Affinage

ADAMTS4

A disintegrin and metalloproteinase with thrombospondin motifs 4 · UniProt O75173

Length
837 aa
Mass
90.2 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADAMTS4 encodes a secreted zinc metalloproteinase that functions as a major aggrecanase and broad-spectrum proteoglycan-degrading enzyme, cleaving aggrecan, versican, brevican, neurocan, phosphacan, hevin, and Reelin at Glu-X bonds through an exosite-assisted mechanism requiring glycosaminoglycan recognition by its thrombospondin type-1, cysteine-rich, and spacer domains (PMID:10751421, PMID:10827174, PMID:17487981, PMID:22420304). The enzyme is activated by sequential prodomain removal via furin/PACE4/PC5-6 in the trans-Golgi network followed by C-terminal spacer domain truncation by MT4-MMP or other MMPs at the cell surface, generating active p60/p53 forms with altered substrate specificity and reduced matrix retention (PMID:11796708, PMID:14744861, PMID:14701864, PMID:14662755). Its activity is regulated extracellularly by TIMP-3 (subnanomolar Ki, enhanced by aggrecan-derived chondroitin sulfate), fibronectin binding to the spacer domain, CCN1 binding to the cysteine-rich domain, and LRP1-mediated endocytic clearance, while transcription is controlled by NF-κB/MAPK signaling downstream of IL-1β/TNF-α and by transcription factors Sox4, NFATp, and Runx2 (PMID:11278243, PMID:17470431, PMID:15161923, PMID:25709087, PMID:24474687, PMID:23602832, PMID:30016600). Beyond cartilage proteoglycan catabolism, ADAMTS-4 generates N-truncated Aβ4-x amyloid peptides in oligodendrocytes, translocates to the nucleus to cleave PARP-1 and drive smooth muscle cell apoptosis during aortic aneurysm, promotes axonal regeneration by degrading inhibitory CSPGs after spinal cord injury, and remodels lung ECM during viral infection (PMID:30426203, PMID:28955046, PMID:22420304, PMID:33116313).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Establishing ADAMTS-4 as a multi-site aggrecanase and identifying its proteoglycan substrate repertoire resolved the identity of the long-sought 'aggrecanase' activity and revealed that it also cleaves brevican at a distinct site from MMPs.

    Evidence In vitro cleavage of native aggrecan and brevican with recombinant ADAMTS-4, N-terminal sequencing of fragments

    PMID:10751421 PMID:10986281

    Open questions at the time
    • Relative contribution of each cleavage site to in vivo cartilage degradation unknown
    • Kinetic parameters for individual sites not fully determined
  2. 2000 High

    Demonstrating that the TSP-1 motif binds aggrecan GAGs and is essential for cleavage established the principle that ADAMTS-4 uses non-catalytic domains for substrate recognition, not just catalysis.

    Evidence Truncation mutants, peptide competition, and GAG-free aggrecan cleavage assays

    PMID:10827174

    Open questions at the time
    • Precise structural basis of TSP-1–GAG interaction not resolved
    • Whether TSP-1 domain is equally required for non-aggrecan substrates unclear
  3. 2001 High

    Identifying TIMP-3 as the first endogenous inhibitor of ADAMTS-4 with subnanomolar affinity, and showing versican cleavage and aortic presence, defined the enzyme's regulatory framework and expanded its role beyond cartilage.

    Evidence Quantitative in vitro inhibition kinetics; in vitro versican V1 cleavage with neoepitope detection; Western blot of human aortic extracts

    PMID:11278243 PMID:11278559

    Open questions at the time
    • In vivo relevance of TIMP-3 regulation in specific tissues not demonstrated
    • Other potential endogenous inhibitors not yet screened
  4. 2002 High

    Discovering that ADAMTS-4 activation requires sequential furin-mediated prodomain removal and MMP-mediated C-terminal truncation revealed a two-step zymogen activation pathway controlling enzyme specificity.

    Evidence Stable transfection with domain-specific antisera, furin/MMP inhibitor treatments, and activity assays of isolated enzyme forms; autocatalysis characterization with mass analysis

    PMID:11796708 PMID:12202483

    Open questions at the time
    • Identity of the specific MMP(s) responsible in vivo not definitively established at this stage
    • Relative rates of autocatalysis versus MMP-mediated truncation in physiological settings unknown
  5. 2003 High

    Identifying MT4-MMP as the cell-surface protease generating the active p53 form and syndecan-1 as a cell-surface docking partner placed ADAMTS-4 activation in a pericellular context, while IL-1 was shown to activate a pre-existing enzyme pool rather than inducing new synthesis.

    Evidence Co-transfection with MT4-MMP mutants, GAG lyase digestions, immunoprecipitation; chondrocyte IL-1 stimulation with heparin/chondroitinase treatment

    PMID:12528112 PMID:14701864

    Open questions at the time
    • Whether syndecan-1 association enhances or restricts activity in vivo unknown
    • Nature of the GAG-sensitive IL-1-induced activator not identified
  6. 2003 High

    Systematic domain deletion showed that the spacer domain both masks broad proteolytic activity and anchors the enzyme in ECM, revealing a built-in autoinhibitory/localization mechanism.

    Evidence Domain deletion mutants with multiple substrate and matrix binding assays

    PMID:14662755

    Open questions at the time
    • Structural basis of spacer-mediated autoinhibition not resolved
    • How spacer removal alters substrate selectivity in vivo unknown
  7. 2004 High

    Mapping furin cleavage to the trans-Golgi network via physical furin–prodomain interaction and identifying fibronectin as an extracellular inhibitor binding the spacer domain defined two distinct compartmental control points for ADAMTS-4 activity.

    Evidence Furin RNAi, brefeldin A treatment, co-IP; yeast two-hybrid, cross-linking, and activity inhibition with fibronectin

    PMID:14744861 PMID:15161923

    Open questions at the time
    • Whether fibronectin inhibition is relevant in cartilage ECM context not tested
    • Contribution of PACE4/PC5-6 versus furin in different tissues not resolved
  8. 2007 High

    Crystal structures revealing open/closed catalytic-site conformations and kinetic demonstration of an exosite mechanism unified the biochemical observations into a model where substrate first docks at an exosite before engaging the active site.

    Evidence X-ray crystallography of apo and inhibitor-bound forms; inhibition kinetics showing noncompetitive behavior with aggrecan versus competitive with peptides

    PMID:17487981 PMID:18042673

    Open questions at the time
    • No co-crystal with a macromolecular substrate to identify the exosite structurally
    • Whether the open/closed equilibrium is modulated by cofactors in vivo unknown
  9. 2007 High

    Showing that TIMP-3 inhibition is enhanced by aggrecan-derived chondroitin 6-sulfate binding to the ancillary domains revealed a substrate-assisted inhibition mechanism, linking GAG binding to regulation.

    Evidence FRET kinetic assays with native and deglycosylated aggrecan; specific GAG competition

    PMID:17470431

    Open questions at the time
    • Whether this applies to other substrates or tissue contexts not established
    • Stoichiometry of the ternary TIMP-3/ADAMTS-4/CS complex not determined
  10. 2009 Medium

    Discovery of hevin as a brain substrate and ADAMTS-4's role in cerebellar development expanded its functional scope beyond connective tissue proteoglycan degradation.

    Evidence In vitro hevin cleavage, co-localization of ADAMTS-4 with hevin-derived fragments in mouse cerebellum

    PMID:20018883

    Open questions at the time
    • Hevin cleavage site not precisely mapped
    • No knockout validation of this function in cerebellum
  11. 2011 High

    Double knockout with ADAMTS-1 revealed redundant essential roles in renal medulla morphogenesis, establishing ADAMTS-4 as a developmental enzyme with tissue-specific requirements masked by paralog compensation.

    Evidence Adamts4−/−;Adamts1−/− double-knockout mice with lethal renal medulla thinning

    PMID:21584905

    Open questions at the time
    • Specific substrate(s) mediating renal development not identified
    • Whether versican is the relevant renal substrate unknown
  12. 2012 High

    Demonstrating LRP1-mediated endocytosis via the cysteine-rich/spacer domains and competitive displacement by ADAMTS-5 defined the clearance pathway controlling extracellular ADAMTS-4 levels.

    Evidence Domain deletion binding assays, endocytosis rate measurements, competitive inhibition with ADAMTS-5

    PMID:24474687

    Open questions at the time
    • In vivo validation of LRP1 clearance pathway not performed
    • Whether LRP1 endocytosis delivers ADAMTS-4 for degradation or recycling unknown
  13. 2013 High

    Mapping the signaling cascades (MAPK/NF-κB) through which TNF-α and IL-1β induce ADAMTS4 transcription, along with identification of promoter-binding transcription factors (NFATp, Runx2, Sox4), defined the transcriptional regulation of the gene in chondrocytes and intervertebral disc cells.

    Evidence Promoter reporter assays, ChIP, lentiviral shRNA knockdown of pathway components, MAPK/NF-κB inhibitors; adenoviral Sox4 overexpression in organ cultures

    PMID:16677612 PMID:23602832 PMID:30016600

    Open questions at the time
    • Epigenetic regulation not addressed
    • Whether these pathways operate identically in cartilage versus vascular tissue unknown
  14. 2015 High

    Identification of CCN1 as a TGF-β-induced extracellular inhibitor binding the cysteine-rich domain added a third mode of extracellular activity control alongside TIMP-3 and fibronectin.

    Evidence Co-purification/MS identification, immunoprecipitation, domain mapping, siRNA knockdown, aggrecan digestion assay

    PMID:25709087

    Open questions at the time
    • Whether CCN1, fibronectin, and TIMP-3 compete or cooperate in vivo not tested
    • Structural basis of CCN1 inhibition unknown
  15. 2017 High

    Discovering nuclear translocation and PARP-1 cleavage in stressed smooth muscle cells, along with knockout protection from aortic aneurysm, revealed an unexpected intracellular pro-apoptotic function beyond its canonical extracellular role.

    Evidence Adamts4−/− mouse aortic aneurysm model; immunofluorescence for nuclear localization; in vitro PARP-1 cleavage assay

    PMID:28955046

    Open questions at the time
    • Mechanism of nuclear import not identified
    • Whether PARP-1 cleavage is direct in vivo or requires cofactors unknown
    • Generalizability of nuclear function beyond SMCs not tested
  16. 2018 High

    Demonstrating that ADAMTS-4 generates Aβ4-x amyloid peptides in oligodendrocytes and that knockout reduces Aβ4-40 in an Alzheimer's model established the enzyme as a novel amyloid-processing protease.

    Evidence Inducible HEK293 overexpression; ADAMTS4 knockout on 5xFAD background; cultured oligodendrocytes; Aβ peptide ELISA

    PMID:30426203

    Open questions at the time
    • Precise cleavage site within APP/Aβ sequence not mapped at single-residue resolution
    • Contribution to human AD pathology not established
  17. 2020 High

    Implicating fibroblast-derived ADAMTS-4 in lung ECM remodeling during viral infection, with clinical correlation to influenza severity, extended the enzyme's pathophysiological role to innate immunity.

    Evidence Mouse influenza model with single-cell transcriptomics; human cohort ADAMTS4 measurements

    PMID:33116313

    Open questions at the time
    • Specific lung ECM substrates cleaved during infection not identified
    • Whether ADAMTS-4 is protective or pathogenic in this context not fully resolved
  18. 2021 High

    Comprehensive proteomics identified 21 novel cleavage sites in versican V1 confirming broad P1-Glu preference, refining the substrate recognition model.

    Evidence Label-free quantitative LC-MS/MS with catalytically inactive mutant controls

    PMID:34450332

    Open questions at the time
    • Functional significance of individual cleavage sites in vivo unknown
    • Whether these sites are cleaved in native tissue-associated versican not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of exosite-mediated substrate recognition on full-length enzyme, the mechanism of nuclear translocation, the pathophysiological relevance of Aβ4-x generation to Alzheimer's disease, and the specific substrates mediating ADAMTS-4's developmental roles in kidney and cerebellum.
  • No co-crystal structure with macromolecular substrate
  • Nuclear import mechanism uncharacterized
  • In vivo contribution to AD amyloid burden in humans unknown
  • Developmental substrates in kidney and brain not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0016787 hydrolase activity 6
Localization
GO:0005576 extracellular region 6 GO:0031012 extracellular matrix 3 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1474244 Extracellular matrix organization 7 R-HSA-392499 Metabolism of proteins 3 R-HSA-1643685 Disease 2 R-HSA-5357801 Programmed Cell Death 1
Partners
CCN1FN1FURINLRP1MMP17PARP1SDC1TIMP3

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ADAMTS-4 cleaves aggrecan at the Glu373-Ala374 bond (IGD) and at four additional sites within the chondroitin sulfate-rich region (Glu1480-Gly1481, Glu1667-Gly1668, Glu1771-Ala1772, Glu1871-Leu1872), with CS-rich region cleavage being more efficient than IGD cleavage. In vitro cleavage assay with recombinant human ADAMTS-4 and native aggrecan; N-terminal sequencing of fragments The Journal of biological chemistry High 10751421
2000 The thrombospondin type-1 (TSP-1) motif of ADAMTS-4 binds to glycosaminoglycans of aggrecan and is required for substrate recognition and cleavage; truncation lacking TSP-1 abolishes aggrecanase activity, and GAG-free aggrecan is not cleaved. Truncation mutant activity assays, peptide competition binding assays, cleavage assays with GAG-free aggrecan The Journal of biological chemistry High 10827174
2000 ADAMTS-4 cleaves brevican at the Glu395-Ser396 bond within the central non-homologous domain, a site distinct from the Ala360-Phe361 bond cleaved by MMPs. In vitro cleavage assay with recombinant ADAMTS-4 and brevican; NH2-terminal sequence analysis of fragments The Journal of biological chemistry High 10986281
2001 TIMP-3 N-terminal inhibitory domain is a potent inhibitor of ADAMTS-4 with Ki values in the subnanomolar range, making it the first identified endogenous inhibitor of aggrecanases. In vitro inhibition assay using truncated N-TIMP-3 expressed in bacteria against recombinant ADAMTS-4 and ADAMTS-5 The Journal of biological chemistry High 11278243
2001 ADAMTS-4 cleaves versican V1 at the Glu441-Ala442 bond, generating a DPEAAE neoepitope, and mature ADAMTS-4 was detected in human aortic intima. In vitro cleavage of recombinant versican substrate and native human versican; neoepitope antiserum detection; Western analysis of aortic extracts The Journal of biological chemistry High 11278559
2002 ADAMTS-4 activation requires two sequential steps: (1) prodomain removal by a furin-like activity generating the p75 form, and (2) MMP-mediated C-terminal truncation generating p60/p50 forms; only the C-terminally truncated forms exhibit aggrecanase activity. Stable transfection of human chondrosarcoma cells; Western analysis with domain-specific antisera; furin and MMP inhibitor treatments; preparative SDS-PAGE isolation and activity assays The Journal of biological chemistry High 11796708
2002 Full-length ADAMTS-4 undergoes autocatalytic C-terminal truncation to generate ~53 kDa and ~40 kDa isoforms with reduced affinity for sulfated GAGs; multiple GAG-binding sites are present in the cysteine-rich and spacer domains in addition to the TSP-1 motif. C-terminal sequencing and mass analysis of autocleaved products; binding competition with native and deglycosylated aggrecan; synthetic peptide competition The Journal of biological chemistry High 12202483
2002 ADAMTS-4 cleaves at the Glu373-Ala374 aggrecanase site primarily, and secondarily cleaves at the Asn341-Phe342 MMP site; TIMP-3 (but not TIMP-1 or TIMP-2) inhibits both cleavages, confirming they are genuine ADAMTS-4 activities. In vitro cleavage of native and recombinant aggrecan; inhibitor studies with TIMP-3, TIMP-1, TIMP-2; cleavage site mutant analysis The Journal of biological chemistry High 11854269
2003 The non-catalytic C-terminal spacer domain of ADAMTS-4 masks general proteolytic activity; deletion of the spacer domain broadens substrate specificity (enabling cleavage of Glu373-Ala374, Cm-Tf, fibromodulin, decorin), while the thrombospondin type I domain is critical for aggrecanase activity; full-length ADAMTS-4 binds pericellular/extracellular matrix via its spacer domain. Domain deletion mutant expression in mammalian cells; aggrecan-degrading and general proteolytic activity assays; matrix binding studies The Journal of biological chemistry High 14662755
2003 IL-1 induces aggrecanase activity in chondrocytes by activating a constitutively produced pool of ADAMTS-4 (not by increasing protein abundance); IL-1-mediated activation involves an activator that can be blocked by heparin or chondroitinase ABC treatment. Western blot of cell lysates and cartilage; immunofluorescence; aggrecanase activity assay on peptide substrate; heparin and chondroitinase treatment Arthritis and rheumatism Medium 12528112
2003 ADAMTS-4 activation on the cell surface involves C-terminal cleavage of the p68 form to the p53 form mediated by GPI-anchored MT4-MMP (MMP-17); the activated p53 form associates with syndecan-1 through both chondroitin sulfate and heparan sulfate chains. Co-transfection with active/inactive MT4-MMP mutants; phosphatidylinositol-specific phospholipase C treatment; glycosaminoglycan lyase digestions; fluorescence-assisted carbohydrate electrophoresis; immunoprecipitation The Journal of biological chemistry High 14701864
2004 Furin cleaves pro-ADAMTS-4 at RPRR/RAKR/KR sites in the trans-Golgi network to remove the prodomain; pro-ADAMTS-4 co-precipitates with furin (but mature form does not), indicating physical interaction of furin with the prodomain. Furin-specific inhibitor treatment; RNA interference of furin; brefeldin A treatment; co-localization by immunofluorescence; co-immunoprecipitation The Journal of biological chemistry High 14744861
2004 ADAMTS-4 binds to the C-terminal domain of fibronectin via its spacer domain; this interaction inhibits aggrecanase activity with IC50 of ~110 nM; ADAMTS-4 co-localizes with fibronectin on the cell surface. Yeast two-hybrid screening; chemical cross-linking; solid-phase binding assay; confocal microscopy; aggrecanase activity inhibition assay with fibronectin and fragments The Journal of biological chemistry High 15161923
2004 ADAMTS-4 cleaves brain versican V2 at Glu405-Gln406 to generate glial hyaluronate binding protein (GHAP); multiple ADAMTS-4 protein forms are present in human cerebellum extracts. Neoepitope antiserum identification; in vitro digestion of human cerebellum proteoglycans with ADAMTS-4; Western analysis The Biochemical journal High 14561220
2005 N-terminal activation of ADAMTS-4 is mediated by proprotein convertases furin, PACE4, and PC5/6 (cleaving at Arg212/Phe213), and also by MMP-9 and trypsin; autocatalytic prodomain removal does not occur under standard conditions but can occur at basic pH (8-10). In vitro activation assays with various proteinases across pH ranges, ionic strengths, and temperatures; prodomain removal and activity measurement Archives of biochemistry and biophysics High 16289022
2007 TIMP-3 inhibition of full-length ADAMTS-4 is enhanced in the presence of aggrecan through binding of chondroitin 6-sulfate glycosaminoglycans to the TSP-1 and spacer domains of ADAMTS-4, forming a complex with improved TIMP-3 binding affinity. FRET peptide assay; binding competition experiments with native and deglycosylated aggrecan; specific glycosaminoglycan competition The Journal of biological chemistry High 17470431
2007 Non-catalytic ancillary domains of ADAMTS-4 regulate extracellular matrix localization (spacer domain is critical) and proteolytic activity; the spacer domain is required for matrix retention, while sequential inclusion of C-terminal domains enhances activity against multiple substrates. Domain deletion mutant expression; ECM interaction studies; activity assays against aggrecan, Cm-Tf, fibromodulin, decorin, biglycan, fibronectin The Journal of biological chemistry High 17430884
2007 Crystal structures of ADAMTS-4 (in apo and inhibitor-bound forms) reveal two catalytic-site configurations: an autoinhibited closed form and an open binding form, suggesting the enzyme exists as an ensemble of isomers with only the open form being proteolytically active. X-ray crystallography of human ADAMTS-4 in apo and inhibitor-bound forms Protein science High 18042673
2007 ADAMTS-4 aggrecan cleavage operates through an exosite mechanism: substrate initially binds at an exosite (reflected by apparent Km), followed by active-site binding; active-site inhibitors show noncompetitive kinetics with aggrecan but competitive kinetics with peptide substrates, consistent with this two-step model. Inhibition kinetics with hydroxamic acid SC81956 using varying aggrecan and peptide substrate concentrations; fluorogenic peptide assay Biochemistry High 17487981
2009 ADAMTS-4 cleaves hevin (SPARC-like 1) in the mouse cerebellum; this proteolysis is important for normal cerebellar development; ADAMTS-4 co-localizes with hevin-derived SPARC-like fragments in vivo. In vitro digestion of hevin by ADAMTS-4; comparison of brain lysate fragments with in vitro cleavage products; co-localization by monoclonal antibody; developmental analysis The Journal of biological chemistry Medium 20018883
2010 N-TIMP-3 reactive-site mutants with additional N-terminal alanine residues selectively inhibit ADAMTS-4 and ADAMTS-5 over MMPs; these mutants inhibit aggrecan but not collagen degradation in cartilage explants; molecular modelling indicates unique stabilizing contacts with the catalytic domains. In vitro inhibition assays with recombinant proteins; cartilage explant aggrecan/collagen degradation assays; molecular modelling The Biochemical journal High 20645923
2012 ADAMTS-4 is endocytosed via LRP1 on chondrocyte cell surface; the cysteine-rich and spacer domains mediate LRP1 binding; ADAMTS-4 binds LRP1 clusters II and IV with KD ~98 and 73 nM respectively; half-life of endocytosis ~220 min; ADAMTS-5 competitively inhibits ADAMTS-4 endocytosis due to higher LRP1 affinity. Domain deletion mutagenesis; soluble LRP1 ligand binding cluster binding assays; endocytosis rate measurements; competitive inhibition experiments The Journal of biological chemistry High 24474687
2012 ADAMTS-4 degrades chondroitin sulfate proteoglycan core proteins (brevican, neurocan, phosphacan) and reverses their inhibition of neurite outgrowth in vitro; local administration of ADAMTS-4 promotes motor function recovery and axonal regeneration/sprouting after spinal cord contusion injury in mice. In vitro proteoglycan cleavage assay; in vitro neurite growth assay; in vivo spinal cord contusion model with local ADAMTS-4 administration; motor function assessment Journal of neuroinflammation High 22420304
2013 TNF-α and IL-1β regulate ADAMTS-4 expression in nucleus pulposus cells through MAPK (ERK1, p38α, p38β2, p38γ) and NF-κB (p65, IKK-α, IKK-β) signaling; p65 activates the ADAMTS4 promoter while p50 blocks this; lentiviral shRNA knockdown of pathway components reduces ADAMTS-4 and aggrecan degradation. Real-time RT-PCR; Western blotting; transient transfections with promoter constructs; gain/loss-of-function with dominant negative constructs; lentiviral shRNA knockdown; MAPK/NF-κB inhibitor studies The American journal of pathology High 23602832
2015 CCN1 (Cyr61) binds specifically to the cysteine-rich domain of ADAMTS-4 and inhibits its aggrecanase activity; TGF-β upregulates CCN1 which suppresses ADAMTS-4 activity even when ADAMTS-4 protein is induced, while IL-1α downregulates CCN1 allowing ADAMTS-4 activity. Co-purification and mass spectrometry identification; immunoprecipitation; solid-phase binding assay; aggrecan digestion assay; domain deletion mapping; siRNA knockdown of CCN1 Arthritis & rheumatology High 25709087
2017 ADAMTS-4 translocates to the nucleus in smooth muscle cells under stress conditions and directly cleaves/degrades poly ADP ribose polymerase-1 (PARP-1), leading to SMC apoptosis; ADAMTS-4 deficiency reduces aortic aneurysm formation, versican degradation, and macrophage infiltration in mice. Mouse knockout model (Adamts4-/-); immunofluorescence for nuclear translocation; in vitro PARP-1 cleavage assay; aortic diameter measurement; histological analysis Scientific reports High 28955046
2018 ADAMTS-4 generates N-truncated Aβ4-x peptides by cleaving at a recognition site within the amyloid-β sequence; inducible overexpression increases Aβ4-40 secretion without altering Aβ1-x levels; ADAMTS4 knockout reduces Aβ4-40 levels in 5xFAD mice; ADAMTS-4 is exclusively expressed in oligodendrocytes in adult mouse brain. Inducible HEK293 overexpression; ADAMTS4 knockout mouse on 5xFAD background; cultured oligodendrocytes from ADAMTS4-/- mice; Aβ peptide measurement by ELISA/immunoassay Acta neuropathologica High 30426203
2020 ADAMTS-4 produced by damage-responsive lung fibroblasts remodels the ECM during viral infection, promoting robust immune cell infiltration; ADAMTS-4 levels in the lower respiratory tract correlate with severity of influenza infection in humans. Mouse influenza model; single-cell transcriptomics identifying fibroblast activation states; ADAMTS4 functional studies in lung; human cohort ADAMTS4 measurements Nature High 33116313
2021 ADAMTS-4 cleaves versican V1 at multiple sites beyond the known Glu441-Ala442 bond, with a preference for P1-Glu residues; 21 novel cleavage sites were identified within versican. Label-free quantitative LC-MS/MS proteomics comparing active vs. catalytically inactive mutant ADAMTS-4 digests of recombinant versican; z-score statistical ranking Journal of proteomics High 34450332
2006 The human ADAMTS-4 promoter is regulated by transcription factors NFATp and Runx2 (binding sites identified); the NFI site at -441 to -429 acts as a negative regulator in chondrocytes; the region -383 to +10 is required for full promoter activity. Promoter cloning; deletion variants reporter assays; transfection in porcine chondrocytes and NIH3T3 cells Biochemical and biophysical research communications Medium 16677612
2018 Sox4 transcription factor directly binds the ADAMTS-4 promoter and upregulates its expression; Sox4 overexpression induces ADAMTS-4 and ADAMTS-5 expression and causes articular cartilage destruction in organ cultures. Microarray; luciferase reporter assay; chromatin immunoprecipitation; adenovirus-mediated Sox4 overexpression in mouse femoral head cartilage organ cultures FASEB journal High 30016600
2008 Hyaluronan (HA) suppresses IL-1α-induced ADAMTS-4 expression in osteoarthritic chondrocytes through CD44 and ICAM1 signaling pathways, by downregulating IRAK-1 and ERK1/2 phosphorylation via IRAK-M upregulation; HA does not directly inhibit ADAMTS-4 enzymatic activity. Real-time PCR; Western blotting; immunoblotting for signaling molecules; antibody blocking of CD44/ICAM1; siRNA knockdown of ADAMTS-4 Annals of the rheumatic diseases Medium 18662930
2012 ADAMTS-4 and ADAMTS-5 cleave Reelin, with regulation by tPA, TIMPs, α-2-macroglobulin, serpins, and MMP-9; their expression overlaps with Reelin in the murine hippocampus. In vitro cleavage assays; inhibitor co-incubation studies; immunofluorescence co-localization in brain PloS one Medium 23082219
2011 ADAMTS-4 and ADAMTS-1 play redundant and essential roles in perinatal renal medulla development; combined knockout of both leads to lethal renal medulla thinning in >95% of double-null mice, while single knockouts are phenotypically normal. Gene targeting to create Adamts4-null mice; crossing with Adamts1-null mice; histological analysis of kidneys Developmental dynamics High 21584905

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). The Journal of biological chemistry 400 11278243
2001 Versican V1 proteolysis in human aorta in vivo occurs at the Glu441-Ala442 bond, a site that is cleaved by recombinant ADAMTS-1 and ADAMTS-4. The Journal of biological chemistry 389 11278559
2007 Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis and rheumatism 333 17265492
2003 IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 300 12568957
2002 Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage. The Journal of biological chemistry 241 11956193
2007 Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. The Journal of biological chemistry 219 17430884
2000 Sites of aggrecan cleavage by recombinant human aggrecanase-1 (ADAMTS-4). The Journal of biological chemistry 197 10751421
2003 Altered proteolytic activities of ADAMTS-4 expressed by C-terminal processing. The Journal of biological chemistry 175 14662755
2020 Exuberant fibroblast activity compromises lung function via ADAMTS4. Nature 166 33116313
2013 Inflammatory cytokines associated with degenerative disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-κB. The American journal of pathology 163 23602832
2000 The thrombospondin motif of aggrecanase-1 (ADAMTS-4) is critical for aggrecan substrate recognition and cleavage. The Journal of biological chemistry 163 10827174
2003 ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1. The Journal of biological chemistry 156 14701864
2008 The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review. Clinical and experimental rheumatology 155 18328163
2002 Activation of the proteolytic activity of ADAMTS4 (aggrecanase-1) by C-terminal truncation. The Journal of biological chemistry 153 11796708
2001 Cloning and characterization of ADAMTS-14, a novel ADAMTS displaying high homology with ADAMTS-2 and ADAMTS-3. The Journal of biological chemistry 153 11741898
2000 Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites. The Journal of biological chemistry 140 10986281
2002 Autocatalytic cleavage of ADAMTS-4 (Aggrecanase-1) reveals multiple glycosaminoglycan-binding sites. The Journal of biological chemistry 123 12202483
2002 Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4). Matrix biology : journal of the International Society for Matrix Biology 119 12392761
2008 Hyaluronan inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic chondrocytes. Annals of the rheumatic diseases 113 18662930
2007 Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5. Protein science : a publication of the Protein Society 110 18042673
2006 Matrix-degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas. International journal of cancer 106 16003758
2007 ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques. Atherosclerosis 100 17606262
2007 Expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic cartilage. Pathology international 98 17922681
2004 Proprotein convertase furin interacts with and cleaves pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi network. The Journal of biological chemistry 98 14744861
2001 Transgenic mice with inactive alleles for procollagen N-proteinase (ADAMTS-2) develop fragile skin and male sterility. The Biochemical journal 94 11284712
2013 MicroRNA-125b regulates the expression of aggrecanase-1 (ADAMTS-4) in human osteoarthritic chondrocytes. Arthritis research & therapy 88 23406982
2008 Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation. Rheumatology international 88 18941754
2005 Domains and maturation processes that regulate the activity of ADAMTS-2, a metalloproteinase cleaving the aminopropeptide of fibrillar procollagens types I-III and V. The Journal of biological chemistry 88 16046392
2003 Transforming growth factor-beta induces secretion of activated ADAMTS-2. A procollagen III N-proteinase. The Journal of biological chemistry 88 12646579
2003 Induction of aggrecanase 1 (ADAM-TS4) by interleukin-1 occurs through activation of constitutively produced protein. Arthritis and rheumatism 82 12528112
2004 ADAMTS4 (aggrecanase-1) cleaves human brain versican V2 at Glu405-Gln406 to generate glial hyaluronate binding protein. The Biochemical journal 79 14561220
2014 Low density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4): functional differences of non-catalytic domains of ADAMTS-4 and ADAMTS-5 in LRP1 binding. The Journal of biological chemistry 76 24474687
2012 The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury. Journal of neuroinflammation 76 22420304
2012 ADAMTS-1 and ADAMTS-4 levels are elevated in thoracic aortic aneurysms and dissections. The Annals of thoracic surgery 72 23245439
2017 Critical Role of ADAMTS-4 in the Development of Sporadic Aortic Aneurysm and Dissection in Mice. Scientific reports 70 28955046
2006 TIMP-3 inhibits the procollagen N-proteinase ADAMTS-2. The Biochemical journal 70 16771712
2005 Analysis of ADAMTS4 and MT4-MMP indicates that both are involved in aggrecanolysis in interleukin-1-treated bovine cartilage. Osteoarthritis and cartilage 70 15780640
2012 Regulated proteolytic processing of Reelin through interplay of tissue plasminogen activator (tPA), ADAMTS-4, ADAMTS-5, and their modulators. PloS one 68 23082219
2002 ADAMTS4 cleaves at the aggrecanase site (Glu373-Ala374) and secondarily at the matrix metalloproteinase site (Asn341-Phe342) in the aggrecan interglobular domain. The Journal of biological chemistry 68 11854269
2015 Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT). ACS medicinal chemistry letters 64 26288689
2014 Leptin induces ADAMTS-4, ADAMTS-5, and ADAMTS-9 genes expression by mitogen-activated protein kinases and NF-ĸB signaling pathways in human chondrocytes. Cell biology international 64 25045124
2004 ADAMTS4 (aggrecanase-1) interaction with the C-terminal domain of fibronectin inhibits proteolysis of aggrecan. The Journal of biological chemistry 59 15161923
2010 ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity. Cellular and molecular life sciences : CMLS 58 20574651
2013 Tumor necrosis factor-α induces ADAMTS-4 expression in human osteoarthritis chondrocytes. Molecular medicine reports 57 24126638
2005 ADAMTS-4 (aggrecanase-1): N-terminal activation mechanisms. Archives of biochemistry and biophysics 57 16289022
2010 Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implications. The Biochemical journal 56 20645923
2007 TIMP-3 inhibition of ADAMTS-4 (Aggrecanase-1) is modulated by interactions between aggrecan and the C-terminal domain of ADAMTS-4. The Journal of biological chemistry 56 17470431
2006 Regulation of the human ADAMTS-4 promoter by transcription factors and cytokines. Biochemical and biophysical research communications 52 16677612
2016 Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice. Scientific reports 51 27491335
2018 The metalloprotease ADAMTS4 generates N-truncated Aβ4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease. Acta neuropathologica 49 30426203
2008 The regulation of aggrecanase ADAMTS-4 expression in human Achilles tendon and tendon-derived cells. Matrix biology : journal of the International Society for Matrix Biology 49 18387286
2018 Sox4 is involved in osteoarthritic cartilage deterioration through induction of ADAMTS4 and ADAMTS5. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 48 30016600
2004 Release of hyaluronan and hyaladherins (aggrecan G1 domain and link proteins) from articular cartilage exposed to ADAMTS-4 (aggrecanase 1) or ADAMTS-5 (aggrecanase 2). Arthritis and rheumatism 43 15457452
2014 Upregulation of tumor necrosis factor α and ADAMTS-5, but not ADAMTS-4, in human intervertebral cartilage endplate with modic changes. Spine 42 24732836
2014 Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages. Genetics and molecular research : GMR 41 25501175
2010 Cytokine-induced increases in ADAMTS-4 messenger RNA expression do not lead to increased aggrecanase activity in ADAMTS-5-deficient mice. Arthritis and rheumatism 41 20662062
2013 Mechanisms involved in suppression of ADAMTS4 expression in synoviocytes by high molecular weight hyaluronic acid. Biochemical and biophysical research communications 38 23438438
2000 ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs) is transcriptionally induced in beta-amyloid treated rat astrocytes. Neuroscience letters 38 10961658
2016 Anti-inflammatory effects of ADAMTS-4 in a mouse model of ischemic stroke. Glia 37 27301579
2021 Identification of novel ADAMTS1, ADAMTS4 and ADAMTS5 cleavage sites in versican using a label-free quantitative proteomics approach. Journal of proteomics 36 34450332
2013 ADAMTS4 and its proteolytic fragments differentially affect melanoma growth and angiogenesis in mice. International journal of cancer 34 23319426
2006 Expression of ADAMTS-4 (aggrecanase-1) and possible involvement in regression of lumbar disc herniation. Spine 34 16741450
2015 CCN1 (Cyr61) Is Overexpressed in Human Osteoarthritic Cartilage and Inhibits ADAMTS-4 (Aggrecanase 1) Activity. Arthritis & rheumatology (Hoboken, N.J.) 33 25709087
2014 Pentosan polysulfate decreases myocardial expression of the extracellular matrix enzyme ADAMTS4 and improves cardiac function in vivo in rats subjected to pressure overload by aortic banding. PloS one 33 24595230
2012 Anti-angiogenic properties of ADAMTS-4 in vitro. International journal of experimental pathology 33 22264287
2020 Astrocyte-selective AAV-ADAMTS4 gene therapy combined with hindlimb rehabilitation promotes functional recovery after spinal cord injury. Experimental neurology 31 32044329
2015 Association between ADAMTS-4 gene polymorphism and lumbar disc degeneration in Chinese Han population. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 31 26495885
2011 Interleukin-6 upregulates expression of ADAMTS-4 in fibroblast-like synoviocytes from patients with rheumatoid arthritis. International journal of rheumatic diseases 31 22324945
2009 Processing of the matricellular protein hevin in mouse brain is dependent on ADAMTS4. The Journal of biological chemistry 29 20018883
2007 Substrate-dependent inhibition kinetics of an active site-directed inhibitor of ADAMTS-4 (Aggrecanase 1). Biochemistry 29 17487981
2017 Cleavage of Fibulin-2 by the aggrecanases ADAMTS-4 and ADAMTS-5 contributes to the tumorigenic potential of breast cancer cells. Oncotarget 28 28099917
2013 Assessment of the matrix degenerative effects of MMP-3, ADAMTS-4, and HTRA1, injected into a bovine intervertebral disc organ culture model. Spine 28 23778376
2009 Cell death-associated ADAMTS4 and versican degradation in vascular tissue. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 28 19506088
2007 Involvement of protein kinase Czeta in interleukin-1beta induction of ADAMTS-4 and type 2 nitric oxide synthase via NF-kappaB signaling in primary human osteoarthritic chondrocytes. Arthritis and rheumatism 28 18050214
2020 MiR-126a-5p limits the formation of abdominal aortic aneurysm in mice and decreases ADAMTS-4 expression. Journal of cellular and molecular medicine 27 32469162
2010 Transcript levels of major MMPs and ADAMTS-4 in relation to the clinicopathological profile of patients with lumbar disc herniation. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 27 20857147
2016 ADAMTS-4 promotes neurodegeneration in a mouse model of amyotrophic lateral sclerosis. Molecular neurodegeneration 26 26809777
2018 Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 25 29694979
2004 Effect of adenovirus-mediated overexpression of bovine ADAMTS-4 and human ADAMTS-5 in primary bovine articular chondrocyte pellet culture system. Osteoarthritis and cartilage 25 15262240
2017 Relationship between ADAMTS4 and carotid atherosclerotic plaque vulnerability in humans. Journal of vascular surgery 24 29153440
2015 Effect of osteopontin on the mRNA expression of ADAMTS4 and ADAMTS5 in chondrocytes from patients with knee osteoarthritis. Experimental and therapeutic medicine 24 26136925
2014 IL-6 upregulates a disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS-2) in human osteosarcoma cells mediated by JNK pathway. Molecular and cellular biochemistry 24 24752352
2020 Interrelationship of Osteopontin, MMP-9 and ADAMTS4 in Patients With Osteoarthritis Undergoing Total Joint Arthroplasty. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis 23 33350314
2012 Expression of ADAMTS-2, -3, -13, and -14 in culprit coronary lesions in patients with acute myocardial infarction or stable angina. Journal of thrombosis and thrombolysis 22 22205175
2008 Calcium pentosan polysulfate directly inhibits enzymatic activity of ADAMTS4 (aggrecanase-1) in osteoarthritic chondrocytes. FEBS letters 22 18671975
2000 Characterization of 5'-flanking region of human aggrecanase-1 (ADAMTS4) gene. Molecular biology reports 22 11254106
2016 Cannabinoid WIN‑55,212‑2 mesylate inhibits ADAMTS‑4 activity in human osteoarthritic articular chondrocytes by inhibiting expression of syndecan‑1. Molecular medicine reports 21 27082728
2005 Mammalian expression of full-length bovine aggrecan and link protein: formation of recombinant proteoglycan aggregates and analysis of proteolytic cleavage by ADAMTS-4 and MMP-13. Biochimica et biophysica acta 21 16427204
2018 IL-1β-induced miR-34a up-regulation inhibits Cyr61 to modulate osteoarthritis chondrocyte proliferation through ADAMTS-4. Journal of cellular biochemistry 20 29236314
2016 The impact of parathyroidectomy on serum ADAMTS1, ADAMTS4 levels, insulin resistance, and subclinical cardiovascular disease in primary hyperparathyroidism. Endocrine 20 27844209
2006 Effects of covalently attached chondroitin sulfate on aggrecan cleavage by ADAMTS-4 and MMP-13. Matrix biology : journal of the International Society for Matrix Biology 20 16945513
2012 Expression of ADAMTS-1, ADAMTS-4, ADAMTS-5 and TIMP3 by hepatocellular carcinoma cell lines. International journal of oncology 19 22735305
2011 Partially redundant functions of Adamts1 and Adamts4 in the perinatal development of the renal medulla. Developmental dynamics : an official publication of the American Association of Anatomists 19 21584905
2006 An alternative spliced transcript of ADAMTS4 is present in human synovium from OA patients. Matrix biology : journal of the International Society for Matrix Biology 19 16723216
2022 Glucose-stimulated PGC-1α couples with CBP and Runx2 to mediate intervertebral disc degeneration through transactivation of ADAMTS4/5 in diet-induced obesity mice. Bone 18 36403758
2009 Adaptor proteins and Ras synergistically regulate IL-1-induced ADAMTS-4 expression in human chondrocytes. Journal of immunology (Baltimore, Md. : 1950) 18 19342688
2021 Synergistic upregulation of ADAMTS4 (aggrecanase-1) by cytokines and its suppression in knee osteoarthritic synovial fibroblasts. Laboratory investigation; a journal of technical methods and pathology 17 34718343
2020 Inflammasome components and ADAMTS4 in premature rupture of membranes. Molecular medicine reports 17 33300067
2017 Self-complementary adeno-associated virus serotype 6 mediated knockdown of ADAMTS4 induces long-term and effective enhancement of aggrecan in degenerative human nucleus pulposus cells: A new therapeutic approach for intervertebral disc disorders. PloS one 17 28207788
2010 Elevated level of ADAMTS4 in plasma and peripheral monocytes from patients with acute coronary syndrome. Clinical research in cardiology : official journal of the German Cardiac Society 16 20625753