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Gene Review

Acan  -  aggrecan

Mus musculus

Synonyms: Agc, Agc1, Aggrecan core protein, CSPCP, Cartilage-specific proteoglycan core protein, ...
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Disease relevance of Acan


High impact information on Acan


Chemical compound and disease context of Acan

  • Monoclonal antibodies that recognize epitopes in these domains were raised against Swarm rat chondrosarcoma aggrecan that was either denatured through reduction and alkylation or partially deglycosylated through chondroitinase ABC digestion or alkali elimination, the latter with or without sulfite addition [9].

Biological context of Acan

  • The discordance of gene expression in cmd chondrocytes may be additional factors contributing to the disrupted cellular architecture of the growth plate resulting from the primary absence of aggrecan [1].
  • To investigate transcriptional regulation of the aggrecan gene by OP-1, we constructed a clone containing a 1 kb region of the 5'-upstream sequence of the mouse aggrecan gene fused to the promoter-less luciferase reporter gene in pGL2-Basic vector [10].
  • The G3 domain of aggrecan, which does not contain an EGF-like motif, did not inhibit mesenchymal chondrogenesis [11].
  • Although the function of these domains is not understood, the uniform expression of the EGF2 domain may indicate a general role of this aggrecan module, while the expression of the EGF1 domain may reflect species specificity [12].
  • The overall amino acid sequence of the mouse aggrecan shows 91.6% identity to rat and 72.5% to human aggrecan [13].

Anatomical context of Acan

  • Immunostaining showed that versican was mainly localized in the interterritorial zone of the articular surface at 2 weeks in mice, whereas aggrecan was in the pericellular zone of prehypertrophic and hypertrophic cells of the growth plate [14].
  • Biochemical analysis of normal articular cartilage and aggrecan-null cartilage from cmd (cartilage matrix deficiency)/cmd mice revealed that versican was present as a proteoglycan aggregate with both link protein and hyaluronan [14].
  • In vitro studies using primary chondrocyte cultures showed that both CDMP-1 and CDMP-2 stimulated equally de novo synthesis of proteoglycan aggrecan in a concentration-dependent manner [15].
  • We investigated the expression pattern of versican, aggrecan, link protein and hyaluronan in the developing limb bud cartilage of the fetal mouse using in situ hybridization and/or immunohistochemistry [16].
  • Versican mRNA expression rapidly disappeared from the tibial cartilage, as cartilage formation progressed during E13-15, but the immunostaining was gradually replaced by aggrecan immunostaining from the diaphysis [16].

Associations of Acan with chemical compounds

  • Chondroitin sulfate chains of versican digested with chondroitinase ABC contained 71% nonsulfated and 28% 4-sulfated unsaturated disaccharides, whereas those of aggrecan contained 25% nonsulfated and 70% 4-sulfated [14].
  • Finally, mice lacking matrilin-1, a non-collagenous glycoprotein that binds to both collagen fibrils and aggrecan, develop normally without detectable abnormalities in their skeleton [17].
  • Following retinoic acid or IL-1alpha stimulation of cartilage explants, aggrecan fragments in medium and extracts contained SELE(1279) or FREEE(1467) C-terminal sequences [18].
  • No difference in Safranin O staining or aggrecan cleavage site neoepitope abundance was seen [19].
  • At confluency, TGF-beta induced Agc expression within 3 h, and cycloheximide blocked this induction, indicating that de novo protein synthesis is essential for this response [20].

Physical interactions of Acan

  • Although matrilin 1 interacts with the collagen II and aggrecan networks of cartilage, suggesting that it may play a role in cartilage tissue organization, studies of collagen extractability indicated that collagen fibril maturation and covalent cross-linking were unaffected by the absence of matrilin 1 [21].
  • Furthermore, the chondroitin sulfate attachment region of aggrecan received GAG side chains more readily when coupled to the G3 domain of aggrecan than when coupled to domains II and III of perlecan [22].

Enzymatic interactions of Acan

  • Further analysis of the media showed the presence of Aggrecanase-cleaved aggrecan fragments, a signature of matrix degradation [23].

Regulatory relationships of Acan

  • The purpose of this study was to examine whether SOX9 modulates aggrecan gene expression and to further identify molecules that regulate Sox9 expression in TC6 cells [5].
  • Compressive force promotes sox9, type II collagen and aggrecan and inhibits IL-1beta expression resulting in chondrogenesis in mouse embryonic limb bud mesenchymal cells [24].
  • Arthritic NADPH oxidase-deficient mice showed irreversible cartilage damage as judged by the enhanced aggrecan VDIPEN expression, and chondrocyte death [25].
  • In cultures of the mouse ATDC5 cell line, MTf is developmentally expressed in parallel with the expression of type II collagen and aggrecan, in the pattern commensurate with the onset of chondrogenesis to form cartilage nodules [26].

Other interactions of Acan


Analytical, diagnostic and therapeutic context of Acan


  1. Disrupted expression of matrix genes in the growth plate of the mouse cartilage matrix deficiency (cmd) mutant. Wai, A.W., Ng, L.J., Watanabe, H., Yamada, Y., Tam, P.P., Cheah, K.S. Dev. Genet. (1998) [Pubmed]
  2. Controlled conversion of an immortalized mesodermal progenitor cell towards osteogenic, chondrogenic, or adipogenic pathways. Poliard, A., Nifuji, A., Lamblin, D., Plee, E., Forest, C., Kellermann, O. J. Cell Biol. (1995) [Pubmed]
  3. Dwarfism and age-associated spinal degeneration of heterozygote cmd mice defective in aggrecan. Watanabe, H., Nakata, K., Kimata, K., Nakanishi, I., Yamada, Y. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  4. Induction of arthritis in BALB/c mice by cartilage link protein: involvement of distinct regions recognized by T and B lymphocytes. Zhang, Y., Guerassimov, A., Leroux, J.Y., Cartman, A., Webber, C., Lalic, R., de Miguel, E., Rosenberg, L.C., Poole, A.R. Am. J. Pathol. (1998) [Pubmed]
  5. SOX9 enhances aggrecan gene promoter/enhancer activity and is up-regulated by retinoic acid in a cartilage-derived cell line, TC6. Sekiya, I., Tsuji, K., Koopman, P., Watanabe, H., Yamada, Y., Shinomiya, K., Nifuji, A., Noda, M. J. Biol. Chem. (2000) [Pubmed]
  6. Mice lacking link protein develop dwarfism and craniofacial abnormalities. Watanabe, H., Yamada, Y. Nat. Genet. (1999) [Pubmed]
  7. Mouse cartilage matrix deficiency (cmd) caused by a 7 bp deletion in the aggrecan gene. Watanabe, H., Kimata, K., Line, S., Strong, D., Gao, L.Y., Kozak, C.A., Yamada, Y. Nat. Genet. (1994) [Pubmed]
  8. Expression of the heparan sulfate proteoglycan, perlecan, during mouse embryogenesis and perlecan chondrogenic activity in vitro. French, M.M., Smith, S.E., Akanbi, K., Sanford, T., Hecht, J., Farach-Carson, M.C., Carson, D.D. J. Cell Biol. (1999) [Pubmed]
  9. Monoclonal antibodies directed against epitopes within the core protein structure of the large aggregating proteoglycan (aggrecan) from the swarm rat chondrosarcoma. Calabro, A., Hascall, V.C., Caterson, B. Arch. Biochem. Biophys. (1992) [Pubmed]
  10. Identification of an osteogenic protein-1 responsive element in the aggrecan promoter. Yeh, L.C., Lee, J.C. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  11. The G3 domain of versican inhibits mesenchymal chondrogenesis via the epidermal growth factor-like motifs. Zhang, Y., Cao, L., Kiani, C.G., Yang, B.L., Yang, B.B. J. Biol. Chem. (1998) [Pubmed]
  12. Expression of alternatively spliced epidermal growth factor-like domains in aggrecans of different species. Evidence for a novel module. Fülöp, C., Walcz, E., Valyon, M., Glant, T.T. J. Biol. Chem. (1993) [Pubmed]
  13. Complete coding sequence, deduced primary structure, chromosomal localization, and structural analysis of murine aggrecan. Walcz, E., Deák, F., Erhardt, P., Coulter, S.N., Fülöp, C., Horvath, P., Doege, K.J., Glant, T.T. Genomics (1994) [Pubmed]
  14. Identification and characterization of versican/PG-M aggregates in cartilage. Matsumoto, K., Kamiya, N., Suwan, K., Atsumi, F., Shimizu, K., Shinomura, T., Yamada, Y., Kimata, K., Watanabe, H. J. Biol. Chem. (2006) [Pubmed]
  15. Cartilage-derived morphogenetic proteins and osteogenic protein-1 differentially regulate osteogenesis. Erlacher, L., McCartney, J., Piek, E., ten Dijke, P., Yanagishita, M., Oppermann, H., Luyten, F.P. J. Bone Miner. Res. (1998) [Pubmed]
  16. In situ hybridization and immunohistochemistry of versican, aggrecan and link protein, and histochemistry of hyaluronan in the developing mouse limb bud cartilage. Shibata, S., Fukada, K., Imai, H., Abe, T., Yamashita, Y. J. Anat. (2003) [Pubmed]
  17. The role of collagen II and cartilage fibril-associated molecules in skeletal development. Aszódi, A., Hunziker, E.B., Olsen, B.R., Fässler, R. Osteoarthr. Cartil. (2001) [Pubmed]
  18. ADAMTS-5 Deficiency Does Not Block Aggrecanolysis at Preferred Cleavage Sites in the Chondroitin Sulfate-rich Region of Aggrecan. East, C.J., Stanton, H., Golub, S.B., Rogerson, F.M., Fosang, A.J. J. Biol. Chem. (2007) [Pubmed]
  19. Lack of tissue inhibitor of metalloproteinases-3 results in an enhanced inflammatory response in antigen-induced arthritis. Mahmoodi, M., Sahebjam, S., Smookler, D., Khokha, R., Mort, J.S. Am. J. Pathol. (2005) [Pubmed]
  20. Transcriptional cross-talk between Smad, ERK1/2, and p38 mitogen-activated protein kinase pathways regulates transforming growth factor-beta-induced aggrecan gene expression in chondrogenic ATDC5 cells. Watanabe, H., de Caestecker, M.P., Yamada, Y. J. Biol. Chem. (2001) [Pubmed]
  21. Normal skeletal development of mice lacking matrilin 1: redundant function of matrilins in cartilage? Aszódi, A., Bateman, J.F., Hirsch, E., Baranyi, M., Hunziker, E.B., Hauser, N., Bösze, Z., Fässler, R. Mol. Cell. Biol. (1999) [Pubmed]
  22. Non-glycosaminoglycan bearing domains of perlecan and aggrecan influence the utilization of sites for heparan and chondroitin sulfate synthesis. Doege, K., Chen, X., Cornuet, P.K., Hassell, J. Matrix Biol. (1997) [Pubmed]
  23. Immortalized cell lines from mouse xiphisternum preserve chondrocyte phenotype. Majumdar, M.K., Chockalingam, P.S., Bhat, R.A., Sheldon, R., Keohan, C., Blanchet, T., Glasson, S., Morris, E.A. J. Cell. Physiol. (2006) [Pubmed]
  24. Compressive force promotes sox9, type II collagen and aggrecan and inhibits IL-1beta expression resulting in chondrogenesis in mouse embryonic limb bud mesenchymal cells. Takahashi, I., Nuckolls, G.H., Takahashi, K., Tanaka, O., Semba, I., Dashner, R., Shum, L., Slavkin, H.C. J. Cell. Sci. (1998) [Pubmed]
  25. Deficiency of NADPH oxidase components p47phox and gp91phox caused granulomatous synovitis and increased connective tissue destruction in experimental arthritis models. van de Loo, F.A., Bennink, M.B., Arntz, O.J., Smeets, R.L., Lubberts, E., Joosten, L.A., van Lent, P.L., Coenen-de Roo, C.J., Cuzzocrea, S., Segal, B.H., Holland, S.M., van den Berg, W.B. Am. J. Pathol. (2003) [Pubmed]
  26. Membrane-bound transferrin-like protein (MTf): structure, evolution and selective expression during chondrogenic differentiation of mouse embryonic cells. Nakamasu, K., Kawamoto, T., Shen, M., Gotoh, O., Teramoto, M., Noshiro, M., Kato, Y. Biochim. Biophys. Acta (1999) [Pubmed]
  27. Gene homologs on human chromosome 15q21-q26 and a chicken microchromosome identify a new conserved segment. Jones, C.T., Morrice, D.R., Paton, I.R., Burt, D.W. Mamm. Genome (1997) [Pubmed]
  28. Impact of mutations of cartilage matrix genes on matrix structure, gene activity and chondrogenesis. So, C.L., Kaluarachchi, K., Tam, P.P., Cheah, K.S. Osteoarthr. Cartil. (2001) [Pubmed]
  29. Establishment of a clonal human mesenchymal cell line that retains multilineage differentiation capacity from a spinal hamartoma. Doiguchi, Y., Tsukazaki, T., Tomonaga, T., Nobuta, M., Fujita, S., Hayashi, T., Nagai, K., Matsumoto, T., Shindo, H., Yamaguchi, A. Cell Tissue Res. (2004) [Pubmed]
  30. Localization and inhibitory effect of basic fibroblast growth factor on chondrogenesis in cultured mouse mandibular condyle. Ogawa, T., Shimokawa, H., Fukada, K., Suzuki, S., Shibata, S., Ohya, K., Kuroda, T. J. Bone Miner. Metab. (2003) [Pubmed]
  31. Histochemical, immunofluorescence, and ultrastructural differences in fetal cartilage among three genetically distinct chondrodystrophic mice. Seegmiller, R.E., Brown, K., Chandrasekhar, S. Teratology (1988) [Pubmed]
  32. Chondrogenic differentiation of clonal mouse embryonic cell line ATDC5 in vitro: differentiation-dependent gene expression of parathyroid hormone (PTH)/PTH-related peptide receptor. Shukunami, C., Shigeno, C., Atsumi, T., Ishizeki, K., Suzuki, F., Hiraki, Y. J. Cell Biol. (1996) [Pubmed]
  33. Immune reactivity to connective tissue antigens in pristane induced arthritis. Morgan, R., Wu, B., Song, Z., Wooley, P.H. J. Rheumatol. (2004) [Pubmed]
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