1 I.L.1. Cartilage Matrix Turnover in vitro
1.1 I.L.1.1. Modulation of Chondrocytic Proteoglycan Metabolism
1.1.1 Purpose and Rationale
Several agents and therapeutic principles addressing musculoskeletal disorders, applied either systemically or intraarticularly, have been discussed to potentially impair the integrity of articular cartilage (Raynauld et al. 2003; Adams et al. 2000; Theiler et al. 1994). Therefore, a reliable cellular assay is of interest to detect chondrodeleterious properties of a test drug in its early developmental stages.
In primary cultures, articular chondrocytes chondrocytesgrown in an artificial matrix after digestion of the original one, maintain their characteristic synthesis and turnover rate of cartilage matrix macromolecules for a long time. These metabolic processes can be influenced pharmacologically. In the following assay, compounds are tested for their effect upon the normal turnover of cartilage matrix by chondrocytes. The test is used to detect...
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Adams ME, Lussier AJ, Peyron JG (2000) A risk-benefit assessment of injections of hyaluronan and its derivatives in the treatment of osteoarthritis of the knee. Drug Safety 23:115–130
Adcocks C, Collin P, Buttle DJ (2002) Catechins from green tea (Camellia sinensis) inhibit bovine and human cartilage proteoglycan and type II collagen degradation in vitro. J Nutr 132:341–346
Archer CW, McDowell J, Bayliss MT et al. (1990) Phenotypic modulation in sub-populations of human articular chondrocytes in vitro. J Cell Sci 97:361–371
Aspden RM, Larsson T, Svensson R, Heinegard D (1991) Computer-controlled mechanical testing machine for small samples of biological viscoelastic material. J Biomed Engineering 13:521–525
Aydelotte MB, Greenhill RR, Kuettner KE (1988) Differences between sub-populations of cultured bovine articular chondrocytes. II. Proteoglycan metabolism. Conn Tiss Res 18:223–234
Aydelotte MB, Kuettner KE (1988) Differences between sub-populations of cultured bovine articular chondrocytes. I. Morphology and cartilage matrix production. Conn Tiss Res 18:205–222
Aydelotte MB, Raiss RX, Caterson B, Kuettner KE (1992) Influence of interleukin-1 on the morphology and proteoglycan metabolism of cultured bovine articular chondrocytes. Conn Tiss Res 28:143–159
Bank RA, Beekman B, Verzijl N et al. (1997) Sensitive fluorimetric quantitation of pyridinium and pentosidine crosslinks in biological samples in a single high-performance liquid chromatographic run. J Chromatogr B Biomed Sci Appl 703:37–44
Bassleer C, Henrotin Y, Franchimont P (1990) In vitro assays of chondrocyte functions: the influence of drugs and hormones. Scand J Rheumatology Suppl 81:13–20
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 19:1433–1438
Benya PD, Schaffer JD (1982) Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell 30:215–224
Blanque R, Cottereaux C, Gardner CR (2001) Phasic production of urinary pyridinium crosslinks in mice: the effect of ovariectomy. Calcif Tissue Int 68:102–108
Bonaventure J, Kadhom N, Cohen-Solal L et al. (1994) Reexpression of cartilage-specific genes by dedifferentiated human articular chondrocytes cultured in alginate beads. Exp Cell Res 212:97–104
Brandt KD (2002) Animal models of osteoarthritis. Biorheology 39:221–235
Brewster M, Lewis EJ, Wilson KL et al. (1998) Ro 32-3555, an orally active collagenase selective inhibitor, prevents structural damage in the STR/ORT mouse model of osteoarthritis. Arthritis Rheumatism 41:1639–1644
Cawston TE, Ellis AJ, Humm G et al. (1995) Interleukin-1 and oncostatin M in combination promote the release of collagen fragments from bovine nasal cartilage in culture. Biochem Biophys Res Commun 215:377–385
Chayen J, Bitensky L, Mehdizadeh S et al. (1994) Testing drugs on human osteoarthritic articular cartilage. Cell Biochem Funct 12:63–68
Eyre DR (1995) The specificity of collagen cross-links as markers of bone and connective tissue degradation. Acta Orthop Scand Suppl 266:166–170
Farndale RW, Buttle DJ, Barrett AJ (1986) Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta 83:173–177
Fitzgerald JB, Jin M, Dean D et al. (2004) Mechanical compression of cartilage explants induces multiple time-dependent gene expression patterns and involves intracellular calcium and cyclic AMP. J Biol Chemistry 279:19502–19511
Gendron C, Kashiwagi M, Hughes C et al. (2003) TIMP-3 inhibits aggrecanase-mediated glycosaminoglycan release from cartilage explants stimulated by catabolic factors. FEBS Lett 555:431–436
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 Verlag, Berlin Heidelberg New York pp 406–420
Guo J, Jourdian GW, MacCallum DK (1989) Culture and growth characteristics of chondrocytes encapsulated in alginate beads. Conn Tiss Res 19:277–297
Henrotin Y, Bassleer C, Franchimont P(1992) In vitro effects of etodolac and acetylsalicylic acid on human chondrocyte metabolism. Agents and Actions 36:317–323
Hunter CJ, Mouw JK, Levenston ME (2004) Dynamic compression of chondrocyte-seeded fibrin gels: effects on matrix accumulation and mechanical stiffness. Osteoarthritis Cartilage 12:117–130
Häuselmann HJ, Fernandes RJ, Mok SS et al. (1994) Phenotypic stability of bovine articular chondrocytes after long-term culture in alginate beads. J Cell Sci 107:17–27
Jacobson PB, Morgan SJ, Wilcox DM et al. (1999) A new spin on an old model. In vivo evaluation of disease progression by magnetic resonance imaging with respect to standard inflammatory parameters and histopathology in the adjuvant arthritis rat. Arthritis Rheumatism 42:2060–2073
James IT, Perret D, Thompson PW (1990) Rapid assay for hard tissue collagen cross-links using isocratic ion-pair reversed-phase liquid chromatography. J Chromatogr 525:43–57
Jortikka M, Lammi MJ, Parkkinen JJ et al. (1993) A high sensitivity dot-blot assay for proteoglycans by cuprolinic blue precipitation. Conn Tiss Res 29:263–272
Kaufmann J, Mueller A, Voigt A et al. (2003) Hydroxypyridinium collagen crosslinks in serum, urine, synovial fluid and synovial tissue in patients with rheumatoid arthritis compared with osteoarthritis. Rheumatology 42:314–320
Kim YJ, Sah RLY, Doong JYH, Grodzinsky AJ (1988) Fluorometric assay of DNA in cartilage explants using Hoechst 33258. Anal Biochem 174:168–176
Kindt E, Gueneva-Boucheva K, Rekhter MD et al. (2003) Determination of hydroxyproline in plasma and tissue using electrospray mass spectrometry. J Pharm Biomed Anal 33:1081–1092
Kisiday JD, Jin M, DiMicco MA et al. (2004) Effects of dynamic compressive loading on chondrocyte biosynthesis in self-assembling peptide scaffolds. J Biomech 37:595–604
Knott L, Bailey AJ (1998) Collagen cross-links in mineralizing tissues: a review of their chemistry, function, and clinical relevance. Bone 22:181–187
Kolibas LM, Goldberg RL (1989) Effect of cytokines and anti-arthritic drugs on glycosaminoglycan synthesis by bovine articular chondrocytes. Agents and Actions 27:245–249
Kozaci LD, Buttle DJ, Hollander AP (1997) Degradation of type II collagen, but not proteoglycan, correlates with matrix metalloproteinase activity in cartilage explant cultures. Arthritis and Rheumatism 40:164–174
Lafeber FPG, van Roy H, Wilbrink B et al. (1992) Human osteoarthritic cartilage is synthetically more active but in culture less vital than normal cartilage. J Rheumatol 19:123–129
Lafeber FPJG, van der Kraan PM, van Roy JLAM et al. (1993) Articular cartilage explant culture; an appropriate in vitro system to compare osteoarthritic and normal human cartilage. Conn Tiss Res 29:287–299
Lane NE, Williams IIIRJ, Schurman DJ, Smith RL (1992) Inhibition of interleukin 1 induced chondrocyte protease activity by a corticosteroid and a nonsteroidal antiinflammatory drug. J Rheumatol 19:135–139
Larsson T, Aspden RM, Heinegard D (1991) Effects of mechanical load on cartilage matrix biosynthesis in vitro. Matrix 11:388–394
Malemud CJ, Stevenson S, Mehraban F et al. (1994) The proteoglycan synthesis repertoire of rabbit chondrocytes maintained in type II collagen gels. Osteoarthritis and Cartilage 2:29–42
Mankin HJ, Dorfman H, Lipiello L (1971) Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. J Bone Joint Surgery 53A:523–537
McCollum R, Martel-Pelletier J, DiBattista J, Pelletier JP (1991) Regulation of interleukin 1 receptors in human articular chondrocytes. J Rheumatol (Suppl 27) 18:85–88
McQuillan DJ, Handley CJ, Robinson HC (1986) Control of proteoglycan biosynthesis. Biochem J 237:741–747
Milner JM, Elliott SF, Cawston TE (2001) Activation of procollagenases is a key control point in cartilage collagen degradation. Interaction of serine and metalloproteinase pathways. Arthritis and Rheumatism 44:2084–2096
Mow VC, Bachrach NM, Setton LA, Guilak F (1994) Stress, strain, pressure and flow fields in articular cartilage and chondrocytes. In: Mow VC, Guilak F, Tran-Son-Tay R, Hochmuth RM (eds) Cell mechanics and cellular engineering. Springer, New York, pp. 345–379
Mueller A, Jakob K, Hein GE (2003) Evaluation of free and peptide-bound collagen crosslink excretion in different skeletal diseases. Ann Rheum Dis 62:65–67
Nixon JS, Bottomley KMK, Broadhurst MJ et al (1991) Potent collagenase inhibitors prevent interleukin-1-induced cartilage degradation in vitro. Int J Tiss Reac 13:237–243
Oegema TRJ, Visco D (1999) Animal models of osteoarthritis. In: An YH, Friedman RJ (eds) Animal models in orthopaedic research. CRC press, Boca Raton pp 349–367
Ostergaard K, Andersen CB, Petersen J et al. (1999) Validity of histopathological grading of articular cartilage from osteoarthritic knee joints. Ann Rheum Dis 58:208–213
Ostergaard K, Petersen J, Andersen CB et al. (1997) Histologic / histochemical grading system for osteoarthritic articular cartilage: reproducibility and validity. Arthritis Rheum 40:1766–1771
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 16:646–655
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 18:19–27
Peterson JT (2004) Matrix metalloproteinase inhibitor development and the remodeling of drug discovery. Heart Failure Rev 9:63–79
Pratta MA, Yao W, Decicco C et al. (2003) Aggrecan protects cartilage collagen from proteolytic cleavage. J Biol Chemistry 278:45539–45545
Raynauld JP, Buckland-Wright C, Ward R et al. (2003) Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee. Arthritis and Rheumatism 48:370–377
Renkiewicz R, Qiu L, Lesch C et al. (2003) Broad–spectrum matrix metalloproteinase inhibitor marimastat–induced musculoskeletal side effects in rats. Arthritis Rheumatism 48:1742–1749
Romeis B (1989) Mikroskopische Technik. 17thedn, Urban & Schwarzenberg, München
Rosenberg L (1971) Chemical basis for the histological use of safranin-O in the study of articular cartilage. J Bone Joint Surgery 53A:69–82
Sauerland K, Plaas AHK, Raiss RX, Steinmeyer J (2003b) The sulfation pattern of chondroitin sulfate from articular cartilage explants in response to mechanical loading. Biochim Biophys Acta 1638:241–248
Sauerland K, Raiss RX, Steinmeyer J (2003a) Proteoglycan metabolism and viability of articular cartilage explants as modulated by the frequency of intermittent loading. Osteoarthritis Cartilage 11:343–350
Seibel MJ, Woitge HW, Farahmand I et al. (1998) Automated and manual assays for urinary crosslinks of collagen: which assay to use?. Exp Clin Endocrinol Diabetes 106:143–148
Seid JM, Rahman S, Graveley R et al. (1993) The effect of interleukin-1 on cytokine gene expression in cultured human articular chondrocytes analyzed by messenger RNA phenotyping. Arthritis and Rheumatism 36:35–43
Shimizu C, Coutts RD, Healey RM et al. (1997) Method of histomorphometric assessment of glycosaminoglycans in articular cartilage. J Orthop Res 15:670–674
Smith SM, Dillon EL, DeKerlegand DE, Davis-Street JE (2004) Variability of collagen crosslinks: impact of sample collection period. Calcif Tissue Int 74:336–341
Steinmeyer J (1997) A computer-controlled mechanical culture system for biological testing of articular cartilage explants. J Biomechanics 30:841–845
Steinmeyer J, Ackermann B, Raiss RX (1997) Intermittant cyclic loading of cartilage explants modulates fibronectin metabolism. Osteoarthritis Cartilage 5:331–341
Steinmeyer J, Daufeldt S, Taiwo YO (1998) Pharmacological effect of tetracyclines on proteoglycanases from interleukin-1-treated articular cartilage. Biochem Pharmacol 55:93–100
Steinmeyer J, Knue S, Raiss RX, Pelzer I (1999) Effects of intermittently applied cyclic loading on proteoglycan metabolism and swelling behaviour of articular cartilage explants. Osteoarthritis Cartilage 7:155–164
Stone PJ, Beiser A, Gottlieb DJ (1998) Circadian variation of urinary excretion of elastin and collagen crosslinks. Proc Soc Exp Biol Med 218:229–233
Sugimoto K, Iizawa T, Harada H et al. (2004) Cartilage degradation independent of MMP/aggrecanases. Osteoarthritis and Cartilage 12:1006–1014
Szafranski JD, Grodzinsky AJ, Burger E et al. (2004) Chondrocyte mechanotransduction: effects of compression on deformation of intracellular organelles and relevance to cellular biosynthesis. Osteoarthritis Cartilage 12:937–946
Theiler R, Ghosh P, Brooks P (1994) Clinical, biochemical and imaging methods of assessing osteoarthritis and clinical trials with agents claiming “chondromodulating” activity. Osteoarthritis and Cartilage 2:1–23
Urban JP (1994) The chondrocyte: A cell under pressure. Brit J Rheumatol 33:901–908
van den Berg W (2001) Lessons from animal models of osteoarthritis. Curr Opin Rheumatol 13:452–456
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 19:140–145
van der Kraan PM, de Lange J, Vitters EL et al. (1994) Analysis of changes in proteoglycan content in murine articular cartilage using image analysis. Osteoarthritis Cartilage 2:207–214
van Valburg AA, van Osch GJ, van der Kraan PM, van den Berg WB (1996) Quantification of morphometric changes in murine experimental osteoarthritis using image analysis. Rheumatol Int 15:181–187
Verbruggen G, Veys EM, Malfait AM et al (1989) Proteoglycan metabolism in tissue cultured human articular cartilage. Influence of piroxicam. J Rheumatol 16:355–362
Verbruggen G, Veys EM, Malfait AM et al (1990) Proteoglycan metabolism in tissue-cultured human articular cartilage. Scand J Rheumatology 19:257–268
Verbruggen G, Veys EM, Wieme N et al. (1990) The synthesis and immobilisation of cartilage-specific proteoglycan by human chondrocytes in different concentrations of agarose. Clin Exp Rheumatol 8:371–378
Verzijl N, Wachsmuth L, TeKoppele JM, Raiss RX (2001) Urinary collagen cross–link excretion in STR/1N mice indicates cartilage destruction as an early event in the development of spontaneous osteoarthritis. Transact Orthop Res Soc 26:271
Wachsmuth LK, Durchfeld-Meyer B, Jahn NI et al. (2002) Dynamics of matrix loss in the spontaneous osteoarthritic mouse strain STR-1N. In: Hascall VC, Kuettner KE (eds) The many faces of osteoarthritis. Birkhäuser, Basel, pp 45–49
Wachsmuth LK, Raiss RX, Berg-Scholl I, Keiffer R (1999) Histological characterization of disease progression and therapeutic intervention in the spontaneous osteoarthritic STR-1N mouse. Transact Orthop Res Soc 24:461
Weithmann KU, Schlotte V, Jeske V et al. (1997) Effects of tiaprofenic acid on urinary pyridinium crosslinks in adjuvant arthritic rats: Comparison with doxycycline. Inflamm Res 46:246–252
Wolf A, Raiss RX, Steinmeyer J (2003) Fibronectin metabolism of cartilage explants in response to the frequency of intermittent loading. J Orthopaedic Res 21:1081–1089
Yang XH, Zhang ZX (1991) Effects of DMSO and glycerol in 35S incorporation of articular cartilage. Cryo-Letters 12:53–58
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2006 Springer-Verlag Berlin Heidelberg New York
About this entry
Cite this entry
Raiss, R. (2006). Safety Pharmacology of Drugs with Osteoarthritis-Related Activity. In: Vogel, H.G., Hock, F.J., Maas, J., Mayer, D. (eds) Drug Discovery and Evaluation. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-29804-5_12
Download citation
DOI: https://doi.org/10.1007/3-540-29804-5_12
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-25638-0
Online ISBN: 978-3-540-29804-5
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences