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

• The lecticans are a family of chondroitin sulfate proteoglycans including aggrecan, versican, neurocan, and brevican [6].
• Limited depolymerization of the side chains and preincubation of the PG-H/aggrecan with anti-glycosaminoglycan antibodies differentially reduced the inhibitory activity of the proteoglycan on cell motility [7].
• Digestions with chondroitinase ABC and hyaluronidase indicated that aggrecan, versican, neurocan, brevican, and phosphacan are retained in PNNs through binding to hyaluronan (HA) [8].
• Further, quantitative real-time PCR was used to demonstrate a down-regulation of steady state mRNA levels coding for aggrecan, collagen II, and link protein in chondrocytes exposed to endoplasmic reticulum stress-inducing conditions [9].
• Complexes of matrilin-1 and biglycan or decorin connect collagen VI microfibrils to both collagen II and aggrecan [10].

Chemical compound and disease context of Agc1

• Effects of brefeldin A on aggrecan core protein synthesis and maturation in rat chondrosarcoma cells [11].
• Addition of 1 microM retinoic acid to chondrosarcoma cultures resulted in aggrecan proteolysis with the release of greater than 90% of the cell layer aggrecan into the medium within 4 days [12].

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

• In the spinal cord at E13, aggrecan is present in the dorsal root entry zone, ventral funiculus, mantle layer, and floor plate, as well as in the dorsal root ganglia and ventral roots [17].
• Localization of aggrecan and versican in the developing rat central nervous system [17].
• At E19, aggrecan is seen throughout the cerebral cortex, whereas the distribution of versican is considerably more limited, being confined essentially to the marginal zone and subplate [17].
• There is strong staining of versican but not of aggrecan in the hippocampus and dentate gyrus by E19, whereas both aggrecan and alpha-versican are present in the fimbria [17].
• A rat chondrosarcoma cell line and primary bovine chondrocytes have been used to study cell-mediated aggrecan catabolism [12].

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

• MMP-13 in perivascular cells may be involved in removal of cartilage matrix proteins such as type II collagen and aggrecan [25].
• Transforming growth factor-beta treatment increased MAPK activity and Sox-9, aggrecan, and collagen type II gene expression [26].
• Cell growth was monitored, as was expression of several relevant genes: collagen types II and X; osteocalcin, Sox9, adipocyte FABP, MyoD, aggrecan, and others [27].
• Brevican is a member of the aggrecan family of chondroitin sulfate proteoglycans that is predominantly expressed in the nervous system [28].
• We have previously reported that loss of Bcl-2 expression alters chondrocyte morphology and modulates aggrecan expression via an apoptosis-independent pathway [29].

Analytical, diagnostic and therapeutic context of Agc1

• The radiolabeled perlecan and aggrecan were immunoprecipitated and analyzed by SDS-PAGE [30].
• Expression of aggrecan, collagen type I, II, IX and X and alkaline phosphatase genes was analyzed by RT-PCR, immunofluorescence and immunohistochemistry in comparison with unstimulated control cells [31].
• This CSPG and four additional large CSPGs were noted to be upregulated on western blotting by a polyclonal antibody directed against the G1 domain of the aggrecan protein core [32].
• Free chains of HAshort and reconstituted complexes with proteoglycan, link protein and aggrecan fragments were examined by electron microscopy after rotary shadowing [33].
• Treatment of chondrocyte cultures with GlcNBu for 6 days significantly increased levels of type II collagen and aggrecan mRNA as determined by Northern blot analysis [34].

References