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Gene Review

ACAN  -  aggrecan

Homo sapiens

Synonyms: AGC1, AGCAN, Aggrecan core protein, CSPCP, CSPG1, ...
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Disease relevance of ACAN


Psychiatry related information on ACAN


High impact information on ACAN

  • This defines the consensus fold for the Link module superfamily, which includes CD44, cartilage link protein, and aggrecan [9].
  • Arthritis induced by proteoglycan aggrecan G1 domain in BALB/c mice. Evidence for t cell involvement and the immunosuppressive influence of keratan sulfate on recognition of t and b cell epitopes [10].
  • In this study, two T cell epitopes residing on G1 within residues 70-84 (peptide G5) and 150-169 (peptide G9) were identified using synthetic peptides and aggrecan-specific T cell lines [10].
  • Our results are consistent with the presence in both normal and arthritic joint cartilage of proteolytic activity against aggrecan based on both classical MMPs and "aggrecanase."[11]
  • The levels of extracted VDIPEN neoepitope relative to collagen or aggrecan in both OA and RA samples were similar to those seen in age-matched control specimens [11].

Chemical compound and disease context of ACAN


Biological context of ACAN

  • Following BMP-6 induction, AGC1 gene expression in P9 cells increased 290-fold over P4 cells [17].
  • In response to specific media formulations, including transforming growth factor beta1 (TGFbeta1), these cells exhibit significant ability to differentiate into a chondrocyte-like phenotype, expressing cartilage-specific genes and proteins such as aggrecan and type II collagen [18].
  • The inverse correlation between serum levels of TIMP-1 and antigenic KS suggests that an upregulation of TIMP-1 synthesis might be responsible for the apparent suppression of cartilage aggrecan catabolism in patients with severe inflammatory changes [19].
  • In aggrecan, these are subject to alternative splicing [20].
  • Genomic structures revealed that all four HAPLN genes were similar in exon-intron organization and were also similar in genomic organization to the 5' exons for the CSPG core protein genes [21].

Anatomical context of ACAN

  • RESULTS: In normal adult articular chondrocytes the expression of both aggrecan and type II collagen genes was significantly down-regulated, whereas matrix-degrading proteases (except MMP-2), as well as the investigated cytokines, were induced by IL-1beta in a dose-dependent manner [22].
  • The proteoglycan aggrecan is an important major component of cartilage matrix that gives articular cartilage the ability to withstand compression [23].
  • We have analysed the aggrecan core protein species present in vivo in both articular cartilage and synovial fluids from normal, acutely injured and osteoarthritic joints [24].
  • Interaction of lumican with aggrecan in the aging human sclera [25].
  • The presence of fibrin glue positively influences on mRNA levels of collagen type II and aggrecan, while blood plasma enhanced only the level of collagen type II expression [26].

Associations of ACAN with chemical compounds

  • The chondroitin sulfate proteoglycan aggrecan forms link protein-stabilized complexes with hyaluronan (HA), via its N-terminal G1-domain, that provide cartilage with its load bearing properties [27].
  • Binding-competition experiments conducted using native and deglycosylated aggrecan provided direct evidence for interaction of the ADAMTS-4 cysteine-rich/spacer domains with aggrecan GAGs [3].
  • ACECLO and INDO increased AGG content by 25% in the alginate beads, while the other NSAID were without significant effect [28].
  • They fully blocked PGE2 production, inhibited IL-6 synthesis, and increased aggrecan synthesis [28].
  • Both aggrecanases showed a similar ability to cleave within the CS2 domain of bovine aggrecan irrespective of age, but showed a much lower ability to cleave within the CS2 domain of human aggrecan [29].

Physical interactions of ACAN

  • Efficient aggrecanase activity requires the presence of sulfated glycosaminoglycans (GAGs) attached to the aggrecan core protein, implying the contribution of substrate recognition/binding site(s) to ADAMTS-4 activity [3].
  • Fibulin-1 has affinity for the common site on versican but may bind to a different site on the aggrecan lectin domain [30].
  • TSG-6 also interacts with aggrecan, with a similar pH dependence, and this can be inhibited by HA [31].
  • Link protein (LP) is an abundant protein of cartilage which stabilizes the interaction of aggrecan with hyaluronic acid (HA) [32].
  • In this study, the rupture force of the single bond between hyaluronan and hyaluronan binding protein - the complex of the hyaluronan binding region of aggrecan and link protein - was directly measured with a nanomechanical testing system as 40+/-11 pN [33].

Enzymatic interactions of ACAN


Regulatory relationships of ACAN


Other interactions of ACAN

  • We show here, in digests with native human aggrecan, that purified ADAMTS4 cleaves primarily at the Glu(373)-Ala(374) site, but also, albeit slowly and secondarily, at the Asn(341)-Phe(342) site [34].
  • Surprisingly, the length of HA required to accommodate two G1-domains was found to be significantly larger for aggrecan than versican, which may reflect differences in the conformation of HA stabilized on binding these proteins [27].
  • RESULTS: Normal chondrocytes showed an increase in aggrecan mRNA and a decrease in MMP-3 mRNA within 1 hour following stimulation, with a return to baseline levels within 24 hours [43].
  • Accordingly, the presence of the cleavage products globular domain 1 (G1)-NITEGE(373) and G1-VDIPEN(341) in vivo has been widely interpreted as evidence for the specific involvement of ADAMTS enzymes and MMPs/cathepsin B, respectively, in aggrecan proteolysis in situ [34].
  • Bovine nasal cartilage was treated with affinity-purified fibronectin fragments and assayed for aggrecan breakdown by monitoring the release of glycosaminoglycans and the aggrecan neoepitope (1771)AGEG [44].

Analytical, diagnostic and therapeutic context of ACAN

  • This new structural information on aggrecan may account for the previously observed stiffness of the interglobular domains when viewed by rotary shadowing electron microscopy (Paulsson, M., Morgelin, M., Wiedemann, H., Beardmore-Gray, M., Dunham, D. G., Hardingham, T. E., Heinegard, D., Timpl, R., and Engel, J. (1987) Biochem. J. 245, 763-772) [45].
  • Gel filtration and protein cross-linking/matrix-assisted laser desorption ionization time-of-flight peptide fingerprinting showed that cLP and AG1 interact in the absence or presence of HA [27].
  • The reliability of the newly established coculture systems is confirmed by causing a clear decrease of intact aggrecan in the coculture medium plus concurrent appearance of additional smaller fragments and a reduction of chondrocyte aggrecan and collagen II gene expression in the presence of monocytes [46].
  • The mRNA of Sox9, type II collagen, and aggrecan were all significantly upregulated by PRP through RT-PCR [47].
  • Analysis of proteoglycan degradation products, both released into culture media and retained within the cartilage matrix, was performed by Western blotting using antibodies specific for the N- and C-terminal neoepitopes generated by aggrecanase- and MMP-related catabolism of the interglobular domain of the aggrecan core protein (IGD) [48].


  1. A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis. Gleghorn, L., Ramesar, R., Beighton, P., Wallis, G. Am. J. Hum. Genet. (2005) [Pubmed]
  2. Identification of a locus for a form of spondyloepiphyseal dysplasia on chromosome 15q26.1: exclusion of aggrecan as a candidate gene. Eyre, S., Roby, P., Wolstencroft, K., Spreckley, K., Aspinwall, R., Bayoumi, R., Al-Gazali, L., Ramesar, R., Beighton, P., Wallis, G. J. Med. Genet. (2002) [Pubmed]
  3. Autocatalytic cleavage of ADAMTS-4 (Aggrecanase-1) reveals multiple glycosaminoglycan-binding sites. Flannery, C.R., Zeng, W., Corcoran, C., Collins-Racie, L.A., Chockalingam, P.S., Hebert, T., Mackie, S.A., McDonagh, T., Crawford, T.K., Tomkinson, K.N., LaVallie, E.R., Morris, E.A. J. Biol. Chem. (2002) [Pubmed]
  4. Induction of arthritis in SCID mice by T cells specific for the "shared epitope" sequence in the G3 domain of human cartilage proteoglycan. Hanyecz, A., Bárdos, T., Berlo, S.E., Buzás, E., Nesterovitch, A.B., Mikecz, K., Glant, T.T. Arthritis Rheum. (2003) [Pubmed]
  5. Membrane type 1 matrix metalloproteinase (MT1-MMP) cleaves the recombinant aggrecan substrate rAgg1mut at the 'aggrecanase' and the MMP sites. Characterization of MT1-MMP catabolic activities on the interglobular domain of aggrecan. Büttner, F.H., Hughes, C.E., Margerie, D., Lichte, A., Tschesche, H., Caterson, B., Bartnik, E. Biochem. J. (1998) [Pubmed]
  6. Human aggrecan keratan sulfate undergoes structural changes during adolescent development. Brown, G.M., Huckerby, T.N., Bayliss, M.T., Nieduszynski, I.A. J. Biol. Chem. (1998) [Pubmed]
  7. Chondroitin sulfate proteoglycans are associated with the lesions of Alzheimer's disease. DeWitt, D.A., Silver, J., Canning, D.R., Perry, G. Exp. Neurol. (1993) [Pubmed]
  8. Chondroitin sulfate proteoglycans are a common component of neuronal inclusions and astrocytic reaction in neurodegenerative diseases. DeWitt, D.A., Richey, P.L., Praprotnik, D., Silver, J., Perry, G. Brain Res. (1994) [Pubmed]
  9. Solution structure of the link module: a hyaluronan-binding domain involved in extracellular matrix stability and cell migration. Kohda, D., Morton, C.J., Parkar, A.A., Hatanaka, H., Inagaki, F.M., Campbell, I.D., Day, A.J. Cell (1996) [Pubmed]
  10. Arthritis induced by proteoglycan aggrecan G1 domain in BALB/c mice. Evidence for t cell involvement and the immunosuppressive influence of keratan sulfate on recognition of t and b cell epitopes. Zhang, Y., Guerassimov, A., Leroux, J.Y., Cartman, A., Webber, C., Lalic, R., de Miguel, E., Rosenberg, L.C., Poole, A.R. J. Clin. Invest. (1998) [Pubmed]
  11. Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. Lark, M.W., Bayne, E.K., Flanagan, J., Harper, C.F., Hoerrner, L.A., Hutchinson, N.I., Singer, I.I., Donatelli, S.A., Weidner, J.R., Williams, H.R., Mumford, R.A., Lohmander, L.S. J. Clin. Invest. (1997) [Pubmed]
  12. Glucosamine sulfate modulates the levels of aggrecan and matrix metalloproteinase-3 synthesized by cultured human osteoarthritis articular chondrocytes. Dodge, G.R., Jimenez, S.A. Osteoarthr. Cartil. (2003) [Pubmed]
  13. Differential modulation of human melanoma cell metalloproteinase expression by alpha2beta1 integrin and CD44 triple-helical ligands derived from type IV collagen. Baronas-Lowell, D., Lauer-Fields, J.L., Borgia, J.A., Sferrazza, G.F., Al-Ghoul, M., Minond, D., Fields, G.B. J. Biol. Chem. (2004) [Pubmed]
  14. The intermediates of aggrecanase-dependent cleavage of aggrecan in rat chondrosarcoma cells treated with interleukin-1. Sandy, J.D., Thompson, V., Doege, K., Verscharen, C. Biochem. J. (2000) [Pubmed]
  15. Expression of a wide range of extracellular matrix molecules in the tendon and trochlea of the human superior oblique muscle. Milz, S., Regner, F., Putz, R., Benjamin, M. Invest. Ophthalmol. Vis. Sci. (2002) [Pubmed]
  16. Detection of aggrecanase- and MMP-generated catabolic neoepitopes in the rat iodoacetate model of cartilage degeneration. Janusz, M.J., Little, C.B., King, L.E., Hookfin, E.B., Brown, K.K., Heitmeyer, S.A., Caterson, B., Poole, A.R., Taiwo, Y.O. Osteoarthr. Cartil. (2004) [Pubmed]
  17. Extended passaging, but not aldehyde dehydrogenase activity, increases the chondrogenic potential of human adipose-derived adult stem cells. Estes, B.T., Wu, A.W., Storms, R.W., Guilak, F. J. Cell. Physiol. (2006) [Pubmed]
  18. Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6. Estes, B.T., Wu, A.W., Guilak, F. Arthritis Rheum. (2006) [Pubmed]
  19. Levels of circulating collagenase, stromelysin-1, and tissue inhibitor of matrix metalloproteinases 1 in patients with rheumatoid arthritis. Relationship to serum levels of antigenic keratan sulfate and systemic parameters of inflammation. Manicourt, D.H., Fujimoto, N., Obata, K., Thonar, E.J. Arthritis Rheum. (1995) [Pubmed]
  20. Alternative splicing in the aggrecan G3 domain influences binding interactions with tenascin-C and other extracellular matrix proteins. Day, J.M., Olin, A.I., Murdoch, A.D., Canfield, A., Sasaki, T., Timpl, R., Hardingham, T.E., Aspberg, A. J. Biol. Chem. (2004) [Pubmed]
  21. A hyaluronan binding link protein gene family whose members are physically linked adjacent to chondroitin sulfate proteoglycan core protein genes: the missing links. Spicer, A.P., Joo, A., Bowling, R.A. J. Biol. Chem. (2003) [Pubmed]
  22. Freshly isolated osteoarthritic chondrocytes are catabolically more active than normal chondrocytes, but less responsive to catabolic stimulation with interleukin-1beta. Fan, Z., Bau, B., Yang, H., Soeder, S., Aigner, T. Arthritis Rheum. (2005) [Pubmed]
  23. TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). Kashiwagi, M., Tortorella, M., Nagase, H., Brew, K. J. Biol. Chem. (2001) [Pubmed]
  24. Analysis of aggrecan in human knee cartilage and synovial fluid indicates that aggrecanase (ADAMTS) activity is responsible for the catabolic turnover and loss of whole aggrecan whereas other protease activity is required for C-terminal processing in vivo. Sandy, J.D., Verscharen, C. Biochem. J. (2001) [Pubmed]
  25. Interaction of lumican with aggrecan in the aging human sclera. Dunlevy, J.R., Rada, J.A. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  26. Fibrin gel improved the spatial uniformity and phenotype of human chondrocytes seeded on collagen scaffolds. Malicev, E., Radosavljevic, D., Velikonja, N.K. Biotechnol. Bioeng. (2007) [Pubmed]
  27. Expression and purification of functionally active hyaluronan-binding domains from human cartilage link protein, aggrecan and versican: formation of ternary complexes with defined hyaluronan oligosaccharides. Seyfried, N.T., McVey, G.F., Almond, A., Mahoney, D.J., Dudhia, J., Day, A.J. J. Biol. Chem. (2005) [Pubmed]
  28. Metabolism of human articular chondrocytes cultured in alginate beads. Longterm effects of interleukin 1beta and nonsteroidal antiinflammatory drugs. Sanchez, C., Mateus, M.M., Defresne, M.P., Crielaard, J.M., Reginster, J.Y., Henrotin, Y.E. J. Rheumatol. (2002) [Pubmed]
  29. Variations in aggrecan structure modulate its susceptibility to aggrecanases. Roughley, P.J., Barnett, J., Zuo, F., Mort, J.S. Biochem. J. (2003) [Pubmed]
  30. The proteoglycans aggrecan and Versican form networks with fibulin-2 through their lectin domain binding. Olin, A.I., Mörgelin, M., Sasaki, T., Timpl, R., Heinegård, D., Aspberg, A. J. Biol. Chem. (2001) [Pubmed]
  31. TSG-6 interacts with hyaluronan and aggrecan in a pH-dependent manner via a common functional element: implications for its regulation in inflamed cartilage. Parkar, A.A., Kahmann, J.D., Howat, S.L., Bayliss, M.T., Day, A.J. FEBS Lett. (1998) [Pubmed]
  32. Link protein is ubiquitously expressed in non-cartilaginous tissues where it enhances and stabilizes the interaction of proteoglycans with hyaluronic acid. Binette, F., Cravens, J., Kahoussi, B., Haudenschild, D.R., Goetinck, P.F. J. Biol. Chem. (1994) [Pubmed]
  33. Direct quantification of the rupture force of single hyaluronan/hyaluronan binding protein bonds. Liu, X., Sun, J.Q., Heggeness, M.H., Yeh, M.L., Luo, Z.P. FEBS Lett. (2004) [Pubmed]
  34. ADAMTS4 cleaves at the aggrecanase site (Glu373-Ala374) and secondarily at the matrix metalloproteinase site (Asn341-Phe342) in the aggrecan interglobular domain. Westling, J., Fosang, A.J., Last, K., Thompson, V.P., Tomkinson, K.N., Hebert, T., McDonagh, T., Collins-Racie, L.A., LaVallie, E.R., Morris, E.A., Sandy, J.D. J. Biol. Chem. (2002) [Pubmed]
  35. Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4). Tortorella, M.D., Liu, R.Q., Burn, T., Newton, R.C., Arner, E. Matrix Biol. (2002) [Pubmed]
  36. Membrane-type 1 MMP (MMP-14) cleaves at three sites in the aggrecan interglobular domain. Fosang, A.J., Last, K., Fujii, Y., Seiki, M., Okada, Y. FEBS Lett. (1998) [Pubmed]
  37. Quantification of a matrix metalloproteinase-generated aggrecan G1 fragment using monospecific anti-peptide serum. Lark, M.W., Williams, H., Hoernner, L.A., Weidner, J., Ayala, J.M., Harper, C.F., Christen, A., Olszewski, J., Konteatis, Z., Webber, R. Biochem. J. (1995) [Pubmed]
  38. Cleavage of native cartilage aggrecan by neutrophil collagenase (MMP-8) is distinct from endogenous cleavage by aggrecanase. Arner, E.C., Decicco, C.P., Cherney, R., Tortorella, M.D. J. Biol. Chem. (1997) [Pubmed]
  39. Inhibition of bovine nasal cartilage degradation by selective matrix metalloproteinase inhibitors. Bottomley, K.M., Borkakoti, N., Bradshaw, D., Brown, P.A., Broadhurst, M.J., Budd, J.M., Elliott, L., Eyers, P., Hallam, T.J., Handa, B.K., Hill, C.H., James, M., Lahm, H.W., Lawton, G., Merritt, J.E., Nixon, J.S., Röthlisberger, U., Whittle, A., Johnson, W.H. Biochem. J. (1997) [Pubmed]
  40. Secreted chondroitin sulfate proteoglycan of human B cell lines binds to the complement protein C1q and inhibits complex formation of C1. Kirschfink, M., Blase, L., Engelmann, S., Schwartz-Albiez, R. J. Immunol. (1997) [Pubmed]
  41. Neuronal matrix metalloproteinase-2 degrades and inactivates a neurite-inhibiting chondroitin sulfate proteoglycan. Zuo, J., Ferguson, T.A., Hernandez, Y.J., Stetler-Stevenson, W.G., Muir, D. J. Neurosci. (1998) [Pubmed]
  42. Specific growth factors during the expansion and redifferentiation of adult human articular chondrocytes enhance chondrogenesis and cartilaginous tissue formation in vitro. Jakob, M., Démarteau, O., Schäfer, D., Hintermann, B., Dick, W., Heberer, M., Martin, I. J. Cell. Biochem. (2001) [Pubmed]
  43. Mechanotransduction via integrins and interleukin-4 results in altered aggrecan and matrix metalloproteinase 3 gene expression in normal, but not osteoarthritic, human articular chondrocytes. Millward-Sadler, S.J., Wright, M.O., Davies, L.W., Nuki, G., Salter, D.M. Arthritis Rheum. (2000) [Pubmed]
  44. Identification of fibronectin neoepitopes present in human osteoarthritic cartilage. Zack, M.D., Arner, E.C., Anglin, C.P., Alston, J.T., Malfait, A.M., Tortorella, M.D. Arthritis Rheum. (2006) [Pubmed]
  45. The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B. Fosang, A.J., Neame, P.J., Last, K., Hardingham, T.E., Murphy, G., Hamilton, J.A. J. Biol. Chem. (1992) [Pubmed]
  46. Paracrine interactions of chondrocytes and macrophages in cartilage degradation: articular chondrocytes provide factors that activate macrophage-derived pro-gelatinase B (pro-MMP-9). Dreier, R., Wallace, S., Fuchs, S., Bruckner, P., Grässel, S. J. Cell. Sci. (2001) [Pubmed]
  47. Tissue-engineered intervertebral disc and chondrogenesis using human nucleus pulposus regulated through TGF-beta1 in platelet-rich plasma. Chen, W.H., Lo, W.C., Lee, J.J., Su, C.H., Lin, C.T., Liu, H.Y., Lin, T.W., Lin, W.C., Huang, T.Y., Deng, W.P. J. Cell. Physiol. (2006) [Pubmed]
  48. Aggrecanase versus matrix metalloproteinases in the catabolism of the interglobular domain of aggrecan in vitro. Little, C.B., Flannery, C.R., Hughes, C.E., Mort, J.S., Roughley, P.J., Dent, C., Caterson, B. Biochem. J. (1999) [Pubmed]
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