Logo of biochemjBJ Latest papers and much more!
Biochem J. 2002 Mar 1; 362(Pt 2): 473–479.
PMCID: PMC1222409

Hyaluronate degradation as an alternative mechanism for proteoglycan release from cartilage during interleukin-1beta-stimulated catabolism.


Data presented previously suggest that release of components of the cartilage matrix, in response to catabolic agents, cannot be accounted for by proteolytic mechanisms alone. In the present study, the release of glycosaminoglycan-containing components from bovine nasal cartilage cultured in the presence of interleukin-1beta, and from bovine nasal, fetal bovine epiphyseal and adult human articular cartilage cultured in the presence of retinoic acid, was accompanied by the loss of link protein and hyaluronate into the culture medium. Chromatographic analysis of the released hyaluronate showed it to be markedly reduced in size relative to that extracted from the corresponding tissue. It is proposed that, under stimulation by catabolic agents, two independent, but concurrent, mechanisms act to promote the release of aggrecan from the cartilage matrix. First, proteolytic cleavage of the aggrecan core protein results in the production of glycosaminoglycan-containing fragments that are free to diffuse from the tissue. Secondly, cleavage of hyaluronate renders portions of the proteoglycan aggregate small enough so that complexes of aggrecan (or fragments containing its G1 domain) and link protein are released from the tissue. It is likely that both mechanisms contribute to cartilage metabolism in normal physiology and pathology.

Full Text

The Full Text of this article is available as a PDF (202K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Hardingham TE, Fosang AJ. Proteoglycans: many forms and many functions. FASEB J. 1992 Feb 1;6(3):861–870. [PubMed]
  • Doege K, Sasaki M, Horigan E, Hassell JR, Yamada Y. Complete primary structure of the rat cartilage proteoglycan core protein deduced from cDNA clones. J Biol Chem. 1987 Dec 25;262(36):17757–17767. [PubMed]
  • Fosang AJ, Hardingham TE. Isolation of the N-terminal globular protein domains from cartilage proteoglycans. Identification of G2 domain and its lack of interaction with hyaluronate and link protein. Biochem J. 1989 Aug 1;261(3):801–809. [PMC free article] [PubMed]
  • Fosang AJ, Neame PJ, Last K, Hardingham TE, Murphy G, Hamilton JA. The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B. J Biol Chem. 1992 Sep 25;267(27):19470–19474. [PubMed]
  • Zheng J, Luo W, Tanzer ML. Aggrecan synthesis and secretion. A paradigm for molecular and cellular coordination of multiglobular protein folding and intracellular trafficking. J Biol Chem. 1998 May 22;273(21):12999–13006. [PubMed]
  • Caterson B, Flannery CR, Hughes CE, Little CB. Mechanisms involved in cartilage proteoglycan catabolism. Matrix Biol. 2000 Aug;19(4):333–344. [PubMed]
  • Ilic MZ, Handley CJ, Robinson HC, Mok MT. Mechanism of catabolism of aggrecan by articular cartilage. Arch Biochem Biophys. 1992 Apr;294(1):115–122. [PubMed]
  • Sandy JD, Thompson V, Doege K, Verscharen C. The intermediates of aggrecanase-dependent cleavage of aggrecan in rat chondrosarcoma cells treated with interleukin-1. Biochem J. 2000 Oct 1;351(Pt 1):161–166. [PMC free article] [PubMed]
  • Sztrolovics Robert, White Robert J, Roughley Peter J, Mort John S. The mechanism of aggrecan release from cartilage differs with tissue origin and the agent used to stimulate catabolism. Biochem J. 2002 Mar 1;362(Pt 2):465–472. [PMC free article] [PubMed]
  • Roughley PJ, White RJ. Age-related changes in the structure of the proteoglycan subunits from human articular cartilage. J Biol Chem. 1980 Jan 10;255(1):217–224. [PubMed]
  • McNicol D, Roughley PJ. Extraction and characterization of proteoglycan from human meniscus. Biochem J. 1980 Mar 1;185(3):705–713. [PMC free article] [PubMed]
  • Cleland RL, Sherblom AP. Isolation and physical characterization of hyaluronic acid prepared from bovine nasal septum by cetylpyridinium chloride precipitation. J Biol Chem. 1977 Jan 25;252(2):420–426. [PubMed]
  • Recklies AD, White C, Melching L, Roughley PJ. Differential regulation and expression of hyaluronan synthases in human articular chondrocytes, synovial cells and osteosarcoma cells. Biochem J. 2001 Feb 15;354(Pt 1):17–24. [PMC free article] [PubMed]
  • Goldberg RL. Enzyme-linked immunosorbent assay for hyaluronate using cartilage proteoglycan and an antibody to keratan sulfate. Anal Biochem. 1988 Nov 1;174(2):448–458. [PubMed]
  • Farndale RW, Buttle DJ, Barrett AJ. Improved quantitation and discrimination of sulphated glycosaminoglycans by use of dimethylmethylene blue. Biochim Biophys Acta. 1986 Sep 4;883(2):173–177. [PubMed]
  • Caterson B, Christner JE, Baker JR, Couchman JR. Production and characterization of monoclonal antibodies directed against connective tissue proteoglycans. Fed Proc. 1985 Feb;44(2):386–393. [PubMed]
  • Sztrolovics R, Alini M, Roughley PJ, Mort JS. Aggrecan degradation in human intervertebral disc and articular cartilage. Biochem J. 1997 Aug 15;326(Pt 1):235–241. [PMC free article] [PubMed]
  • Liu J, Cassidy JD, Allan A, Neame PJ, Mort JS, Roughley PJ. Link protein shows species variation in its susceptibility to proteolysis. J Orthop Res. 1992 Sep;10(5):621–630. [PubMed]
  • Mort JS, Poole AR, Roughley PJ. Age-related changes in the structure of proteoglycan link proteins present in normal human articular cartilage. Biochem J. 1983 Jul 15;214(1):269–272. [PMC free article] [PubMed]
  • Tiku ML, Yan YP, Chen KY. Hydroxyl radical formation in chondrocytes and cartilage as detected by electron paramagnetic resonance spectroscopy using spin trapping reagents. Free Radic Res. 1998 Sep;29(3):177–187. [PubMed]
  • Flannery CR, Little CB, Hughes CE, Caterson B. Expression and activity of articular cartilage hyaluronidases. Biochem Biophys Res Commun. 1998 Oct 29;251(3):824–829. [PubMed]
  • Ratcliffe A, Tyler JA, Hardingham TE. Articular cartilage cultured with interleukin 1. Increased release of link protein, hyaluronate-binding region and other proteoglycan fragments. Biochem J. 1986 Sep 1;238(2):571–580. [PMC free article] [PubMed]
  • Fosang AJ, Tyler JA, Hardingham TE. Effect of interleukin-1 and insulin like growth factor-1 on the release of proteoglycan components and hyaluronan from pig articular cartilage in explant culture. Matrix. 1991 Feb;11(1):17–24. [PubMed]
  • Morales TI, Hascall VC. Correlated metabolism of proteoglycans and hyaluronic acid in bovine cartilage organ cultures. J Biol Chem. 1988 Mar 15;263(8):3632–3638. [PubMed]
  • Ng CK, Handley CJ, Preston BN, Robinson HC. The extracellular processing and catabolism of hyaluronan in cultured adult articular cartilage explants. Arch Biochem Biophys. 1992 Oct;298(1):70–79. [PubMed]
  • Nishida Y, D'Souza AL, Thonar EJ, Knudson W. Stimulation of hyaluronan metabolism by interleukin-1alpha in human articular cartilage. Arthritis Rheum. 2000 Jun;43(6):1315–1326. [PubMed]
  • Yamaguchi Y. Lecticans: organizers of the brain extracellular matrix. Cell Mol Life Sci. 2000 Feb;57(2):276–289. [PubMed]
  • Roughley PJ, Barrett AJ. The degradation of cartilage proteoglycans by tissue proteinases. Proteoglycan structure and its susceptibility to proteolysis. Biochem J. 1977 Dec 1;167(3):629–637. [PMC free article] [PubMed]
  • Barry FP, Rosenberg LC, Gaw JU, Gaw JU, Koob TJ, Neame PJ. N- and O-linked keratan sulfate on the hyaluronan binding region of aggrecan from mature and immature bovine cartilage. J Biol Chem. 1995 Sep 1;270(35):20516–20524. [PubMed]
  • Pratta MA, Tortorella MD, Arner EC. Age-related changes in aggrecan glycosylation affect cleavage by aggrecanase. J Biol Chem. 2000 Dec 15;275(50):39096–39102. [PubMed]
  • Lee ER, Lamplugh L, Leblond CP, Mordier S, Magny MC, Mort JS. Immunolocalization of the cleavage of the aggrecan core protein at the Asn341-Phe342 bond, as an indicator of the location of the metalloproteinases active in the lysis of the rat growth plate. Anat Rec. 1998 Sep;252(1):117–132. [PubMed]
  • Singer II, Scott S, Kawka DW, Bayne EK, Weidner JR, Williams HR, Mumford RA, Lark MW, McDonnell J, Christen AJ, et al. Aggrecanase and metalloproteinase-specific aggrecan neo-epitopes are induced in the articular cartilage of mice with collagen II-induced arthritis. Osteoarthritis Cartilage. 1997 Nov;5(6):407–418. [PubMed]
  • Lark MW, Bayne EK, Flanagan J, Harper CF, Hoerrner LA, Hutchinson NI, Singer II, Donatelli SA, Weidner JR, Williams HR, et al. Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. J Clin Invest. 1997 Jul 1;100(1):93–106. [PMC free article] [PubMed]
  • van Meurs JB, van Lent PL, Holthuysen AE, Singer II, Bayne EK, van den Berg WB. Kinetics of aggrecanase- and metalloproteinase-induced neoepitopes in various stages of cartilage destruction in murine arthritis. Arthritis Rheum. 1999 Jun;42(6):1128–1139. [PubMed]
  • Plaas AH, Sandy JD. A cartilage explant system for studies on aggrecan structure, biosynthesis and catabolism in discrete zones of the mammalian growth plate. Matrix. 1993 Mar;13(2):135–147. [PubMed]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem chemical compound records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records. Multiple substance records may contribute to the PubChem compound record.
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...