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Gene Review

Acan  -  aggrecan

Rattus norvegicus

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

  • Much higher concentrations of rat chondrosarcoma chondroitin sulfate proteoglycan (aggrecan) core proteins had no significant effect in these assays [1].
  • Overexpression of a single helix-loop-helix-type transcription factor, scleraxis, enhances aggrecan gene expression in osteoblastic osteosarcoma ROS17/2.8 cells [2].
  • Focal cerebral ischemia induces changes in both MMP-13 and aggrecan around individual neurons [3].
  • At P9, aggrecan and versican immunoreactivity is most intense in the inner and outer plexiform and ganglion cell layers, accompanied by diffuse staining in the inner and outer nuclear layers [4].
  • Importantly, the results suggest that exposure of chondrocytes to interleukin-1 in inflamed joints, such as occurs in rheumatoid arthritis, leads to the rapid loss of coordination of the synthesis of aggrecan and hyaluronan, two of the critical constituents of the proteoglycan aggregate [5].

High impact information on Agc1


Chemical compound and disease context of Agc1


Biological context of Agc1

  • DNA comprising the rat aggrecan gene (83 kb including the 30-kb first intron) was surveyed for active elements, which would impart selective expression to the aggrecan promoter in transfection assays in vitro [13].
  • A 4.7-kb DNA fragment (P3) with cell-specific enhancer activity was discovered approximately 12 kb upstream of the transcription start site; this active DNA fragment is position- and orientation-independent, and strongly stimulates aggrecan promoter expression in chondrocytes, while weakly suppressing transcription in fibroblasts [13].
  • Chemical and enzymatic deglycosylation show that the differences revealed by the three antibodies arise from differential glycosylation of aggrecan [14].
  • These results suggest that the vitamin D metabolite activates a new pattern of gene expression which results in a more rapid turnover of the aggrecan mRNA [15].
  • Consistent with these in vivo effects, rCTGF/CCN2 enhanced type II collagen and aggrecan mRNA expression in mouse bone marrow-derived stromal cells and induced chondrogenesis in vitro [16].

Anatomical context of Agc1


Associations of Agc1 with chemical compounds

  • The localization of aggrecan and mRNA splice variants of versican in the developing rat central nervous system has been examined by using specific polyclonal antibodies to the nonhomologous glycosaminoglycan attachment regions of these hyaluronan-binding chondroitin sulfate proteoglycans [17].
  • Removal of brefeldin A rapidly restored chondroitin sulfate chain elongation and sulfation on the aggrecan core protein precursor reaching 100% of control in 2 h and consistently establishing a higher steady state rate (up to 120%) by 4 h [18].
  • It is suggested that cell-mediated catabolism of the aggrecan interglobular domain in these culture systems, whether promoted by retinoic acid or interleukin 1, primarily involves cleavage of the Glu373-Ala374 bond by aggrecanase [12].
  • The binding properties of the C-type CRD from the cartilage proteoglycan, aggrecan, can also be modeled based on the mannose-binding CRD frame-work [19].
  • Experiments using the transcriptional inhibitor actinomycin D also supported a nondirect effect of 1,25(OH)2D3 on the expression of the aggrecan gene [15].

Physical interactions of Agc1

  • IGFBP-2 also bound the proteoglycan aggrecan, an effect reduced by digestion of its glycosaminoglycans [20].
  • The structure of the rat aggrecan CLD in a Ca(2+)-dependent complex with fibronectin type III repeats 3-5 of rat tenascin-R provides detailed support for such crosslinking [21].

Regulatory relationships of Agc1

  • This work indicates that neurons can directly regulate the composition of their extracellular matrix by regulated synthesis and differential glycosylation of aggrecan in a cell type-specific manner [14].
  • ET-1 also stimulated proteoglycan synthesis and increased the amount of mRNA specific for the aggrecan gene [22].
  • In this article, we report that Bcl-2 affects the morphology and regulates the expression of aggrecan in a rat chondrocyte cell line (IRC) [23].
  • IGF-1 also induces in cells from 1-month old rats an increase in the expression of mRNAs specific for aggrecan and type II collagen molecules as shown with RT-PCR [24].

Other interactions of Agc1


Analytical, diagnostic and therapeutic context of Agc1


  1. Functional characterization of chondroitin sulfate proteoglycans of brain: interactions with neurons and neural cell adhesion molecules. Grumet, M., Flaccus, A., Margolis, R.U. J. Cell Biol. (1993) [Pubmed]
  2. Overexpression of a single helix-loop-helix-type transcription factor, scleraxis, enhances aggrecan gene expression in osteoblastic osteosarcoma ROS17/2.8 cells. Liu, Y., Watanabe, H., Nifuji, A., Yamada, Y., Olson, E.N., Noda, M. J. Biol. Chem. (1997) [Pubmed]
  3. Focal cerebral ischemia induces changes in both MMP-13 and aggrecan around individual neurons. Nagel, S., Sandy, J.D., Meyding-Lamade, U., Schwark, C., Bartsch, J.W., Wagner, S. Brain Res. (2005) [Pubmed]
  4. Developmental changes of aggrecan, versican and neurocan in the retina and optic nerve. Popp, S., Maurel, P., Andersen, J.S., Margolis, R.U. Exp. Eye Res. (2004) [Pubmed]
  5. Differential effects of interleukin-1 on hyaluronan and proteoglycan metabolism in two compartments of the matrix formed by articular chondrocytes maintained in alginate. D'Souza, A.L., Masuda, K., Otten, L.M., Nishida, Y., Knudson, W., Thonar, E.J. Arch. Biochem. Biophys. (2000) [Pubmed]
  6. The C-type lectin domains of lecticans, a family of aggregating chondroitin sulfate proteoglycans, bind tenascin-R by protein-protein interactions independent of carbohydrate moiety. Aspberg, A., Miura, R., Bourdoulous, S., Shimonaka, M., Heinegârd, D., Schachner, M., Ruoslahti, E., Yamaguchi, Y. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  7. Inhibitory effects of PG-H/aggrecan and PG-M/versican on avian neural crest cell migration. Perris, R., Perissinotto, D., Pettway, Z., Bronner-Fraser, M., Mörgelin, M., Kimata, K. FASEB J. (1996) [Pubmed]
  8. Composition of perineuronal net extracellular matrix in rat brain: a different disaccharide composition for the net-associated proteoglycans. Deepa, S.S., Carulli, D., Galtrey, C., Rhodes, K., Fukuda, J., Mikami, T., Sugahara, K., Fawcett, J.W. J. Biol. Chem. (2006) [Pubmed]
  9. Multiple signals induce endoplasmic reticulum stress in both primary and immortalized chondrocytes resulting in loss of differentiation, impaired cell growth, and apoptosis. Yang, L., Carlson, S.G., McBurney, D., Horton, W.E. J. Biol. Chem. (2005) [Pubmed]
  10. Complexes of matrilin-1 and biglycan or decorin connect collagen VI microfibrils to both collagen II and aggrecan. Wiberg, C., Klatt, A.R., Wagener, R., Paulsson, M., Bateman, J.F., Heinegård, D., Mörgelin, M. J. Biol. Chem. (2003) [Pubmed]
  11. Effects of brefeldin A on aggrecan core protein synthesis and maturation in rat chondrosarcoma cells. Calabro, A., Hascall, V.C. J. Biol. Chem. (1994) [Pubmed]
  12. Cell-mediated catabolism of aggrecan. Evidence that cleavage at the "aggrecanase" site (Glu373-Ala374) is a primary event in proteolysis of the interglobular domain. Lark, M.W., Gordy, J.T., Weidner, J.R., Ayala, J., Kimura, J.H., Williams, H.R., Mumford, R.A., Flannery, C.R., Carlson, S.S., Iwata, M. J. Biol. Chem. (1995) [Pubmed]
  13. A remote upstream element regulates tissue-specific expression of the rat aggrecan gene. Doege, K., Hall, L.B., McKinnon, W., Chen, L., Stephens, D.T., Garrison, K. J. Biol. Chem. (2002) [Pubmed]
  14. Aggrecan glycoforms contribute to the molecular heterogeneity of perineuronal nets. Matthews, R.T., Kelly, G.M., Zerillo, C.A., Gray, G., Tiemeyer, M., Hockfield, S. J. Neurosci. (2002) [Pubmed]
  15. 1,25-Dihydroxyvitamin D3 down-regulates aggrecan proteoglycan expression in immortalized rat chondrocytes through a post-transcriptional mechanism. Horton, W.E., Balakir, R., Precht, P., Liang, C.T. J. Biol. Chem. (1991) [Pubmed]
  16. Regeneration of defects in articular cartilage in rat knee joints by CCN2 (connective tissue growth factor). Nishida, T., Kubota, S., Kojima, S., Kuboki, T., Nakao, K., Kushibiki, T., Tabata, Y., Takigawa, M. J. Bone Miner. Res. (2004) [Pubmed]
  17. Localization of aggrecan and versican in the developing rat central nervous system. Popp, S., Andersen, J.S., Maurel, P., Margolis, R.U. Dev. Dyn. (2003) [Pubmed]
  18. Differential effects of brefeldin A on chondroitin sulfate and hyaluronan synthesis in rat chondrosarcoma cells. Calabro, A., Hascall, V.C. J. Biol. Chem. (1994) [Pubmed]
  19. Binding of sugar ligands to Ca(2+)-dependent animal lectins. II. Generation of high-affinity galactose binding by site-directed mutagenesis. Iobst, S.T., Drickamer, K. J. Biol. Chem. (1994) [Pubmed]
  20. Insulin-like growth factor binding protein-2 binds to cell surface proteoglycans in the rat brain olfactory bulb. Russo, V.C., Bach, L.A., Fosang, A.J., Baker, N.L., Werther, G.A. Endocrinology (1997) [Pubmed]
  21. Structural basis for interactions between tenascins and lectican C-type lectin domains: evidence for a crosslinking role for tenascins. Lundell, A., Olin, A.I., Mörgelin, M., al-Karadaghi, S., Aspberg, A., Logan, D.T. Structure (2004) [Pubmed]
  22. Endothelin 1 receptors, signal transduction and effects on DNA and proteoglycan synthesis in rat articular chondrocytes. Khatib, A.M., Lomri, A., Moldovan, F., Soliman, H., Fiet, J., Mitrovic, D.R. Cytokine (1998) [Pubmed]
  23. Bcl-2 regulates chondrocyte morphology and aggrecan gene expression independent of caspase activation and full apoptosis. Feng, L., Balakir, R., Precht, P., Horton, W.E. J. Cell. Biochem. (1999) [Pubmed]
  24. Articular chondrocytes from aging rats respond poorly to insulin-like growth factor-1: an altered signaling pathway. Messai, H., Duchossoy, Y., Khatib, A.M., Panasyuk, A., Mitrovic, D.R. Mech. Ageing Dev. (2000) [Pubmed]
  25. Immunolocalization of matrix metalloproteinase-13 on bone surface under osteoclasts in rat tibia. Nakamura, H., Sato, G., Hirata, A., Yamamoto, T. Bone (2004) [Pubmed]
  26. Differentiation of mesenchymal stem cells towards a nucleus pulposus-like phenotype in vitro: implications for cell-based transplantation therapy. Risbud, M.V., Albert, T.J., Guttapalli, A., Vresilovic, E.J., Hillibrand, A.S., Vaccaro, A.R., Shapiro, I.M. Spine. (2004) [Pubmed]
  27. In vitro chondrocyte differentiation using costochondral chondrocytes as a source of primary rat chondrocyte cultures: an improved isolation and cryopreservation method. Gartland, A., Mechler, J., Mason-Savas, A., MacKay, C.A., Mailhot, G., Marks, S.C., Odgren, P.R. Bone (2005) [Pubmed]
  28. cDNA cloning and the identification of an aggrecanase-like cleavage site in rat brevican. Yamada, H., Watanabe, K., Shimonaka, M., Yamasaki, M., Yamaguchi, Y. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  29. Coordinate down-regulation of cartilage matrix gene expression in Bcl-2 deficient chondrocytes is associated with decreased SOX9 expression and decreased mRNA stability. Kinkel, M.D., Horton, W.E. J. Cell. Biochem. (2003) [Pubmed]
  30. Perlecan is a component of cartilage matrix and promotes chondrocyte attachment. SundarRaj, N., Fite, D., Ledbetter, S., Chakravarti, S., Hassell, J.R. J. Cell. Sci. (1995) [Pubmed]
  31. Transgene-activated mesenchymal cells for articular cartilage repair: a comparison of primary bone marrow-, perichondrium/periosteum- and fat-derived cells. Park, J., Gelse, K., Frank, S., von der Mark, K., Aigner, T., Schneider, H. The journal of gene medicine. (2006) [Pubmed]
  32. Hyperoxia alone causes changes in lung proteoglycans and hyaluronan in neonatal rat pups. Juul, S.E., Krueger, R.C., Scofield, L., Hershenson, M.B., Schwartz, N.B. Am. J. Respir. Cell Mol. Biol. (1995) [Pubmed]
  33. Evidence of a defined spatial arrangement of hyaluronate in the central filament of cartilage proteoglycan aggregates. Mörgelin, M., Paulsson, M., Heinegård, D., Aebi, U., Engel, J. Biochem. J. (1995) [Pubmed]
  34. N-butyryl glucosamine increases matrix gene expression by chondrocytes. Poustie, M.W., Carran, J., McEleney, K., Dixon, S.J., Anastassiades, T.P., Bernier, S.M. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
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