Disease relevance of ADAMTS5

• As demonstrated by immunohistochemistry and confocal microscopy in situ, ADAMTS5 expression is confined to proliferating glioblastoma cells of surgical tumor sections and with lower intensity to astroglial cells in normal brain sections, as opposed to brevican [1].
• Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis [2].
• After surgically induced joint instability, there was significant reduction in the severity of cartilage destruction in the ADAMTS5 knockout mice compared with wild-type mice [2].
• Forced expression of ADAMTS-5 in glioma cell lines stimulated cell invasion [3].
• Metalloproteinase ADAMTS-1 but not ADAMTS-5 is manifold overexpressed in neurodegenerative disorders as Down syndrome, Alzheimer's and Pick's disease [4].

High impact information on ADAMTS5

• Finally, the third group comprises genes that are expressed in cells of endothelial tissue and cartilage including E-selectin, fibronectin-1, matrix Gla protein, and aggrecanase-2 [5].
• Here we show that despite ablation of ADAMTS-5 activity, aggrecanolysis can still occur at two preferred sites in the chondroitin sulfate-rich region [6].
• ADAMTS-5, but not ADAMTS-1, -4, or -9, was up-regulated 8-fold by retinoic acid and 17-fold by IL-1alpha treatment [6].
• ADAMTS-5 Deficiency Does Not Block Aggrecanolysis at Preferred Cleavage Sites in the Chondroitin Sulfate-rich Region of Aggrecan [6].
• RESULTS: ADAMTS-4, but not ADAMTS-5, was induced in human chondrocytes infected with B burgdorferi [7].

Biological context of ADAMTS5

• These genes are differentially regulated during mouse embryogenesis and in adult tissues, with Adamts5 highly expressed in the peri-implantation period in embryo and trophoblast [8].
• In this study we have characterized the substrate specificity of ADAM-TS5 and compared it with that of ADAM-TS4 [9].
• Drug treatment also significantly decreased collagenase (p < 0.02) and metalloprotease (p < 0.04) activities, as well as the levels of gene expression of MMP-1 (p < 0.01), MMP-13 (p < 0.05), cathepsin K, and ADAMTS-5 (p = 0.01) [10].
• CONCLUSION: HMW-HA may have a structure-modifying effect for OA by down-regulation of aggrecanase-2 in FLS [11].
• With regard to cartilage pathobiology, ADAMTS-5 is the major aggrecanase responsible for cartilage destruction, whereas inadequate control of oxidative stress and decreased expression of transforming growth factor-beta receptors could predispose to osteoarthritis [12].

Anatomical context of ADAMTS5

• Expression and activity of ADAMTS-5 in synovium [13].
• ADAMTS-5 was immunolocalized in human arthritic synovium, where staining was mostly pericellular, particularly in the synovial lining and around blood vessels; some matrix staining was also seen [13].
• ADAMTS5-mediated aggrecanolysis in murine epiphyseal chondrocyte cultures [14].
• METHODS: Bovine articular cartilage discs (live or freeze-killed) were cultured in the presence of IL-1 or were incubated in digestion buffer containing recombinant human ADAMTS-4 (rHuADAMTS-4; aggrecanase 1) or rHuADAMTS-5 (aggrecanase 2) [15].
• CONCLUSIONS: ADAMTS-5 expression is restricted to decidualized stromal cells of the human endometrium in vivo and is subject to regulation by cytokines in vitro [16].

Associations of ADAMTS5 with chemical compounds

• ADAMTS11 possesses a number of conserved domains that have been shown to play a role in integrin binding, cell-cell interactions, and extracellular matrix binding [17].
• ADAMTS-5 was expressed constitutively in synovium with little or no transcriptional regulation by recombinant human interleukin-1 alpha or all-trans-retinoate, factors previously shown to upregulate aggrecanase activity in cartilage [13].
• All three ADAMTS-5 isoforms bound to sulfated GAGs (heparin and chondroitin sulfate (CS)) [18].
• RESULTS: Both aggrecanase-1 and aggrecanase-2 are able to cleave bovine and human biglycan at a site within their central leucine-rich repeat regions [19].
• Retinoic acid was more effective than interleukin-1alpha (IL) in promoting cleavage at these sites in ADAMTS-5-deficient cartilage [6].

Enzymatic interactions of ADAMTS5

• ADAM-TS5 cleaved aggrecan approximately 2-fold slower than ADAM-TS4 [9].

Regulatory relationships of ADAMTS5

• In contrast, aggrecanase-2 protein may be regulated by a post-translational mechanism in OA and RA ST [20].
• IL18 up regulated mRNA expression of aggrecanase-2, but not aggrecanase-1 [21].
• Secreted ADAMTS-4 was not inhibited by BMS-345541 in these explants, whereas ADAMTS-5 secretion was blocked in the same concentration range that inhibited aggrecan degradation [22].

Other interactions of ADAMTS5

• Furthermore, OA, RA, and nonarthritis ST contained similar amounts of immunoreactive aggrecanase-2 [20].
• Finally, the zymogen of stromelysin (MMP-3) was not activated by either ADAM-TS4 or ADAM-TS5 [9].
• The possibility that synovium-derived ADAMTS-5 may play a role in cartilage aggrecan breakdown is discussed [13].
• Further truncation (deletion of the TSR-1 domain) of ADAMTS-5 significantly reduced aggrecanase activity, although appreciable GAG (heparin)-binding affinity was maintained [18].
• In vitro, glioblastoma-derived ADAMTS5 degrades recombinant human brevican to several smaller fragments [1].

Analytical, diagnostic and therapeutic context of ADAMTS5

• Aggrecanase-2 mRNA expression was quantitatively analysed by real time RT-PCR [21].
• In situ hybridization and immunohistochemistry demonstrated that ADAMTS-5 is expressed predominantly in glioblastoma cells [3].
• Frontal cortex of controls, DS, AD and PD were homogenized and extracted proteins were used for immunoblotting using antibodies against ADAMTS-1 and ADAMTS-5 [4].
• When the expression levels of these ADAMTS species were examined by real-time quantitative PCR, only ADAMTS-5 was found to be overexpressed in glioblastoma tissues compared to control normal brain tissues (P <0.05) [3].

References