids. J Biol Chem 276:20458–20465PubMedGoogle Scholar
  5. Bigg HF, Rowan AD (2001) Inhibition of metalloproteinases as a therapeutic target in rheumatoid arthritis and osteoarthritis. Curr Opin Pharmacol 1:314–320PubMedGoogle Scholar
  6. Billinghorst RC, Wu W, Ionescu M, Reiner A, Dahlberg L, Chen J, van Wart H, Poole AR (2000) Comparison of the degradation of type II collagen and proteoglycan in nasal and articular cartilages induced by interleukin-1 and selective inhibition of type II collagen cleavage by collagenase. Arthritis Rheum 43:664–672Google Scholar
  7. Borkakoti N (1998) Matrix metalloproteases: variations on a theme. Prog Biophys Mol Biol 70:73–94PubMedGoogle Scholar
  8. Borkakoti N (2004) Matrix metalloprotease inhibitors: design from structure. Biochem Soc Trans 32:17–20PubMedGoogle Scholar
  9. Bottomley KM, Borkakoti N, Bradshaw D, Brown PA, Broadhurst MJ, Budd JM, Elliott L, Eyers P, Hallam TJ, Handa BK, Hill CH, James M, Lahm HW, Lawton G, Merritt JE, Nixon JS, Röthlisberger U, Whittle A, Johnson WH (1997) Inhibition of bovine nasal cartilage degradation by selective matrix metalloprotease inhibitors. Biochem J 323:483–488Google Scholar
  10. Chang C, Werb Z (2001) The many faces of metalloproteases: cell growth, invasion and metastasis. Trends Cell Biol 11:S37–S43PubMedCentralPubMedGoogle Scholar
  11. Close DR (2001) Matrix metalloproteinase inhibitors in rheumatic diseases. Ann Rheum Dis 60:iii62–iii67Google Scholar
  12. Dahlberg L, Billinghurst RC, Manner P, Nelson F, Webb G, Ionescu M, Reiner A, Tanzer M, Zukor D, Chen J, van Wart HE, Poole AR (2000) Selective enhancement of collagenase-mediated cleavage of resident type II collagen in cultured osteoarthritic cartilage and arrest with a synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1). Arthritis Rheum 43:673–682PubMedGoogle Scholar
  13. Devel L, Beau F, Amoura M, Vera L, Cassar-Lajeunesse E, Garcia S, Czarny B, Stura EA, Dive V (2012) Simple pseudo dipeptides with a P2 a novel inhibitor family of MMPs and other Metzincins. J Biol Chem 287:26647–26656PubMedCentralPubMedGoogle Scholar
  14. Devy L, Dransfield DT (2011) New strategies for the next generation of matrix-metalloproteinase inhibitors: selectively targeting membrane-anchored MMPs with therapeutic antibodies. Biochem Res Int.
  15. Downs JT, Lane CL, Nestor NB, McLellan TJ, Kelly MA, Karam GA, Mezes PS, Pelletier JP, Otterness IG (2001) Analysis of collagenase-cleavage of type II collagen using a neoepitope ELISA. J Immunol Methods 247:25–34PubMedGoogle Scholar
  16. Galasso O, Familiari F, De Gori M, Gasparini G (2012) Recent findings on the role of gelatinases (matrix metalloproteinases -2 and -9) in osteoarthritis. Adv Orthop. doi:10.1155/2012/834208Google Scholar
  17. Hattori S, Fujisaki H, Kiriyama T, Yokoyama T, Irie S (2002) Real-time zymography and reverse zymography: a method for detecting activities of metalloproteinases and their inhibitors using FITC-labeled collagen and casein as substrates. Anal Biochem 301:27–34PubMedGoogle Scholar
  18. Jackson MT, Moradi B, Smith MM, Jackson CJ, Little CB (2014) Activation of matric metalloproteinases 2,9 and 13 by activated protein C in human osteoarthritic cartilage cells. Arthritis Rheumatol 66:1525–1536PubMedGoogle Scholar
  19. Jin G, Huang X, Black R, Wolfson M, Rauch C, McGregor H, Ellestad G, Cowling R (2002) A continuous fluorometric assay for tumor necrosis factor-alpha converting enzyme. Anal Biochem 302:269–275PubMedGoogle Scholar
  20. Kaji M, Moriyama S, Sasaki H, Saitoh Y, Kiriyama M, Fukai I, Yamakawa Y, Mitsui A, Toyama T, Nemori R, Fujii Y (2003) Gelatinolytic activity of matrix metalloproteinase in lung cancer studied using film in situ zymography stamp method. Lung Cancer 39:125–130PubMedGoogle Scholar
  21. Kerkvliet EHM, Jansen IDC, Schoenmaker TAM, Docherty AJP, Beertsen W, Everts V (2003) Low molecular weight inhibitors of matrix metalloproteinases can enhance the expression of matrix metalloproteinase-2 (gelatinase A) without inhibiting its activation. Cancer 97:1582–1588PubMedGoogle Scholar
  22. Kim JR, Kim CH (2004) Association of a high activity of matrix metalloproteinase-9 to low levels of tissue inhibitors of metalloproteinase-1 and -3 in human hepatitis B-viral hepatoma cells. Int J Biochem Cell Biol 36:2293–2306PubMedGoogle Scholar
  23. Knight CG, Willenbrock F, Murphy G (1992) A novel coumarin-labeled peptide for sensitive continuous assays of the matrix metalloproteinases. FEBS Lett 296:263–266PubMedGoogle Scholar
  24. Letavic MA, Axt MZ, Barberia JT, Carty TJ, Danley DE, Geoghegan KF, Halim NS, Hoth LR, Kamath AV, Laird ER, Lopresti-Morrow LL, McClure KF, Mitchell PG, Natarajan V, Noe MC, Pandit J, Reeves L, Schulte GK, Snow SL, Sweeney FJ, Tan DH, Yu CH (2002) Synthesis and biological activity of selective pipecolic acid-based TNF-α converting enzyme (TACE) inhibitors. Bioorg Med Chem Lett 12:1378–1390Google Scholar
  25. Letavic MA, Barberia JT, Carty TJ, Hardink JR, Liras J, Lopresti-Morrow LL, Mitchell PG, Noe MC, Reeves LM, Snow SL, Stam EJ, Sweeney FJ, Vaughn ML, Yu CH (2003) Synthesis and biological activity of piperazine-based dual MMP-13 and TNF-α converting enzyme inhibitors. Bioorg Med Chem Lett 13:3243–3246PubMedGoogle Scholar
  26. Levin JI, DiJoseph JF, Killar LM, Sharr MA, Skotnicki JS, Patel DV, Xiao XY, Shi L, Navre M, Campbell DA (1998) The asymmetric synthesis and in vivo characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of metalloproteinases. Bioorg Med Chem Lett 8:1163–1168PubMedGoogle Scholar
  27. Lewis EJ, Bishop J, Bottomley KMK, 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 121:540–546PubMedCentralPubMedGoogle Scholar
  28. Li N, Shi Z, Tang Y, Wang Z, Song S (2011) New hope for the treatment of osteoarthritis through selective inhibition of MMP-13. Curr Med Chem 18:977–1001PubMedGoogle Scholar
  29. Liu JR, Yang BF, Chen BQ, Yng YM, Dong HW, Song YQ (2004) Inhibition of α-ionone on SGC-7901 cell proliferation and upregulation of metalloproteinases-1 and -2 expression. World J Gastroenterol 10:167–171PubMedGoogle Scholar
  30. Maquoi E, Noël A, Frankenne F, Angliker H, Murphy G, Foidart JM (1998) Inhibition of matrix metalloprotease 2 maturation and HT1089 invasiveness by a synthetic furin factor. FEBS Lett 424:262–266PubMedGoogle Scholar
  31. Maquoi E, Munaut C, Colige A, Lambert C, Frankenne F, Noël A, Grams F, Krell HW, Foidart JM (2002) Stimulation of matrix metalloproteinase-9 expression in human fibrosarcoma cells by synthetic matrix metalloproteinase inhibitors. Exp Cell Res 275:110–121PubMedGoogle Scholar
  32. Martel-Pelletier J, Welsch DJ, Pelletier JP (2001) Metalloproteases and inhibitors of arthritic diseases. Best Pract Res Clin Rheumatol 15:805–829PubMedGoogle Scholar
  33. Martel-Pelletier J, Wildi LM, Pelletier JP (2012) Future therapies for osteoarthritis. Bone 51:297–311PubMedGoogle Scholar
  34. Martin-Chouly CAE, Astier A, Jacob C, Prunaux MP, Bertrand C, Lagente V (2004) Modulation of matrix metalloproteinase production by type 4 phosphodiesterase inhibitors. Life Sci 75:823–840PubMedGoogle Scholar
  35. Matter H, Schudok M (2004) Recent advances in the design of metalloprotease inhibitors. Curr Opin Drug Discov Devel 7:513–535PubMedGoogle Scholar
  36. Matter H, Schudok M, Schwab W, Thorwart W, Barbier D, Billen G, Haase B, Neises B, Weithmann KU, Wollmann T (2002) Tetrahydroisoquinoline-3-carboxylate based matrix-metalloprotease inhibitors: design, synthesis and structure-activity relationship. Bioorg Med Chem 10:3529–3544PubMedGoogle Scholar
  37. Meszaros E, Malemud CJ (2012) Prospects for treating osteoarthritis: enzyme-protein interactions regulating matric metalloproteinase activity. Ther Adv Chronic Dis 3:219–229PubMedCentralPubMedGoogle Scholar
  38. Mott JD, Werb Z (2004) Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol 16:558–564PubMedCentralPubMedGoogle Scholar
  39. Naqvi T, Duong TT, Hashem G, Shiga M, Zhang Q, Kapila S (2005) Relaxin’s induction of metalloproteinases is associated with the loss of collagen and glycosaminoglycans in synovial joint fibrocartilaginous explants. Arthritis Res Ther 7:R1–R11PubMedCentralPubMedGoogle Scholar
  40. Nelson FC, Santos ED, Levin JI, Chen JM, Skotnicki JS, DiJoseph JF, Sharr MA, Sung A, Killar LM, Cowling R, Jin G, Roth CE, Albright JD (2002) Benzodiazepine inhibitors of MMPs and TACE. Bioorg Med Chem Lett 12:2867–2870PubMedGoogle Scholar
  41. Nicholson AC, Malik SB, Logsdon JM Jr, van Meir EG (2005) Functional evolution of ADAMTS genes: evidence from analyses of phylogeny and gene organization. BMC Evol Biol 5:11–24PubMedCentralPubMedGoogle Scholar
  42. O’Grady RL, Nethery A, Hunter N (1984) A fluorescent screening assay for collagenase using collagen labeled with 2-methoxy-2,4-diphenyl-3(2H)-furanone. Anal Biochem 140:490–494PubMedGoogle Scholar
  43. Peppard J, Pham Q, Clark A, Farley D, Sakane Y, Graves R, George J, Norey C (2003) Development of an assay suitable for high-throughput screening to measure matrix metalloprotease activity. Assay Drug Dev Technol 1:425–433Google Scholar
  44. Perlman H, Bradley K, Liu H, Cole S, Shamiyeh E, Smith RC, Walsh K, Fiore S, Koch AE, Firestein GS, Haines GK III, Pope RM (2003) IL-6 and matrix metalloproteinase-1 are regulated by the cyclin-dependent kinase inhibitor p21 in synovial fibroblasts. J Immunol 170:838–845PubMedGoogle Scholar
  45. Reichelt A, Gaul C, Frey RR, Kennedy A, Martin SF (2002) Design, synthesis, and evaluation of matrix metalloprotease inhibitors bearing cyclopentane-derived peptidomimetics as P1′ and P2′ replacements. J Org Chem 76:4062–4075Google Scholar
  46. Rosenblum G, Meroueh SO, Kleifeld O, Brown S, Singson SP, Fridman R, Mobashery S, Sagi I (2003) Structural basis for potent slow binding inhibition of human matrix metalloprotease-1 (MMP-2). J Biol Chem 278:27009–27015PubMedGoogle Scholar
  47. Sabatini M, Lesur C, Thomas M, Chomel A, Anract P, de Nanteuil G, Pastoureau P (2005) Effect of inhibition of matrix metalloproteinases on cartilage loss in vitro and in a guinea pig model of osteoarthritis. Arthritis Rheum 52:171–180Google Scholar
  48. Sadowski T, Steinmeyer J (2001) Effects of non-steroidal antiinflammatory drugs and dexamethasone on the activity and expression of matrix metalloproteinase-1, matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 by bovine articular chondrocytes. Osteoarthritis Cartilage 9:407–415PubMedGoogle Scholar
  49. Sartor L, Pezzato E, Dell’Aica I, Caniato R, Biggin S, Garbisa S (2002) Inhibition of matrix-proteinases by polyphenols: chemical insights for anti-inflammatory and anti-invasion drug design. Biochem Pharmacol 64:229–237PubMedGoogle Scholar
  50. Sato T, Koike L, Miyata Y, Hirata M, Mimaki Y, Sashida Y, Yano M, Ito A (2002) Inhibition of activator protein-1 binding activity and phosphatidylinositol 3-kinase pathway by nobiletin, a polymethoxy flavonoid, results in augmentation of metalloproteinases-1 production and suppression of production of matrix metalloproteinases-1 and –9 in human fibrosarcoma HT-1080 cells. Cancer Res 62:1025–1029PubMedGoogle Scholar
  51. Skiles JW, Gonnella NC, Jeng AY (2004) The design, structure and clinical update of small molecular weight matrix metalloproteinase inhibitors. Curr Med Chem 11:2911–2977PubMedGoogle Scholar
  52. Skotnicki JS, DiGrandi MJ, Levin JI (2003) Design strategies for the identification of MMP-13 and TACE-inhibitors. Curr Opin Drug Discov Devel 6:742–759PubMedGoogle Scholar
  53. Steinmeyer J, Daufeldt S, Taiwo YO (1998) Pharmacological effect of tetracyclines on proteoglycans from interleukin-1 treated articular cartilage. Biochem Pharmacol 55:93–100PubMedGoogle Scholar
  54. Tsukida T, Moriyama H, Inoue Y, Kondo H, Yoshino K, Nishimura SI (2004) Synthesis and biological activity of selective azasugar-based TACE inhibitors. Bioorg Med Chem Lett 14:1569–1572PubMedGoogle Scholar
  55. Valleala H, Hanemaaijer R, Mandelin J, Salminen A, Teronen O, Mönkkönen J, Konttinen YT (2003) Regulation of MMP-9 (gelatinase B) in activated human monocytes/macrophages by two different types of bisphosphonates. Life Sci 73:2413–2420PubMedGoogle Scholar
  56. Vandenbroucke RE, Libert C (2014) Is there hope for therapeutic matric metalloproteinase inhibition? Nat Rev Drug Discov 13:904–927PubMedGoogle Scholar
  57. Wang M, Sampson ER, Jin H, Li J, Ke Q-H, Im H-J, Chen D (2013) MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther 15:R5PubMedCentralPubMedGoogle Scholar
  58. Yoshioka H, Oyamada I, Usuku G (1987) An assay of collagenase activity using enzyme-linked immunosorbent assay for mammalian collagenase. Anal Biochem 166:22–26Google Scholar
  59. Zask A, Gu Y, Albright JD, Du X, Hogan M, Levin JI, Chen JM, Killar LM, Sung A, DiJoseph JF, Sharr MA, Roth CE, Skala S, Jin G, Cowling R, Mohler KM, Barone D, Black R, March C, Skotnicki JS (2003) Synthesis and SAR of bicyclic heteroaryl hydroxamic acid MMP and TACE inhibitors. Bioorg Med Chem Lett 13:1487–1490PubMedGoogle Scholar
  60. Zhang Y, Xu J, Levin J, Hegen M, Li G, Robertshaw H, Brennan F, Cummons T, Clarke D, Vansell N, Nickerson-Nutter C, Barone D, Mohler K, Black R, Skotnicki J, Gibbons J, Feldmann M, Frost P, Larsen G, Lin LL (2004) Identification and characterization of 4-[[4-(2-butynyloxy) phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3-S)-thiomorpholinecarboxamide (TMI 1), a novel dual tumor necrosis factor-a-converting enzyme/matrix metalloprotease inhibitor for the treatment of rheumatoid arthritis. J Pharmacol Exp Ther 309:348–355Google Scholar

Aggrecanase Inhibition

  1. Abbaszade I, Liu RQ, Yang F, Rosenfeld SA, Ross OH, Link JR, Ellis DM, Tortorella MD, Pratta MA, Hollis JM, Wynn R, Duke JL, George HJ, Hillman MC Jr, Murphy K, Wiswall BH, Copeland RA, Decicco CP, Bruckner R, Nagase H, Itoh Y, Newton RC, Magolda RL, Trzaskos JM, Hollis GF, Arner EC, Burn TC (1999) Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. J Biol Chem 274:23443–23450PubMedGoogle Scholar
  2. Arner EC, Hughes CE, Diciccio CP, Caterson B, Tortorella MD (1998) Cytokine-induced cartilage proteoglycan degradation is mediated by aggrecanase. Osteoarthritis Cartilage 6:214–228PubMedGoogle Scholar
  3. Bonassar LJ, Sandy JD, Lark MW, Plaas AKH, Frank EH, Grodzinsky AJ (1997) Inhibition of cartilage degradation and changes in physical properties induced by IL-1β and retinoic acid using matrix metalloproteinase inhibitors. Arch Biochem Biophys 344:404–412PubMedGoogle Scholar
  4. Bottomley KM, Borkakoti N, Bradshaw D, Brown PA, Broadhorst MJ, Budd JM, Elliott L, Eyers P, Hallam TJ, Handa BK, Hill CH, James M, Lahm HW, Lawton G, Merritt JE, Nixon JS, Röthlisberger U, Whittle A, Johnson WH (1997) Inhibition of bovine nasal cartilage degradation by selective matrix metalloproteinase inhibitors. Biochem J 323:483–488Google Scholar
  5. Cherney RJ, Mo RT, Meyer DT, Wang L, Yao W, Wasserman ZL, Liu RQ, Covington MB, Tortorella MD, Arner EC, Qian M, Christ DD, Trzaskos JM, Newton RC, Magolda RL, Decicco CP (2003) Potent and selective aggrecanase inhibitors containing cyclic P1 substituents. Bioorg Med Chem Lett 13:1297–1300PubMedGoogle Scholar
  6. Farndale RW, Sayers CA, Barrett AJ (1982) A direct spectrophotometric microassay for sulfated glycosaminoglycans in cartilage cultures. Connect Tissue Res 9:247–248PubMedGoogle Scholar
  7. Gendron C, Kashiwagi M, Hughes C, Caterson B, Nagase H (2003) TIMP-3 inhibits aggrecanase-mediated glycosaminoglycan release from cartilage explants stimulated by catabolic factors. FEBS Lett 555:431–436PubMedGoogle Scholar
  8. Gilbert AM, Bikker JA, O’Neil V (2011) Advances in the development of novel aggrecanase inhibitors. Expert Opin Ther Pat 21:1–12PubMedGoogle Scholar
  9. Hashimoto G, Aoki T, Nakamura N, Tanzawa K, Okada Y (2001) Inhibition of ADAMTS4 (aggrecanase-1) by tissue inhibitors of metalloproteinases (TIMP-1, 2, 3 and 4). FEBS Lett 494:192–195PubMedGoogle Scholar
  10. Hashimoto G, Shimoda M, Okada Y (2004) ADAMTS4 (aggrecanase-1) interaction with the C-terminal domain of fibronectin inhibits proteolysis of aggrecan. J Biol Chem 279:33483–33491Google Scholar
  11. 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 276:12501–12504PubMedGoogle Scholar
  12. Liacini A, Sylvester J, Zafarullah M (2005) Tripolide suppresses proinflammatory cytokine-induced matrix metalloproteinase and aggrecanase-1 gene expression in chondrocytes. Biochem Biophys Res Commun 327:320–327PubMedGoogle Scholar
  13. Little CB, Flannery CR, Hughes CE, Mort SJ, Roughley PJ, Dent C, Caterson B (1999) Aggrecanase versus metalloproteases in the catabolism of the interglobular domain of aggrecan in vitro. Biochem J 344:61–68PubMedCentralPubMedGoogle Scholar
  14. Little C, Hughes C, Curtis C, Janusz M, Bohme R, Wang-Weigand S, Taiwo Y, Mitchell P, Otterness I, Flannery C, Caterson B (2002a) Matrix metalloproteinases are involved in C-terminal and interglobular domain processing of cartilage aggrecan in late stage of cartilage degradation. Matrix Biol 21:271–288PubMedGoogle Scholar
  15. Little CB, Hughes CE, Curtis CL, Jones SA, Caterson B, Flannery CR (2002b) Cyclosporin A inhibition of aggrecanase-mediated proteoglycan catabolism in articular cartilage. Arthritis Rheum 46:124–129PubMedGoogle Scholar
  16. Malfait AM, Liu RQ, Ijiri K, Komiya S, Tortorella MC (2002) Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage. J Biol Chem 277:22201–22208PubMedGoogle Scholar
  17. Miller JA, Liu RQ, Davis GL, Pratta MA, Trzaskos JM, Copeland RA (2003) A microplate assay specific for the enzyme aggrecanase. Anal Biochem 314:260–265PubMedGoogle Scholar
  18. Munteanu SE, Ilic MZ, Handley CJ (2000) Calcium pentosan polysulfate inhibits the catabolism of aggrecan in articular cartilage explant cultures. Arthritis Rheum 43:2211–2218PubMedGoogle Scholar
  19. Munteanu SE, Ilic MZ, Handley CJ (2002) Highly sulphated glycosaminoglycans inhibit aggrecanase degradation of aggrecan by bovine articular cartilage explant cultures. Matrix Biol 21:429–440PubMedGoogle Scholar
  20. Noe MC, Snow SL, Wolf-Gouveia LA, Mitchell PG, Lopresti-Morrow L, Reeves LM, Yocum SA, Liras JL, Vaughn M (2004) 3-Hydroxy-4-arylsulfonyltetrahydropyranyl-3-hydroxamic acids are novel inhibitors of MMP-13 and aggrecanase. Bioorg Med Chem Lett 14:4727–4730PubMedGoogle Scholar
  21. Nuti E, Santamaria S, Casalini F, Yamamoto K, Marinelli L, La Pietra V, Novellino E, Orlandini E, Nencetti S, Marini AM, Salerno S, Taliani S, Da Settimo F, Nagase H, Rossello A (2013) Arylsulphonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: synthesis and biological evaluation. Eu J Med Chem 62:379–394Google Scholar
  22. Patwari P, Gao G, Lee JH, Grodzinsky AJ, Sandy JD (2005) Analysis of ADAMTS4 and MT4-MMP indicates that both are involved in aggrecanolysis in interleukin-1-treated bovine cartilage. Osteoarthritis Cartilage 13:269–277PubMedCentralPubMedGoogle Scholar
  23. Peppard J, Glickman F, He Y, Si H, Doughty J, Goldberg R (2003) Development of a high-throughput screening assay for inhibitors of aggrecan cleavage using luminescent oxygen channelling (AlphaScreen). J Biomol Screen 8:149–156Google Scholar
  24. Pratta MA, Yao W, Decicco C, Tortorella MD, Liu RQ, Copeland RA, Magolda R, Newton RC, Trzaskos JM, Arner EC (2003) Aggrecan protects cartilage collagen from proteolytic cleavage. J Biol Chem 278:45539–45545PubMedGoogle Scholar
  25. Sabatini M, Bardiot A, Lesur C, Moulharat N, Thomas M, Richard I, Fradin A (2002) Effects of peroxisome proliferator-activated receptor γ on proteoglycan degradation and matrix metalloproteinase production in rat cartilage in vitro. Osteoarthritis Cartilage 10:673–679Google Scholar
  26. Sabatini M, Lesur C, Thomas M, Chomel A, Anract P, de Nateuil G, Pastoureau P (2005) Effect of inhibition of matrix metalloproteases on cartilage loss in vitro and in a guinea pig model of osteoarthritis. Arthritis Rheum 52:171–180Google Scholar
  27. Sandy JD, Gamett D, Verscharen C (1998) Chondrocyte-mediated catabolism of aggrecan: aggrecanase-dependent cleavage induced by interleukin-1 or retinoic acid can be inhibited by glucosamine. Biochem J 355:59–66Google Scholar
  28. Sawa M, Kiyoi T, Kurokawa K, Kumihara H, Yamamoto M, Miyasaka T, Ito Y, Hirayama R, Inoue T, Kirii Y, Nishiwaki E, Ohmoto H, Maeda Y, Ishibushi E, Inoue Y, Yoshino K, Kondo H (2002) New type of metalloprotease inhibitor: design and synthesis of new phosphonamide-based hydroxamic acids. J Med Chem 45:919–929PubMedGoogle Scholar
  29. Simpson PJ (2011) Oral aggrecanase inhibitor may slow postinjury cartilage breakdown. Nat Rev Rheumatol 7:131PubMedGoogle Scholar
  30. Song RH, Tortorella H, 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 56:575–585PubMedGoogle Scholar
  31. Stanton H, Rogerson FM, East CJ, Golub SB, Lawlor KE, Meeker CT, Little CB, Last K, Farmer PJ, Campbell JK, Fourle AM, Fosang AJ (2005) ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro. Nature 434:648–652PubMedGoogle Scholar
  32. Tortorella MD, Burn TC, Pratta MA, Abbaszade I, Hollis JM, Liu R, Rosenfeld SA, Copeland RA, Decicco CP, Wynn R, Rockwell A, Yang F, Duke JL, Solomon K, George H, Bruckner R, Nagase H, Itoh Y, Ellis DM, Ross H, Wiswall BH, Murphy K, Hillman MC Jr, Hollis GF, Arner EC (1999) Purification and cloning of aggrecanase-1: a member of the ADAMSTS family of proteins. Science 284:1664–1666PubMedGoogle Scholar
  33. Tortorella MD, Pratta M, Liu RQ, Austin J, Ross OH, Abbaszade I, Burn T, Arner E (2000) Sites of aggrecan cleavage by recombinant aggrecanase-1 (ADAMTS-4). J Biol Chem 275:18566–18573PubMedGoogle Scholar
  34. Tortorella MD, Malfait AM, Deciccio C, Arner E (2001) The role of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) in a model of cartilage degradation. Osteoarthritis Cartilage 9:539–552PubMedGoogle Scholar
  35. Tortorella MD, Arner EC, Hills R, Easton A, Korte-Sarfaty J, Fok K, Wittwer AJ, Liu RQ, Malfait AM (2004) α 2-Macroglobulin is a novel substrate for ADAMTS-4 and ADAMTS-5 and represents an endogenous inhibitor of these enzymes. J Biol Chem 279:17553–17561Google Scholar
  36. Vankemmelbeke MN, Jones GC, Fowles C, Ilic MZ, Handley CJ, Day AJ, Knight CG, Mort JS, Buttle DJ (2003) Selective inhibition of ADAMTS-1, -4 and -5 by catechin gallate esters. Eur J Biochem 270:2394–2403PubMedGoogle Scholar
  37. Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore HN, Goodfellow CL, Marcotte PA, Tapang M, Morgan DW, Michaelides MR, Davidsen SK (2002) Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors. J Med Chem 45:219–232PubMedGoogle Scholar
  38. Wight TN (2005) The ADAMTS proteases, extracellular matrix, and vascular disease. Arterioscler Thromb Vasc Biol 25:12–14PubMedGoogle Scholar
  39. Xiang-JS HY, Rush TS, Thomason JR, Ipek M, Sum PE, Abrous L, Sabatini JJ, Georgiadis K, Reifenberg E, Majumdar M, Morris EA, Tam S (2006) Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors. Bioorg Med Chem Lett 16:311–316PubMedGoogle Scholar

In Vivo Methods for Anti-osteoarthritic Activity: General Considerations

  1. Adams ME, Billingham MFJ (1982) Animal models of degenerative joint disease. Curr Top Pathol 71:265–297PubMedGoogle Scholar
  2. Aigner T, Cook JL, Gerwin N, Glasson SS, Laverty S, Little CB, McIlwraith W, Kraus VB (2010) Histopathology atlas of animal model systems – overview of guiding principles. Oseoarthritis Cartilage 18:S2–S6Google Scholar
  3. Alam MR, Lee HB, Kim MS, Kim NS (2011) Surgical model of osteoarthritis secondary to medial patellar luxation in dogs. Vet Med 56:123–130Google Scholar
  4. Ameye L, Young MF (2002) Mice deficient in small leucine-rich proteoglycans. novel in vivo models for osteoporosis, osteoarthritis, Ehlers-Danlos syndrome, muscular dystrophy, and corneal diseases. Glycobiology 12:107R–116RGoogle Scholar
  5. Bendele AM (2001) Animal models of osteoarthritis. J Musculoskelet Neuronal Interact 1:363–376PubMedGoogle Scholar
  6. Bendele AM (2002) Animal models of osteoarthritis in an era of molecular biology. J Musculoskelet Neuronal Interact 2:501–503PubMedGoogle Scholar
  7. Bendele AM, Hulman JF (1988) Spontaneous cartilage degeneration in guinea pigs. Arthritis Rheum 31:561–565PubMedGoogle Scholar
  8. Bonnet CS, Walsh DA (2005) Osteoarthritis, angiogenesis and inflammation. Rheumatology (Oxford) 44:7–16Google Scholar
  9. Burton-Wurster N, Todhunter RJ, Lust G (1993) Animal models of osteoarthritis. In: Woessner JF, Howell DS (eds) Joint cartilage degradation. Basic and clinical aspects. Marcel Dekker, New York, pp 347–384Google Scholar
  10. Carney SL (1991) Cartilage research, biochemical, histologic, and immunohistochemical markers in cartilage, and animal models of osteoarthritis. Curr Opin Rheumatol 3:669–675PubMedGoogle Scholar
  11. Cohen-Solal M, Funck-Brentano T, Hay E (2013) Animal models of osteoarthritis for the understanding of bone contribution. Bonekey Rep 2:422. doi:10.1038/bonekey.2013.156PubMedCentralPubMedGoogle Scholar
  12. Colombo C, Butler M, O’Byrne E, Hickman L (1983) A new model of osteoarthritis in rabbits. I: development of knee joint pathology following lateral meniscectomy and section of the fibular collateral and sesamoid ligaments. Arthritis Rheum 26:875–886PubMedGoogle Scholar
  13. Combe R, Bramwell S, Field MJ (2004) The monosodium iodoacetate model of osteoarthritis: a model of chronic nociceptive pain in rats? Neurosci Lett 370:236–240PubMedGoogle Scholar
  14. Cook JL, Hung CT, Kuroki K, Stoker AM, Cook CR, Pfeiffer FM, Sherman SL, Stannard JP (2014) Animal models of cartilage repair. Bone Joint Res 4:89–94Google Scholar
  15. Fang H, Beier F (2014) Mouse models of osteoarthritis: modeling risk factors and assessing outcomes. Nat Rev Immunol 10:413–421Google Scholar
  16. Farkas T, Boyd RD, Schaffler MB, Radin EL, Burr DB (1987) Early vascular changes in rabbit subchondral bone after repetitive impulsive loading. Clin Orthop 30:259–267Google Scholar
  17. Ford-Hutchinson AF, Ali Z, Seerattan RA, Cooper DML, Hallgrímsson B, Salo PT, Jirik FR (2005) Degenerative knee joint disease in mice lacking 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (Papss2) activity: a putative model of human PAPSS2 deficiency-associated arthrosis. Osteoarthritis Cartilage 13:418–425PubMedGoogle Scholar
  18. Glasson SS, Askew R, Sheppard B, Carito BA, Blanchet T, Ma HL, Flannery CR, Kanki K, Wang E, Peluso D, Yang Z, Majumdar MK, Morris EA (2004) Characterization and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum 50:2547–2558PubMedGoogle Scholar
  19. 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 degeneration in a murine model of osteoarthritis. Nature 434:644–648Google Scholar
  20. Greenwald RA (1991) Animal models for evaluation of arthritis drugs. Methods Find Exp Clin Pharmacol 13:75–83PubMedGoogle Scholar
  21. Greenwald RA (1993) Cartilage degradation in animal models of inflammatory joint disease. In: Woessner JF, Howell DS (eds) Joint cartilage degradation. Basic and clinical aspects. Marcel Dekker, New York, pp 385–408Google Scholar
  22. Greenwald RA, Diamond HS (eds) (1988) CRC handbook of animal models for the rheumatic diseases, vol 1. CRC Press, Boca RatonGoogle Scholar
  23. Gregory MH, Capito N, Kuroki K, Stoker AM, Cook JL, Sherman SL (2012) A review of translational animal models for knee osteoarthritis. Arthitis. doi:10.1155/2012/764621Google Scholar
  24. Haakenstad LH (1969) Chronic bone and joint diseases in relation to conformation in the horse. Equine Vet J 1:248Google Scholar
  25. Han F, Kipnes JR, Li Y, Tuan RS, Hall DJ (2002) The murine COMP (cartilage oligomeric matrix protein) promoter contains a potent transcriptional repressor region. Osteoarthritis Cartilage 10:638–645PubMedGoogle Scholar
  26. Hess EV, Herman JH (1986) Cartilage metabolism and anti-inflammatory drugs in osteoarthritis. Am J Med 81:36–43PubMedGoogle Scholar
  27. Hinz B, Brune K (2004) Pain and osteoarthritis: new drugs and mechanisms. Curr Opin Rheumatol 16:628–633PubMedGoogle Scholar
  28. Johnson K, Terkeltaub R (2003) Upregulated and expression in osteoarthritis can promote both chondrocyte MMP-13 expression and calcification via chondrocyte extracellular PPi excess. Osteoarthritis Cartilage 12:321–335Google Scholar
  29. Kalbhen DA (1983) Pharmakologische Beurteilung von Möglichkeiten einer Knorpelschutztherapie bei degenerativen Gelenkerkrankungen (Arthrose). Z Rheumatol 42:187–194PubMedGoogle Scholar
  30. Kalbhen DA (1987) Chemical model of osteoarthritis – a pharmacological evaluation. J Rheumatol 14:130–131PubMedGoogle Scholar
  31. Kamekura S, Hoshi K, Shimoaka T, Chung U, Chikuda H, Yamada T, Uchida M, Ogata N, Seichi NK, Kawaguchi H (2005) Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 13:632–641PubMedGoogle Scholar
  32. Konttinen YT, Michelsson JE, Tolvanen E, Bergroth V (1990) Primary inflammatory reaction in synovial fluid and tissue in rabbit immobilization osteoarthritis. Clin Orthop Relat Res 260:280–286PubMedGoogle Scholar
  33. Kyostio-Moore S, Nambiar B, Hutto E, Ewing PJ, Piraino S, Berthelette P, Sookdeo C, Matthews G, Armentano D (2011) STR/ort mice, a model for spontaneous osteoarthritis, exhibit elevated levels of both local and systemic inflammatory markers. Comp Med 61:346–354Google Scholar
  34. Lindenhayn K, Haupt R, Kristan J, Regling G (1984) Proteinase activity in the joint cartilage of sheep following mechanical arthrosis induction using an impulse stress instrument. Beitr Orthop Traumatol 31:507–511PubMedGoogle Scholar
  35. Little CB, Smith MM (2008) Animal models of osteoarthritis. Curr Rheumatol Rev 4:175–182Google Scholar
  36. Little CB, Zaki S (2012) What constitutes an “animal model of osteoarthritis” – the need for consensus? Osteoarthritis Cartilage 20:261–267PubMedGoogle Scholar
  37. Liu C (2014) Recombinant progranulin prevents the loss of proteoglycan in surgically induced osteoarthritis model. J Cytol Histol 5:6Google Scholar
  38. Loeser RF, Olex AL, McNulty MA, Carlson CS, Callahan M, Ferguson C, Fetrow JS (2013) Disease progression and phasic changes in gene expression in a mouse model of osteoarthritis. PLoS One 8:e54633PubMedCentralPubMedGoogle Scholar
  39. Lust G, Rendano VT, Summers BA (1985) Canine hip dysplasia: concepts and diagnosis. J Am Vet Med Assoc 187:638–640PubMedGoogle Scholar
  40. Malemud CJ (1993) Markers of osteoarthritis and cartilage research in animal models. Curr Opin Rheumatol 5:494–502PubMedGoogle Scholar
  41. Malfait AM, Little CB, McDougall JJ (2013) A commentary on modeling osteoarthritis pain in small animals. Osteoarthritis Cartilage 21:1316–1326PubMedCentralPubMedGoogle Scholar
  42. Mazières B, Herou P, Dambreville JM, Thiechart H (1984) Die Wirkung eines Glykosaminoglykan-Peptid-Komplexes (GAG-Peptid-Komplex) bei experimenteller Arthrose am Kaninchen. Akt Rheumatol 9:133–138Google Scholar
  43. Meacock SCR, Bodmer JL, Billingham MFJ (1990) Experimental osteoarthritis in guinea pigs. J Exp Pathol 71:279–293Google Scholar
  44. Meyer-Carrive I, Ghosh P (1992) Effects of tiaprofenic acid (Surgam) on cartilage proteoglycans in the rabbit joint immobilization model. Ann Rheum Dis 51:448–455PubMedCentralPubMedGoogle Scholar
  45. Moskowitz RW (1990) The relevance of animal models in osteoarthritis. Scand J Rheumatol Suppl 81:21–23PubMedGoogle Scholar
  46. Moskowitz RW (1992) Experimental models of osteoarthritis. In: Moskowitz RW, Howell DS, Goldberg VM, Mankin HJ (eds) Osteoarthritis: diagnosis and medical/surgical management, 2nd edn. W.B. Saunders, Philadelphia, pp 213–232Google Scholar
  47. Moskowitz RW, Davis W, Sammarco J, Martens M, Baker J, Mayor M, Burstein AH, Frankel BH (1973) Experimentally induced degenerative joint lesions following partial meniscectomy in the rabbit. Arthritis Rheum 16:397–405PubMedGoogle Scholar
  48. Moskowitz RW, Howell DS, Goldberg VM, Muniz O, Pita JC (1979) Cartilage proteoglycan alterations in an experimentally induced model of rabbit osteoarthritis. Arthritis Rheum 22:155–163PubMedGoogle Scholar
  49. Oegema TR, Visco D (1999) Animal models of osteoarthritis. In: Friedman RJ, An YH (eds) Animal models in orthopaedic research. CRC Press/LLC, Boca Raton, pp 349–367Google Scholar
  50. Onur T, Wu R, Dang A (2014) Characterisation of osteoarthritis in a small animal model of type 2 diabetes mellitus. Bone Joint Res 3:203–211PubMedCentralPubMedGoogle Scholar
  51. Palmoski MJ, Brandt KD (1982) Aspirin aggravates the degeneration of canine joint cartilage caused by immobilization. Arthritis Rheum 25:1333–1342PubMedGoogle Scholar
  52. Pita JC, Manicourt DH, Muller FJ, Howell DS (1986) Studies on the potential reversibility of osteoarthritis in some experimental animal models. In: Kuettner KE, Schleyerbach R, Hascall VC (eds) Articular cartilage biochemistry. Raven, New York, pp 349–363Google Scholar
  53. Poole R, Blake S, Buschmann M, Goldring S, Lavery S, Lockwood S, Matyas J, McDougall J, Pritzer K, Rudolphi K, van den Berg W, Yaksh T (2010) Recommendations for the use of preclinical models in the study and treatment of osteoarthritis. Osteoarthritis Cartilage 18:S10–S16PubMedGoogle Scholar
  54. Pritzker KPH (1994) Animal models for osteoarthritis: processes, problems, and prospects. Ann Rheum Dis 53:406–420PubMedCentralPubMedGoogle Scholar
  55. Pritzker KPH, Chateauvert JM, Grynpas MD, Renlund RC, Turnquist J, Kessler MJ (1989) Rhesus macaques as an experimental model for degenerative arthritis. P R Health Sci J 8:99–102PubMedGoogle Scholar
  56. Regling G, Buntrock P, Geiss W (1989) Monoiodoacetic acid-induced arthropathy of the rabbit knee – a contribution to the pathogenesis of arthrosis. Beitr Orthop Traumatol 36:193–203PubMedGoogle Scholar
  57. Rintala M, Metsaranta M, Saamanen AM, Vuorio E, Ronning O (1997) Abnormal craniofacial growth and early mandibular osteoarthritis in mice harbouring a mutant type II collagen transgene. J Anat 190(Pt 2):201–208PubMedCentralPubMedGoogle Scholar
  58. Scharstuhl A, Diepens R, Lensen J, Vitters E, van Beuningen H, van der Kraan P, van den Berg W (2003) Adenoviral overexpression of Smad-7 and Smad-6 differentially regulates TGF-β-mediated chondrocyte proliferation and proteoglycan synthesis. Osteoarthritis Cartilage 11:773–782PubMedGoogle Scholar
  59. Schwartz ER (1985) Surgically induced osteoarthritis in guinea pigs: studies of proteoglycans, collagens, and non-collagen proteins. In: Peyron JG (ed) Osteoarthritis: current clinical and fundamental problems. Proceedings of a workshop held in Paris, 9–11 Apr 1984. Geigy, Rueil-Malmaison, pp 273–288Google Scholar
  60. Serra R, Johnson M, Filvaroff EH, LaBorde J, Sheehan DM, Derynck R, Moses HL (1997) Expression of a truncated, kinase-defective TGF-β type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. J Cell Biol 139:541–552PubMedCentralPubMedGoogle Scholar
  61. Teeple E, Jay GD, Eisaid KA, Fleming BC (2013) Animal models of osteoarthritis: challenges of model selection and analysis. AAPS J 15:438–446PubMedCentralPubMedGoogle Scholar
  62. Thiede RM, Lu Y, Markel D (2012) A review of the treatment methods for cartilage defects. Vet Comp Orthop Traumatol 25:89–94Google Scholar
  63. Todhunter RJ, Lust G (1992) Synovial joint anatomy, biology and pathobiology. In: Auer J (ed) Equine surgery. Saunders, Philadelphia, pp 844–866Google Scholar
  64. Torelli SR, Sc R, Volpi RS, Sequeira JL, Grassioto IQ (2005) Histopathological evaluation of treatment with chondroitin sulphate for osteoarthritis induced by continuous immobilization in rabbits. J Vet Med A Physiol Pathol Clin Med 52:45–51PubMedGoogle Scholar
  65. Ueblacker P, Wagner B, Krüger A, Voigt S, DeSantis G, Kennerknecht E, Brill T, Hillemanns M, Salzmann GM, Imhoff AB, Plank C, Gänsbacher B, Martinek V (2004) Inducible nonviral gene expression in the treatment of osteochondral defects. Osteoarthritis Cartilage 12:711–719PubMedGoogle Scholar
  66. Van Lent PLEM, Holthuysen AEM, Slöetjes A, Lubberts E, van den Berg WB (2002) Local overexpression of adeno-viral IL-4 protects cartilage from metalloproteinase-induced destruction during immune complex-mediated arthritis by preventing activation of pro-MMPs. Osteoarthritis Cartilage 10:234–243PubMedGoogle Scholar
  67. Wadhwa S, Embree MC, Kilts T, Young MF, Ameye LG (2005) Accelerated osteoarthritis in the temporomandibular joint of biglycan/fibromodulin double-deficient mice. Osteoarthritis Cartilage 13:817–827PubMedGoogle Scholar
  68. Wieland HA, Michaelis M, Kirschbaum BJ, Rudolphi KA (2005) Osteoarthritis – an untreatable disease? Nat Rev Drug Discov 4:331–343PubMedGoogle Scholar
  69. Williams JM, Uebelhart D, Ongchi DR, Kuettner KE, Thonar EJMA (1992) Animal models of articular cartilage repair. In: Kuettner KE, Schleyerbach R, Pyron JG, Hascall VC (eds) Articular cartilage and osteoarthritis. Raven, New York, pp 511–525Google Scholar
  70. Xu L, Peng H, Wu D, Hu K, Goldring MB, Olsen BR, Li Y (2005) Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. J Biol Chem 280:548–555PubMedGoogle Scholar
  71. Zaka R, Williams CJ (2005) Genetics of chondrocalcinosis. Osteoarthritis Cartilage 13:745–750PubMedGoogle Scholar
  72. Zhang YW, Su Y, Lanning N, Swiatek PJ, Bronson RT, Sigler R, Marin RW, Woude GFV (2005) Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease. Proc Natl Acad Sci U S A 102:11740–11745PubMedCentralPubMedGoogle Scholar
  73. Zhang R-X, Ren K, Dubner R (2013) Osteoarthritis pain mechanisms: basic studies in animal models. Osteoarthritis Cartilage 21:1308–1315PubMedCentralPubMedGoogle Scholar
  74. Zhao Y-P, Liu B, Tian Q-Y, Wei J-I, Richborough B, Liu C-J (2014) Progranulin protects against osteoarthritis through interacting with TNF-a and b-catenin signaling. Ann Rheum Dis doi:10.1136/annrheumdis-2014-205779Google Scholar

Canine Anterior Cruciate Ligament (ACL) Transection Model

  1. Abatangelo G, Botti P, Del Bue M, Gei G, Samson JC, Cortivo R, DeGalateo A, Martelli M (1989) Intra-articular sodium hyaluronate injections in the Pond-Nuki experimental model of osteoarthritis in dogs. I. Biochemical results. Clin Orthop Relat Res 241:278–285PubMedGoogle Scholar
  2. Adams ME, Pelletier JP (1988) Canine anterior cruciate ligament transection model of osteoarthritis. In: Greenwald RA, Diamond HS (eds) CRC handbook of animal models for the rheumatic diseases, vol 2. CRC Press, Boca Raton, pp 57–81Google Scholar
  3. Amiel D, Toyoguchi T, Kobayashi K, Bowden K, Amiel ME, Healey M (2003) Long-term effect of sodium hyaluronate (Hyalgan) on osteoarthritis progression in a rabbit model. Osteoarthritis Cartilage 11:636–643PubMedGoogle Scholar
  4. Appleyard RC, Gosh P, Swain MV (1999) Biomechanical, histological and immunohistological studies of patella cartilage in an ovine model of osteoarthritis induced by lateral meniscectomy. Osteoarthritis Cartilage 7:281–294PubMedGoogle Scholar
  5. Behets C, Williams JM, Chappard D, Devogelaer JP, Manicourt DH (2004) Effects of calcitonin on subchondral trabecular bone changes and on osteoarthritic cartilage lesions after acute cruciate ligament deficiency. J Bone Miner Res 19:1821–1826PubMedGoogle Scholar
  6. Bendele AM (1987) Progressive chronic osteoarthritis in femorotibial joints of partial medial meniscectomized guinea pigs. Vet Pathol 24:444–448PubMedGoogle Scholar
  7. Bendele AM, White SL, Hulman JF (1989) Osteoarthritis in guinea pigs. Histopathologic and scanning electron microscope features. Lab Anim Sci 39:115–121PubMedGoogle Scholar
  8. Bendele A, McComb J, Gould T, McAbee T, Sennelo G, Chlipala E, Guy M (1999) Animal models of arthritis: relevance to human disease. Toxicol Pathol 27:134–142PubMedGoogle Scholar
  9. Boileau C, Martel-Pelletier J, Jouzeau JY, Netter P, Moldovan F, Laufer S, Ries S, Pelletier JP (2002) Licofelone (ML-3000), a dual inhibitor of 5-lipoxygenase and cyclooxygenase, reduces the level of cartilage chondrocyte death in vivo in experimental dog osteoarthritis: inhibition of pro-apoptotic factors. J Rheumatol 29:1446–1453PubMedGoogle Scholar
  10. Boileau C, Martel-Pelletier J, Brunet J, Tardif G, Schrier D, Flory C, El-Kattan A, Boily M, Pelletier JP (2005) Oral treatment with PD-0200347, an oral α 2 δ ligand, reduces the development of experimental osteoarthritis by inhibiting metalloproteinases and inducible oxide synthase gene expression and synthesis of cartilage chondrocytes. Arthritis Rheum 52:488–500PubMedGoogle Scholar
  11. Brandt KD, Adams ME (1989) Exuberant repair of articular cartilage damage. Effect of anterior cruciate ligament transection in the dog. Trans Orthop Res Soc 14:584Google Scholar
  12. Brandt KD, Braunstein EM, Visco DM, O’Connor B, Heck D, Albrecht M (1991a) Anterior (cranial) cruciate ligament transection in the dog: a bona fide model of osteoarthritis, not merely of cartilage injury and repair. J Rheumatol 18:436–446PubMedGoogle Scholar
  13. Brandt KD, Myers SL, Burr D, Albrecht M (1991b) Osteoarthritic changes in canine articular cartilage, subchondral bone and synovium 54 months after transection of the anterior cruciate ligament. Arthritis Rheum 34:1560–1570PubMedGoogle Scholar
  14. Burkhardt D, Hwa SY, Ghosh P (2001) A novel microassay for the quantitation of sulfated glycosaminoglycan content of histological sections: its application to determine the effects of Diacerhein on cartilage in an ovine model of osteoarthritis. Osteoarthritis Cartilage 9:238–247PubMedGoogle Scholar
  15. Caron JP, Fernandes JC, Martel-Pelletier J, Tardif G, Mineau F, Geng C, Pelletier JP (1996) Chondroprotective effect of intraarticular injections of interleukin-1 antagonist in experimental arthritis: suppression of collagenase-1 expression. Arthritis Rheum 39:1535–1544PubMedGoogle Scholar
  16. Colombo C (1988) Partial lateral meniscectomy with section of fibular collateral and sesamoid ligaments in the rabbit. In: Greenwald RA, Diamond HS (eds) CRC handbook of animal models for the rheumatic diseases, vol 2. CRC Press, Boca Raton, pp 27–55Google Scholar
  17. Diaz-Gallego L, Prieto JG, Coronel P, Gamazo LE, Gimeno M, Alvarez AI (2005) Apoptosis and nitric oxide in an experimental model of osteoarthritis in rabbit after hyaluronic acid treatment. J Orthop Res 23:1370–1376PubMedGoogle Scholar
  18. DiPasquale G, Caputo CB, Crissman JW (1988) Rabbit partial medial meniscectomy. In: Greenwald RA, Diamond HS (eds) CRC handbook of animal models for the rheumatic diseases, vol 2. CRC, Boca Raton, pp 19–25Google Scholar
  19. Doschak MR, Wohl GR, Hanley DA, Bray RC, Zernicke RF (2004) Antiresorptive therapy conserves some periarticular bone and ligament mechanical properties after anterior cruciate ligament disruption in the rabbit knee. J Orthop Res 22:942–948PubMedGoogle Scholar
  20. Ghosh P, Read R, Armstrong S, Wilson D, Marshall R, McNair P (1993) The effects of intra-articular administration of hyaluran in a model of early osteoarthritis in sheep. I. Gait analysis, radiological and morphological studies. Semin Arthritis Rheum 6(Suppl 1):31–42Google Scholar
  21. Hannan H, Ghosh P, Bellenger C, Taylor T (1987) Systemic administration of glycosaminoglycan polysulfate (Arteparon) provides partial protection of articular cartilage from damage produced by meniscectomy in the canine. J Orthop Res 5:47–59PubMedGoogle Scholar
  22. Hayamai T, Pickarski M, Wesolowski GA, Mclane J, Bone DJ, Rodan GA, Duong LT (2004) The role of subchondral bone remodeling in osteoarthritis. Reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum 50:1193–1206Google Scholar
  23. Janusz MJ, Bendele AM, Brown KK, Taiwo YO, Hsieh L, Heitmeyer SA (2002) Induction of osteoarthritis in the rat by surgical tear of the meniscus: inhibition of joint damage by a matrix metalloproteinase inhibitor. Osteoarthritis Cartilage 10:785–791PubMedGoogle Scholar
  24. Johnson RG (1986) Transection of the canine anterior cruciate ligament: a concise review of experience with this model of degenerative joint disease. Exp Pathol 30:209–213PubMedGoogle Scholar
  25. Kawano T, Miura H, Mawatari T, Moro-Oka T, Nakanishi Y, Higaki H, Iwamoto Y (2003) Mechanical effects of the intraarticular administration of high molecular weight hyaluronic acid plus phospholipid on synovial joint lubrication and prevention of articular cartilage degeneration in experimental osteoarthritis. Arthritis Rheum 48:1923–1929PubMedGoogle Scholar
  26. Kiapour AM, Murray MM (2014) Basic science of anterior cruciate ligament injury and repair. Bone Joint Res 3:20–31PubMedCentralPubMedGoogle Scholar
  27. Kobayashi T, Notoya K, Nakamura A, Akimoto K (2005) Fursultiamine, a vitamin B1 derivate, enhances chondroprotective effects of glucosamine hydrochloride and chondroitin sulfate in rabbit experimental osteoarthritis. Inflamm Res 54:249–255PubMedGoogle Scholar
  28. Kraus VB, Huebner JL, Stabler T, Flahiff CM, Setton LA, Fink C, Vilim V, Clark AG (2004) Ascorbic acid increases the severity of spontaneous osteoarthritis in a guinea pig model. Arthritis Rheum 50:1822–1831PubMedGoogle Scholar
  29. Layton MW, Arsever C, Bole GG (1987) Use of guinea pig myectomy osteoarthritis model in the examination of cartilage-synovium interactions. J Rheumatol 14/Spec no:125–126Google Scholar
  30. Machner A, Pap G, Schwarzberg H, Eberhardt R, Roessner A, Neumann W (1999) Störung sensibler Gelenkinnervation als begünstigender Faktor für die Arthroseentstehung. Eine tierexperimentelle Untersuchung am Rattenmodel. (Deterioration in sensible joint innervation as a possible cause for the development of osteoarthritis. An animal study in rats). Z Rheumatol 58:148–154PubMedGoogle Scholar
  31. Moreau M, Rialland P, Pelletier J-P, Martel-Pelletier J, Lajeunesse D, Boileau C, Caron J, Frank D, Lussier B, re del Castillo J, Beauchamp G, Gauvin D, Bertaim T, Thibaud D, Troncy E (2011) Tiludronate treatment improves structural changes and symptoms of osteoarthritis in the canine anterior cruciate ligament model. Arthritis Res Ther 13:R98PubMedCentralPubMedGoogle Scholar
  32. Matyas JR, Atley L, Ionescu M, Eyre DR, Poole AR (2004) Analysis of cartilage biomarkers in the early phases of canine experimental osteoarthritis. Arthritis Rheum 50:543–552PubMedGoogle Scholar
  33. McDevitt C, Gilbertson E, Muir H (1977) An experimental model of osteoarthritis; early morphological and biochemical changes. J Bone Joint Surg 59B:24–35Google Scholar
  34. Moore EE, Bendele AM, Thompson DL, Littau A, Waggie KS, Reardon B, Ellsworth JL (2005) Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage 13:623–631PubMedGoogle Scholar
  35. Myers SL, Brandt KD, O’Connor BL (1991) Low dose prednisone treatment does not reduce the severity of osteoarthritis in dogs after cruciate ligament transection. J Rheumatol 18:1856–1862PubMedGoogle Scholar
  36. Myers SL, Brandt KD, Burr DB, O’Connor BL, Albrecht M (1999) Effects of a bisphosphonate on bone histomorphometry and dynamics in the canine cruciate deficiency model of osteoarthritis. J Rheumatol 26:2845–2853Google Scholar
  37. Naveen SV, Ahmad RE, Hui WJ, Suhaeb AM, Murali MR, Shanmugam R, Kamarul T (2014) Histology, glycosaminoglycan level and cartilage stiffness in monoiodoacetate-induced osteoarthritis: comparative analysis with anterior cruciate ligament transaction in rat model with human osteoarthritis. Int J Med Sci 11:97–105PubMedCentralPubMedGoogle Scholar
  38. Newton CH, Fetter DA, Bashey RI, Jimenez SA (1984) Clinical studies and pathological changes in articular cartilage in experimental canine osteoarthrosis and effects of the in vivo administration of a glycosaminoglycan peptide (GAG-peptide-complex) from bone marrow and cartilage. Akt Rheumatol 9:128–132Google Scholar
  39. Obara T, Yamaguchi T, Moriya Y, Namba K (1993) Tissue distribution of fluorescein-labeled sodium hyaluronate in experimentally-induced osteoarthritis. Jpn Pharmacol Ther 21(Suppl 2):193–200Google Scholar
  40. Pelletier JP, Martel-Pelletier J (1985) Cartilage degradation by neutral proteoglycanases in experimental osteoarthritis: suppression by steroids. Arthritis Rheum 28:1393PubMedGoogle Scholar
  41. Pelletier JP, Martel-Pelletier J (1991) In vivo protective effects of prophylactic treatment with tiaprofenic acid or intraarticular corticosteroids on osteoarthritic lesions in the experimental dog model. J Rheumatol 18(Suppl 27):127–130Google Scholar
  42. Pelletier JP, Caron JP, Evans C, Robbins PD, Georgescu HI, Javanovic D, Fernandes JC (1997) In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis Rheum 40:1012–1019PubMedGoogle Scholar
  43. Pelletier JP, Boileau C, Boily M, Brunet J, Mineau F, Geng C, Reboul P, Laufer S, Lajeunesse D, Martel-Pelletier J (2005) The protective effect of licofelone on experimental osteoarthritis is correlated with the downregulation of gene expression and protein synthesis of several major catabolic factors: MMP-13, cathepsin K and aggrecanases. Arthritis Res Ther 7:R1091–R1102PubMedCentralPubMedGoogle Scholar
  44. Pickarski M, Hayami T, Zhuo Y, Duong LT (2011) Molecular changes in articular cartilage and subchondral bone in the rat anterior cruciate ligament transaction and meniscectomised models of osteoarthritis. BMC Musculoskelet Disord 12:197–210PubMedCentralPubMedGoogle Scholar
  45. Pond MJ, Nuki G (1973) Experimentally-induced osteoarthritis in the dog. Ann Rheum Dis 32:387PubMedCentralPubMedGoogle Scholar
  46. Pozi A, Kim SE, Conrad BP, Horodyski M, Banks SA (2013) Ex vivo pathomechanics of the canine Pond-Nuki model. PLoS One 8:e81383Google Scholar
  47. Sabatini M, Lesur C, Thomas M, Chomel A, de Nanteuil G, Pastoureau P (2005) Effect of inhibition of matrix metalloproteinase on cartilage loss in vitro and in a guinea pig model of osteoarthritis. Arthritis Rheum 52:171–180Google Scholar
  48. Schiavinato A, Lini E, Guidolin D, Pezzoli G, Botti P, Martelli M, Cortivo R, DeGalateo A, Abatangelo G (1989) Intra-articular sodium hyaluronate injections in the Pond-Nuki experimental model of osteoarthritis in dogs. II. Morphological findings. Clin Orthop Relat Res 241:286–299PubMedGoogle Scholar
  49. Schwartz E (1988) Surgically induced osteoarthritis in guinea pigs. In: Greenwald RA, Diamond HS (eds) CRC handbook of animal models for the rheumatic diseases, vol 2. CRC press, Boca Raton, pp 89–95Google Scholar
  50. Smith GN, Myers SL, Brandt KD, Mickler EA, Albrecht ME (1999) Diacerhein treatment reduces the severity of osteoarthritis in the canine cruciate-deficiency model of osteoarthritis. Arthritis Rheum 42:545–554PubMedGoogle Scholar
  51. Smith GN, Mickler EA, Albrecht ME, Myers SL, Brandt KD (2002) Severity of medial meniscus damage in the canine knee after anterior cruciate ligament transection. Osteoarthritis Cartilage 10:321–326PubMedGoogle Scholar
  52. Strassle BW, Mark L, Leventhal L, Piesla MJ, Li XJ, Kennedy JD, Glasson SS, Whiteside GT (2010) Inhibition of osteoclasts prevents cartilage loss and pain in a rat model of degenerative joint disease. Osteoarthritis Cartilage 18:1319–1328PubMedGoogle Scholar
  53. Tiraloche G, Girard C, Chouinard L, Sampalis J, Moquin L, Ionescu M, Reiner A, Pole AR, Laverty S (2005) Effect of oral glucosamine on cartilage degradation in a rabbit model of osteoarthritis. Arthritis Rheum 52:1118–1128PubMedGoogle Scholar
  54. Vignon E, Arlot M, Hartman D, Moyer B, Ville G (1983) Hypertrophic repair of articular cartilage in experimental osteoarthrosis. Ann Rheum Dis 42:82–88PubMedCentralPubMedGoogle Scholar
  55. Wancket LM, Baragi V, Bove S, Kilgore K, Korytko PJ, Guzman RE (2005) Anatomical localization of cartilage degradation markers in a surgically induced osteoarthritis model. Toxicol Pathol 33:484–489PubMedGoogle Scholar
  56. Wenz W, Graf J, Brocai DR, Breusch SJ, Mittacht M, Thomas O, Niethard FU (1998) Wirksamkeit von intraartikulär applizierter Hyaluronsäure auf Frühformend der Femoropatellararthrose. Eine experimentelle Untersuchung an Hunden (Effectiveness of intra-articular application of hyaluronic acid on early forms of femoropatellar arthrosis. An experimental study in dogs). Z Orthop Grenzgebiete 136:298–3003Google Scholar
  57. Xie X, Wu H, Zhao S, Xie G, Huangfu X, Zhao J (2013) The effect of platelet-rich plasma on patterns of gene expression in a dog model of anterior cruciate ligament reconstruction. J Surg Res 180:80–88PubMedGoogle Scholar
  58. Zhang X, Mao Z, Yu C (2004) Suppression of early experimental osteoarthritis by gene transfer of interleukin-1 receptor antagonist and interleukin-10. J Orthop Res 22:742–750Google Scholar

Chymopapain-Induced Cartilage Degeneration in the Rabbit

  1. Chandrasekhar S, Esterman MA, Hoffman HA (1987) Microdetermination of proteoglycans and glycosaminoglycans in the presence of guanidine hydrochloride. Anal Biochem 161:103–108PubMedGoogle Scholar
  2. Cohen SB, Gill SS, Baer GS, Leo BM, Scheld WM, Diduch DR (2004) Reducing joint destruction due to septic arthrosis using an adenosine2A receptor agonist. J Orthop Res 22:427–435PubMedGoogle Scholar
  3. Farndale RW, Buttle DJ, Barrett AJ (1986) Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethyl-methylene blue. Biochim Biophys Acta 883:173–177PubMedGoogle Scholar
  4. Furman BD, Mangiapani DS, Zeitler E, Bailey KN, Horne PH, Huebner JL, Kraus VB, Guilak F, Olson SA (2014) Targeting pro-inflammatory cytokines following joint injury: acute intra-articular inhibition of interleukin-1 following knee injury prevents post-traumatic arthritis. Arthritis Res Ther 16:R134PubMedCentralPubMedGoogle Scholar
  5. Khan HM, Ashraf M, Hashmi AS, Ahmad MUD, Anjum AA (2013) Papain-induced progressive degenerative changes in articular cartilage of rat femorotibial joint and its histopathological grading. J Animal Plant Sci 23:350–358Google Scholar
  6. Kikuchi T, Sakuta T, Yamaguchi T (1998) Intra-articular injection of collagenase induces experimental osteoarthritis in mature rabbits. Osteoarthritis Cartilage 6:177–186PubMedGoogle Scholar
  7. Mankin HJ, Dorfman H, Lipiello L (1971) Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. J Bone Joint Surg Am 53A:523–537Google Scholar
  8. Muehleman C, Green J, Williams JM, Kuettner KE, Thonart EJMA, Sumner DR (2002) The effect of bone remodeling inhibition by zoledronic acid in an animal model of cartilage matrix damage. Osteoarthritis Cartilage 10:226–233PubMedGoogle Scholar
  9. Pomonis JD, Boulet JM, Gottshall SL, Phillips S, Sellers R, Bunton T, Walker K (2005) Development and pharmacological characterization of a rat model of osteoarthritis pain. Pain 114:339–346PubMedGoogle Scholar
  10. Romeis B (1989) Mikroskopische Technik, 17th edn. Urban & Schwarzenberg, MünchenGoogle Scholar
  11. Rosenberg L (1971) Chemical basis for the histological use of safranin-O in the study of articular cartilage. J Bone Joint Surg Am 53A:69–82Google Scholar
  12. Saez-Llorens X, Jafari HS, Olsen KD, Nariuchi H, Hansen EJ, McCracken GH Jr (1991) Induction of suppurative arthritis in rabbits by haemophilus endotoxin, tumor necrosis factor-alpha, and interleukin-1 beta. J Infect Dis 163:1267–1273PubMedGoogle Scholar
  13. Scharstuhl A, Glansbeek HL, van Beuningen HM, Vitters EL, van der Kraan PM, van den Berg WB (2002) Inhibition of endogenous TGF-β during experimental osteoarthritis prevents osteophyte formation and impairs cartilage repair. J Immunol 169:507–514PubMedGoogle Scholar
  14. Van den Berg WB, van Osch GJM, van der Kraan PM, van Beuningen HM (1993) Cartilage destruction and osteophytes in instability-induced murine osteoarthritis: role of TGFβ in osteophyte formation? Agents Actions 40:215–219PubMedGoogle Scholar
  15. Van der Kraan PM, Vitters EL, van de Putte LB, van den Berg (1989) Development of osteoarthritic lesions in mice by “metabolic” and “mechanical” alterations in the knee joints. Am J Pathol 135:1001–1014PubMedCentralPubMedGoogle Scholar
  16. Van der Kraan PM, Vitters EL, van Beuningen HM, van de Putte LBA, van den Berg WB (1990) Degenerative knee joint lesions in mice after a single intra-articular collagenase injection. A new model of osteoarthritis. J Exp Pathol (Oxford) 71:19–31Google Scholar
  17. Van der Sluijs JA (1992) The reliability of the Mankin score for osteoarthritis. J Orthop Res 10:58–61PubMedGoogle Scholar
  18. Van Osch GJVM, Blankevoort L, van der Kraan PM, Janssen B, Hekman E, Huiskes R (1995) Laxity characteristics of normal and pathological murine knee joints in vitro. J Orthop Res 13:783–791PubMedGoogle Scholar
  19. Williams JM, Downey C, Thonar EJMA (1988) Increase in levels of serum keratan sulfate following cartilage proteoglycan degradation in the rabbit knee joint. Arthritis Rheum 31:557–560PubMedGoogle Scholar
  20. Williams JM, Ongchi DR, Thonar EJMA (1993) Repair of articular cartilage injury following intra-articular chymopapain-induced matrix proteoglycan loss. J Orthop Res 11:705–716PubMedGoogle Scholar

Spontaneous OA Model in STR/1 N Mice

  1. Benjamin M, Ralphs JR, Archer CW, Mason RM, Chambers M, Dowthwaite GP (1995) Cytoskeletal changes in articular fibrocartilage are an early indicator of osteoarthritis in STR/ORT mice. Orthop Res Soc 20:246Google Scholar
  2. Brewster M, Lewis EJ, Wilson KL, Greenham AK, Bottomley KM (1998) Ro 32–3555, an orally active collagenase selective inhibitor, prevents structural damage in the STR/ORT mouse model of osteoarthritis. Arthritis Rheum 41:1639–1644PubMedGoogle Scholar
  3. Chambers MG, Cox L, Chong L, Suri N, Cover P, Bayliss MT, Mason RM (2001) Matrix metalloproteinases and aggrecanases cleave aggrecan in different zones of normal cartilage but colocalize in the development of osteoarthritis lesions on STR/ort mice. Arthritis Rheum 44:1455–1465PubMedGoogle Scholar
  4. Dunham J, Chambers MG, Jasani MK, Bitenski L, Chayen J (1989) Quantitative criteria for evaluating the early development of osteoarthritis and the effect of diclofenac sodium. Agents Actions 28:93–97PubMedGoogle Scholar
  5. Flannelly J, Chambers MG, Dudhia J, Hembry RM, Murphy G, Mason RM, Bayliss MT (2002) Metalloproteinase and tissue inhibitor of metalloproteinase expression in the murine STR/ort model of osteoarthritis. Osteoarthritis Cartilage 10:722–733PubMedGoogle Scholar
  6. Gaffen JD, Bayliss MT, Mason RM (1997) Elevated aggrecan mRNA in an early murine osteoarthritis. Osteoarthritis Cartilage 5:227–233PubMedGoogle Scholar
  7. Glant TT, Szabo G, Nagase H, Jacobs JJ, Ikecz K (1998) Progressive polyarthritis induced in BALB/c mice by aggrecan from normal and osteoarthritic human cartilage. Arthritis Rheum 41:1007–1018PubMedGoogle Scholar
  8. Kyostio-Moore S, Nambiar B, Hutto E, Ewing PJ, Piraino S, Berthelette P, Sookdeo C, Matthews G, Armentano D (2011) STR/ort mice, a model for spontaneous osteoarthritis, exhibit elevated levels of both local and systemic inflammatory markers. Comp Med 61:346–354Google Scholar
  9. Manion CV, Hochgeschwender U, Edmundson AB, Hugli TE, Gabalia CR (2011) Dietary aspartyl-phenylalanine-1-methy ester delays osteoarthritis and prevents associated bone loss in STR/ORT mice. Rheumatology 50:1244–1249PubMedCentralPubMedGoogle Scholar
  10. Mason RM, Chambers MG, Flanelly J, Gaffen DJ, Didhia J, Bayliss MT (2001) The STR/ort mouse and its use as a model of osteoarthritis. Osteoarthritis Cartilage 9:85–91PubMedGoogle Scholar
  11. Nakamura Y (1990) Histochemical and immunohistochemical studies on knee joint cartilage in spontaneous osteoarthritis in C57 black mice. J Tokyo Med Coll 48:308–319Google Scholar
  12. Pataki A, Graf HP, Witzemann E (1990) Spontaneous osteoarthritis of the knee-joint in C57BL mice receiving chronic oral treatment with NSAID’s or prednisone. Agents Actions 29:210–217PubMedGoogle Scholar
  13. Poulet B, Westerhof TAT, Hamilton RW, Shefelbine SJ, Pitsillides AA (2013) Spontaneous osteoarthritis in Str/ort mice is unlikely due to greater vulnerability to mechanical trauma. Osteoarthritis Cartilage 21:756–763PubMedGoogle Scholar
  14. Price JS, Chambers MG, Poole AR, Fradin A, Mason RM (2002) Comparison of collagenase-cleaved articular cartilage collagen in mice in the naturally occurring STR/ort model of osteoarthritis and in collagen-induced arthritis. Osteoarthritis Cartilage 10:172–179PubMedGoogle Scholar
  15. Raiss RX, Caterson B (1992) Immunohistochemical localization of chondroitin sulfate isomers in the knee joint of osteoarthritic mice. In: Kuettner KE, Schleyerbach R, Pyron JG, Hascall VC (eds) Articular cartilage and osteoarthritis. Raven, New York, pp 714–715Google Scholar
  16. Raiss RX, Bartlett RR, Schleyerbach R (1992) Genetically induced mouse models of rheumatic diseases. Effects of leflunomide on articular manifestations. In: Kuettner KE, Schleyerbach R, Pyron JG, Hascall VC (eds) Articular cartilage and osteoarthritis. Raven, NewYork, pp 712–713Google Scholar
  17. Rudolphi K, Gerwin N, Verziji N, van der Kraan P, van den Berg W (2003) Pralnacasan, an inhibitor of interleukin-1â converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthritis Cartilage 11:738–746PubMedGoogle Scholar
  18. Schünke M, Tillmann B, Brück M, Müller-Ruchholtz W (1988) Morphologic characteristics of developing osteoarthritic lesions in the knee cartilage of STR/1 N mice. Arthritis Rheum 31:898–905PubMedGoogle Scholar
  19. Sokoloff L, Crittenden LB, Yamamoto RS, Jay GE (1962) The genetics of degenerative joint disease in mice. Arthritis Rheum 5:531–545PubMedGoogle Scholar
  20. Van der Kraan PM, Vitters EL, van Beuningen HM, van de Putte LB, van den Berg WB (1990) Degenerative joint lesions in mice after a single intra-articular collagenase injection. J Exp Pathol 71:19–31Google Scholar
  21. Walton M (1977a) Degenerative joint disease in the mouse knee; histological observations. J Pathol 123:109–122PubMedGoogle Scholar
  22. Walton M (1977b) Degenerative joint disease in the mouse knee; radiological and morphological observations. J Pathol 123:97–107PubMedGoogle Scholar
  23. Walton M (1977c) Studies of degenerative joint disease in the mouse knee joint; scanning electron microscopy. J Pathol 123:211–217PubMedGoogle Scholar
  24. Walton M (1979) Patella displacement and osteoarthrosis of the knee joint in mice. J Pathol 127:165–172PubMedGoogle Scholar
  25. Wilhelmi G, Meyer R (1983) Zur Prüfung potentieller Antiarthrotika an der spontanen Arthrose der Maus. Z Rheumatol 42:203–205PubMedGoogle Scholar

Transgenic Mice as Models of Osteoarthritis

  1. Ameye L, Young MF (2002) Mice deficient in small leucine-rich proteoglycans: novel in vivo models of osteoporosis, osteoarthritis, Ehlers-Danlos syndrome, muscular dystrophy, and corneal diseases. Glycobiology 12:107R–116RGoogle Scholar
  2. Ameye L, Aria D, Jepsen K, Oldberg A, Xu T, Young MF (2002) Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis. FASEB J 16:673–680PubMedGoogle Scholar
  3. Fässler R, Schnegelsberg PNJ, Dausman J, Shinya T, Muatgaki Y, McCarthy MT, Olsen BR, Jaenisch R (1994) Mice lacking α1(IX) collagen develop noninflammatory degenerative joint disease. Proc Natl Acad Sci U S A 91:5070–5074PubMedCentralPubMedGoogle Scholar
  4. Garofalo S, Vuorio E, Metsäranta M, Rosati R, Toman D, Vaughan J, Lozano G, Mayne R, Ellard J, Horton W, de Crombrugghe B (1991) Reduced amounts of cartilage collagen fibrils and growth plate anomalies in transgenic mice harboring a glycine-to-cysteine mutation in the mouse type II procollagen α 1-chain gene. Proc Natl Acad Sci U S A 88:9648–9652PubMedCentralPubMedGoogle Scholar
  5. Garofalo S, Metsäranta M, Ellard J, Smith C, Horton W, Vuorio E, de Crombrugghe B (1993) Assembly of cartilage collagen fibrils is disrupted by overexpression of normal type II collagen in transgenic mice. Proc Natl Acad Sci U S A 90:3825–3829PubMedCentralPubMedGoogle Scholar
  6. Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, Flannery CL, Peluso D, Kanki K, Yang Z, Majumdar M, Morris EA (2005) Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434:644–648Google Scholar
  7. Huang M-J, Wang L, Jin D-D, Zhang Z-M, Chen T-Y, Jia C-H, Wang Y, Zhen X-C, Huang B, Yan B, Chen Y-H, Li S-F, Yang J-C, Bai X-C (2014) Enhancement of the synthesis of n-3 PUFAs in fat-1 transgenic mice inhibits mTORC1 signalling and delays surgically induced osteoarthritis in comparison with wild-type mice. Ann Rheum Dis 73:1719–1727PubMedGoogle Scholar
  8. Helminen HJ, Säämänen AM, Salminen H, Hyttinen MM (2002) Transgenic mouse models for studying the role of cartilage macromolecules in osteoarthritis. Rheumatology 41:848–856PubMedGoogle Scholar
  9. Holmbeck K, Bianco P, Caterina J, Yamada S, Kromer M, Kuznetsov SA, Mankani M, Robey PG, Poole AR, Pidoux I, Ward JM, Birkedal-Hansen H (1999) MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99:81–92PubMedGoogle Scholar
  10. Hosaka Y, Saito T, Sugita S, Hikata T, Kobayashi H, Fukai A, Taniguchi Y, Hiraya M, Akiyama H, Chung U-I, Kawaguchi H (2013) Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development. Proc Natl Acad Sci U S A 110:1875–1880PubMedCentralPubMedGoogle Scholar
  11. Kyrkanides S, Tallents RH, Miller JH, Olschowka ME, Johnson R, Yang MY, Olschowka JA, Brouxhon SM, O’Banion MK (2011) Osteoarthritis accelerates and exacerbates Alzheimer’s disease pathology in mice. J Neuroinflammation 8:112PubMedCentralPubMedGoogle Scholar
  12. Metsäranta M, Garolfo S, Decker G, Rintala M, de Crombrugghe B, Vuorio E (1992) Chondrodysplasia in transgenic mice harboring a 15 amino acid deletion in triple helical domain of pro α1(II) collagen chain. J Cell Biol 118:203–212PubMedGoogle Scholar
  13. Morko JP, Söderström M, Säämänen AMK, Salminen HJ, Vuorio EI (2004) Upregulation of cathepsin K expression in articular chondrocytes in a transgenic mouse model of osteoarthritis. Ann Rheum Dis 63:649–655PubMedCentralPubMedGoogle Scholar
  14. Nakata K, Ono K, Miyazaki J, Olson BR, Muragaki Y, Adachi E, Yamamura KI, Kimura T (1993) Osteoarthritis associated with mild chondrodysplasia in transgenic mice expressing α1(IX) collagen chains with a central deletion. Proc Natl Acad Sci U S A 90:2870–2874PubMedCentralPubMedGoogle Scholar
  15. Neuhold LA, Killar L, Zhao W, Sung MLA, Warner L, Kulik J, Turner J, Wu W, Billinghurst C, Meijers T, Poole AR, Babij P, DeGennaro LJ (2001) Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest 107:35–44PubMedCentralPubMedGoogle Scholar
  16. Säämänen AM, Vuorio E (2004) Generation and use of transgenic mice as models for osteoarthritis. Methods Mol Med 101:1–23PubMedGoogle Scholar
  17. Säämänen AMK, Salminen HJ, Dean PB, de Crombrugghe B, Vuorio EI, Metsäranta MPH (2000) Osteoarthritis-like lesions in transgenic mice harboring a small deletion mutation in type II collagen gene. Osteoarthritis Cartilage 8:248–257PubMedGoogle Scholar
  18. Salminen HJ, Säämänen AMK, Vankemmelbeke MN, Auho PK, Perälä MP, Vuorio EI (2002) Differential expression patterns of matrix metalloproteinases and their inhibitors during development of osteoarthritis in a transgenic mouse model. Ann Rheum Dis 61:591–597PubMedCentralPubMedGoogle Scholar
  19. Vandenberg P, Khillan JS, Prockop DJ, Helminen A, Kontusaari S, Ala-Kokko L (1991) Expression of a partially deleted gene of human type II procollagen (COL2A1) in transgenic mice produces chondrodysplasia. Proc Natl Acad Sci U S A 88:7640–7644PubMedCentralPubMedGoogle Scholar
  20. Xu L, Flahiff CM, Waldman BA, Wu D, Olsen BR, Setton LA, Li Y (2003) Osteoarthritis-like changes and decreased mechanical function of articular cartilage in the joints of mice with the chondrodysplasia gene (cho). Arthritis Rheum 48:2509–2518PubMedGoogle Scholar
  21. Zemmyo M, Meharra EJ, Kühn K, Creighton-Achermann L, Lotz M (2003) Accelerated, aging-dependent development of osteoarthritis in α1 integrin-deficient mice. Arthritis Rheum 48:2873–2880PubMedGoogle Scholar

Copyright information

© Crown Copyright 2015

Authors and Affiliations

  1. 1.AalenGermany
  2. 2.Global Medicines Development Respiratory ProjectsAstraZeneca R&DCheshireEngland, UK

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