Affinage

ADAMTS4

A disintegrin and metalloproteinase with thrombospondin motifs 4 · UniProt O75173

Length
837 aa
Mass
90.2 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADAMTS4 (aggrecanase-1) is a secreted, multidomain metalloprotease that remodels the extracellular and pericellular matrix by cleaving large chondroitin sulfate proteoglycans, most prominently aggrecan, which it cuts at the Glu373-Ala374 interglobular-domain bond and at multiple more efficiently processed sites in the chondroitin sulfate-rich region (PMID:10751421, PMID:11854269). It also cleaves versican (V1 at Glu441-Ala442 and many additional sites, V2 to generate brain GHAP), brevican, and other CNS proteoglycans, establishing distinct roles in connective tissue and neural matrix turnover (PMID:10986281, PMID:11278559, PMID:14561220, PMID:22420304, PMID:34450332). Substrate recognition and activity depend critically on its C-terminal ancillary domains: the thrombospondin type-1 motif and cysteine-rich/spacer domains bind glycosaminoglycans to position substrate, sequential inclusion of these domains progressively enhances proteolysis, and aggrecan cleavage proceeds through an exosite mechanism in which substrate first docks at an exosite before the scissile peptide enters the active site (PMID:10827174, PMID:12202483, PMID:17430884, PMID:17487981). The enzyme is produced as a latent zymogen activated by furin/proprotein convertase removal of the prodomain in the trans-Golgi and by GPI-anchored MT4-MMP (MMP-17)-mediated C-terminal truncation at the cell surface, where the active form is retained via syndecan-1; this activation step, rather than new synthesis, drives IL-1-induced cartilage aggrecanolysis (PMID:11796708, PMID:14744861, PMID:14701864, PMID:15780640). The spacer domain confines full-length enzyme to the pericellular matrix and masks broad proteolytic activity, so its removal releases the enzyme and broadens substrate specificity (PMID:14662755, PMID:15161923). ADAMTS4 activity is restrained by TIMP-3 (a potent inhibitor whose efficacy is enhanced by aggrecan GAGs), fibronectin (via the spacer domain), and CCN1 (via the cysteine-rich domain), and the enzyme is cleared by LRP1-mediated endocytosis (PMID:11278243, PMID:15161923, PMID:17470431, PMID:24474687, PMID:25709087). Transcriptionally it is driven by inflammatory cytokine signaling through PKCζ, MyD88/IRAK1/TRAF6, MAPK and NF-κB pathways and by Runx2, NFATp, and Sox4, and is repressed post-transcriptionally by miR-125b (PMID:23602832, PMID:23406982, PMID:30016600, PMID:18050214, PMID:19342688). Beyond matrix remodeling, ADAMTS4 cleaves APP/Aβ to generate N-truncated Aβ4-x peptides in oligodendrocytes, translocates to the nucleus of stressed smooth muscle cells to degrade PARP-1 and promote apoptosis in aortic aneurysm, and modulates neuroinflammation and CNS injury responses (PMID:28955046, PMID:30426203, PMID:27301579).

Mechanistic history

Synthesis pass · year-by-year structured walk · 33 steps
  1. 2000 High

    Established the defining enzymatic identity of ADAMTS4 as aggrecanase-1 by mapping the precise aggrecan bonds it cleaves, distinguishing aggrecanase from MMP-type cleavage.

    Evidence In vitro cleavage of native aggrecan with recombinant ADAMTS4 and N-terminal sequencing of fragments

    PMID:10751421

    Open questions at the time
    • Did not address how non-catalytic domains contribute to site selection
    • Cleavage efficiency in cell/tissue context not yet defined
  2. 2000 High

    Showed that substrate recognition is not purely active-site-driven but requires GAG-mediated binding through the thrombospondin type-1 motif, defining an ancillary-domain recognition mechanism.

    Evidence Domain truncation mutagenesis, TSP-1 peptide competition, and assays with GAG-free aggrecan

    PMID:10827174

    Open questions at the time
    • Contributions of cysteine-rich and spacer domains to GAG binding not yet resolved
    • Structural basis of exosite binding not defined
  3. 2000 High

    Extended the substrate range beyond aggrecan to brevican, showing ADAMTS4 cleaves CNS proteoglycans at sites distinct from MMPs.

    Evidence In vitro digestion of brevican with purified ADAMTS4 and MMPs with N-terminal sequencing

    PMID:10986281

    Open questions at the time
    • In vivo relevance of brevican cleavage not established
    • Cell type producing the enzyme in brain not identified
  4. 2001 High

    Identified TIMP-3 as the selective endogenous inhibitor of ADAMTS4, localizing the inhibitory activity to the TIMP-3 N-terminal domain.

    Evidence In vitro inhibition kinetics with recombinant TIMP domains

    PMID:11278243

    Open questions at the time
    • How TIMP-3 engages the catalytic site structurally not resolved
    • Physiological regulation of TIMP-3/ADAMTS4 balance in tissue untested
  5. 2001 High

    Demonstrated versican as a physiological substrate and detected mature ADAMTS4 in vascular tissue, broadening its role to connective tissue beyond cartilage.

    Evidence In vitro versican cleavage with neoepitope antisera plus Western analysis of aortic intima

    PMID:11278559

    Open questions at the time
    • Functional consequence of vascular versican cleavage not tested at this stage
    • Activation state of the detected tissue enzyme unknown
  6. 2002 High

    Defined the activation requirement for ADAMTS4: only C-terminally truncated p60/p53 forms are proteolytically active, and truncation is mediated by a GPI-anchored MMP, separating zymogen maturation from full enzymatic competence.

    Evidence Stable expression in chondrosarcoma cells, form fractionation with activity assays, and pharmacological inhibition

    PMID:11796708

    Open questions at the time
    • Identity of the GPI-anchored MMP not yet established
    • Relationship of truncation to substrate specificity not defined
  7. 2002 High

    Established that C-terminal ancillary domains carry GAG-binding sites and that autocatalytic truncation reduces GAG affinity, linking domain composition to matrix anchoring.

    Evidence C-terminal sequencing of autocatalytic fragments and GAG-binding competition with synthetic peptides

    PMID:12202483

    Open questions at the time
    • Physiological trigger for autocatalysis not defined
    • Quantitative impact on substrate cleavage in tissue not measured
  8. 2002 High

    Showed ADAMTS4 also cleaves the aggrecan MMP-site secondarily, and that this is TIMP-3-sensitive, reinforcing its mechanistic distinction from MMPs.

    Evidence In vitro digestion of aggrecan and G1-G2 constructs with selective TIMP inhibitors

    PMID:11854269

    Open questions at the time
    • Biological significance of the secondary MMP-site cleavage unclear
    • Order/kinetics relative to primary cleavage not resolved in vivo
  9. 2003 High

    Revealed that the spacer domain masks general proteolytic activity and confines the enzyme to the pericellular matrix, so domain removal expands substrate range and releases the enzyme.

    Evidence Domain deletion mutants assayed against multiple substrates with localization analysis

    PMID:14662755

    Open questions at the time
    • In vivo prevalence of spacer-deleted forms unknown
    • Mechanism of substrate masking at structural level not resolved here
  10. 2003 High

    Identified furin as the trans-Golgi prodomain-processing protease for pro-ADAMTS4 while noting a parallel furin-independent route.

    Evidence Co-localization, reciprocal co-IP, furin RNAi, and inhibitor/brefeldin A treatment

    PMID:14744861

    Open questions at the time
    • Identity of the furin-independent pathway not defined
    • Whether prodomain removal alone confers activity not fully separated from C-terminal events
  11. 2003 High

    Identified MT4-MMP (MMP-17) as the GPI-anchored protease that truncates ADAMTS4 to the active p53 form at the cell surface, where syndecan-1 retains it.

    Evidence Co-transfection with active/inactive MT4-MMP, PI-PLC and GAG lyase treatments, and anti-syndecan-1 co-IP

    PMID:14701864

    Open questions at the time
    • Regulation of MT4-MMP availability in tissue not addressed
    • Whether other surface proteases substitute in vivo unknown
  12. 2004 High

    Defined fibronectin as a spacer-domain-dependent inhibitor and co-localization partner, adding a matrix-based brake on aggrecanase activity.

    Evidence Yeast two-hybrid, cross-linking, solid-phase binding, and inhibition assays with domain mapping

    PMID:15161923

    Open questions at the time
    • In vivo relevance of fibronectin inhibition not tested
    • Competition with substrate GAG binding not quantified
  13. 2004 Medium

    Linked ADAMTS4 to generation of the brain proteoglycan fragment GHAP via versican V2 cleavage, reinforcing a CNS matrix role.

    Evidence Anti-neoepitope analysis of purified GHAP and in vitro digestion of cerebellar proteoglycans

    PMID:14561220

    Open questions at the time
    • In vivo enzyme responsible not genetically confirmed
    • Functional consequence of GHAP generation untested
  14. 2005 High

    Clarified the biochemical constraints on activation, showing prodomain removal under physiological conditions requires proprotein convertases (furin, PACE4, PC5/6) rather than autocatalysis.

    Evidence In vitro incubation of pro-ADAMTS4 with multiple proteases across conditions with activity assays

    PMID:16289022

    Open questions at the time
    • Relative in vivo contribution of each convertase not defined
    • Integration with C-terminal MT4-MMP step not resolved
  15. 2005 Medium

    Demonstrated in cartilage explants that IL-1-driven aggrecanolysis depends on MT4-MMP-mediated ADAMTS4 activation rather than increased enzyme synthesis.

    Evidence Western analysis of ADAMTS4 species and aggrecan fragments with GPI/MMP pharmacological inhibition in explants

    PMID:15780640

    Open questions at the time
    • Single-lab explant system; genetic confirmation absent
    • Distinction from ADAMTS5 contribution incomplete
  16. 2006 Medium

    Mapped the transcriptional control of the ADAMTS4 promoter in chondrocytes, identifying NFATp, Runx2 and a chondrocyte-specific NFI repressor element.

    Evidence Promoter-luciferase deletion reporter assays and mRNA analysis in chondrocytes

    PMID:11254106 PMID:16677612

    Open questions at the time
    • Direct factor binding (e.g., ChIP) not shown for all sites
    • Cytokine-responsive elements not yet integrated
  17. 2007 High

    Systematized the domain hierarchy controlling activity and localization, showing sequential ancillary domains progressively enhance proteolysis and that the spacer domain governs ECM localization (versus cysteine-rich for ADAMTS5).

    Evidence Comparative domain-deletion mutagenesis with multi-substrate assays against ADAMTS5

    PMID:17430884

    Open questions at the time
    • Structural mechanism of domain cooperation not resolved here
    • In vivo consequences of domain configuration untested
  18. 2007 High

    Provided structural and kinetic mechanisms: crystal structures revealed open/closed catalytic configurations, and kinetics defined an exosite-mediated aggrecan cleavage with implications for inhibitor design.

    Evidence X-ray crystallography of apo/inhibitor-bound enzyme; enzyme kinetics with aggrecan and peptide substrates plus active-site inhibitor

    PMID:17487981 PMID:18042673

    Open questions at the time
    • Substrate-bound structure not solved
    • Physiological trigger switching open/closed states unknown
  19. 2007 Medium

    Showed aggrecan GAG binding enhances TIMP-3 inhibition, revealing substrate-inhibitor interplay at the ancillary domains.

    Evidence FRET peptide assay with aggrecan-binding competition and solid-phase binding

    PMID:17470431

    Open questions at the time
    • Single-lab mechanistic study; in vivo relevance untested
    • Structural basis of the ternary complex unresolved
  20. 2009 Medium

    Identified upstream cytokine signaling requirements (PKCζ, MyD88/IRAK1/TRAF6, Ras/ROS) for IL-1β-driven ADAMTS4 induction via NF-κB.

    Evidence siRNA/shRNA knockdown and pharmacological inhibition with NF-κB pathway and ADAMTS4 mRNA readouts in chondrocytes

    PMID:18050214 PMID:19342688

    Open questions at the time
    • Promoter elements engaged by these pathways not fully mapped
    • Single-lab studies; in vivo validation limited
  21. 2009 Medium

    Extended substrate range to the matricellular protein hevin and linked ADAMTS4 proteolysis to cerebellar development in vivo.

    Evidence In vitro hevin digestion and in vivo co-localization in mouse cerebellum

    PMID:20018883

    Open questions at the time
    • Genetic loss-of-function effect on hevin in vivo not shown
    • Functional outcome of the SPARC-like fragment unresolved
  22. 2011 Medium

    Revealed a developmental role through genetic redundancy: Adamts4 alone is dispensable, but Adamts1/Adamts4 double knockouts die perinatally with renal medulla defects.

    Evidence Gene targeting and genetic cross with histological renal analysis

    PMID:21584905

    Open questions at the time
    • Molecular substrate underlying the renal phenotype unidentified
    • Extent of redundancy with other ADAMTS members untested
  23. 2012 High

    Established LRP1-mediated endocytosis as the clearance route for ADAMTS4 via cysteine-rich/spacer binding, with slower turnover than ADAMTS5.

    Evidence Domain mutagenesis, soluble LRP1 cluster binding affinity, and endocytosis kinetics with competition assays

    PMID:24474687

    Open questions at the time
    • In vivo contribution of LRP1 clearance to matrix turnover not quantified
    • Regulation of LRP1 availability not addressed
  24. 2012 Medium

    Demonstrated CNS therapeutic relevance: ADAMTS4 degrades inhibitory CSPGs (brevican, neurocan, phosphacan) and promotes axonal regeneration and motor recovery after spinal cord injury.

    Evidence In vitro CSPG degradation and neurite outgrowth assays plus in vivo spinal cord contusion model

    PMID:22420304

    Open questions at the time
    • Endogenous versus exogenous enzyme contribution not separated
    • Long-term and mechanistic basis of recovery not fully defined
  25. 2012 Medium

    Added Reelin to the substrate repertoire under multi-inhibitor control, connecting ADAMTS4 to hippocampal Reelin processing.

    Evidence In vitro cleavage with inhibitor dissection and hippocampal immunolocalization

    PMID:23082219

    Open questions at the time
    • In vivo Reelin processing by ADAMTS4 genetically unconfirmed
    • Functional consequence for Reelin signaling untested
  26. 2013 Medium

    Defined cytokine-driven transcriptional control in nucleus pulposus cells through MAPK/NF-κB and showed ADAMTS4 contributes non-redundantly to aggrecan degradation alongside ADAMTS5.

    Evidence Promoter assays, pathway inhibitors, lentiviral shRNA silencing, and aggrecan degradation assays

    PMID:23406982 PMID:23602832

    Open questions at the time
    • miR-125b regulation shown by reporter, not in vivo
    • Relative ADAMTS4/ADAMTS5 contribution context-dependent
  27. 2015 Medium

    Identified CCN1 as a cysteine-rich-domain-binding inhibitor that keeps ADAMTS4 latent, revealing an additional endogenous brake unmasked by CCN1 knockdown.

    Evidence LC-MS/MS co-purification, immunoprecipitation, solid-phase binding, aggrecan digestion, and siRNA knockdown

    PMID:25709087

    Open questions at the time
    • Structural basis of CCN1 inhibition unresolved
    • In vivo relevance to OA progression untested
  28. 2016 Medium

    Uncovered an anti-inflammatory role in CNS glia, where ADAMTS4 suppresses microglial/astrocyte pro-inflammatory responses and improves outcome after cerebral ischemia.

    Evidence Recombinant treatment and siRNA silencing in glia with cytokine measurement and a middle cerebral artery occlusion model

    PMID:27301579

    Open questions at the time
    • Molecular mechanism of anti-inflammatory action undefined
    • Substrate mediating glial effects unidentified
  29. 2017 Medium

    Revealed a non-canonical intracellular function: stress-induced nuclear translocation and PARP-1 cleavage driving smooth muscle apoptosis in aortic aneurysm/dissection.

    Evidence Adamts4-/- mouse aneurysm model, nuclear translocation imaging, and direct PARP-1 cleavage assay

    PMID:28955046

    Open questions at the time
    • Mechanism of nuclear import for a secreted protease unexplained
    • PARP-1 cleavage relies on a single study
  30. 2018 High

    Established ADAMTS4 as an oligodendrocyte-specific generator of N-truncated Aβ4-x peptides, implicating it in amyloid processing.

    Evidence Recognition-site mapping, inducible overexpression with Aβ ELISA, ADAMTS4-/- mice, and ADAMTS4-/- oligodendrocyte cultures

    PMID:30426203

    Open questions at the time
    • Contribution to amyloid pathology in human disease not established
    • Regulation of oligodendrocyte ADAMTS4 expression unclear
  31. 2018 Medium

    Identified Sox4 (and Sox11) as direct transcriptional activators of ADAMTS4 promoting cartilage destruction.

    Evidence Luciferase reporter, ChIP, and adenoviral overexpression in femoral head organ cultures

    PMID:30016600

    Open questions at the time
    • Integration with cytokine-driven regulation not mapped
    • In vivo Sox4-ADAMTS4 axis in OA untested
  32. 2020 Medium

    Linked ADAMTS4 to acute infection biology, showing damage-responsive lung fibroblasts produce it to remodel ECM and promote immune infiltration, with levels tracking influenza severity.

    Evidence Single-cell transcriptomics, mouse influenza model, and human BALF measurements across cohorts

    PMID:33116313

    Open questions at the time
    • Specific ECM substrate driving immune infiltration not defined
    • Causal mechanism in humans remains correlative
  33. 2021 Medium

    Refined substrate-site preference by mapping 21 novel versican V1 cleavage sites and a P1-Glu preference, expanding the proteolytic landscape.

    Evidence In vitro versican digestion with active versus inactive enzyme and label-free LC-MS/MS proteomics

    PMID:34450332

    Open questions at the time
    • Biological significance of individual novel sites untested
    • In vivo occurrence of these cleavages not confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a secreted matrix protease achieves nuclear localization and intracellular PARP-1 cleavage, and how its diverse extracellular and intracellular activities are coordinated across tissues, remains unresolved.
  • No mechanism for nuclear import of ADAMTS4 established
  • Integration of matrix-remodeling, anti-inflammatory, and apoptotic functions not unified
  • Substrate driving most in vivo phenotypes often unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016787 hydrolase activity 3 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005576 extracellular region 3 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 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3
Partners
CCN1FN1FURINLRP1MMP17SDC1TIMP3

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ADAMTS4 (aggrecanase-1) cleaves aggrecan at the Glu373-Ala374 bond in the interglobular domain and at four additional sites within the chondroitin sulfate-rich region (KEEE1667-1668GLGS, GELE1480-1481GRGT, TAQE1771-1772AGEG, VSQE1871-1872LGQR), with cleavage in the CS-rich region occurring more efficiently than at the IGD site. In vitro cleavage assay with recombinant human ADAMTS4 on native aggrecan, followed by N-terminal sequence analysis of fragments The Journal of biological chemistry High 10751421
2000 The thrombospondin type-1 (TSP-1) motif of ADAMTS4 binds to glycosaminoglycans of aggrecan and is required for aggrecan substrate recognition and cleavage; truncated ADAMTS4 lacking the TSP-1 motif failed to cleave aggrecan, TSP-1 peptides blocked cleavage by competing with enzyme binding, and GAG-free aggrecan was not cleaved. Domain truncation mutagenesis, peptide competition assays, aggrecan cleavage assays with GAG-free aggrecan The Journal of biological chemistry High 10827174
2000 ADAMTS4 cleaves brevican at the Glu395-Ser396 bond within the central non-homologous domain, a different site from that cleaved by MMPs (Ala360-Phe361), demonstrating substrate specificity distinct from MMP family members. In vitro digestion of brevican with purified ADAMTS4 and MMPs, followed by N-terminal sequence analysis of cleavage fragments The Journal of biological chemistry High 10986281
2001 ADAMTS4 cleaves versican V1 at the Glu441-Ala442 bond, generating the DPEAAE neoepitope, as demonstrated by recombinant enzyme cleavage of recombinant and native human versican substrates; mature ADAMTS4 protein was also detected in aortic intima extracts. In vitro cleavage assay with recombinant ADAMTS4 and recombinant/native versican V1 substrates; Western analysis with neoepitope antisera; Western analysis of aortic tissue The Journal of biological chemistry High 11278559
2001 TIMP-3 is a potent inhibitor of ADAMTS4 (aggrecanase-1) with Ki values in the subnanomolar range; the N-terminal inhibitory domain of TIMP-3 alone is sufficient for this inhibition, whereas TIMP-1, TIMP-2 and TIMP-4 do not effectively inhibit ADAMTS4. In vitro inhibition kinetics assay with N-terminal TIMP-3 domain expressed from bacterial inclusion bodies The Journal of biological chemistry High 11278243
2002 ADAMTS4 activation requires C-terminal truncation from the p75 (or p68) form to the p60/p53 forms; only the p60 and p53 forms exhibit aggrecanase and versicanase activity; this truncation is mediated by a MMP (GPI-anchored type) and blocked by TIMP-1, MMP inhibitors, furin inhibitors, and inhibitors of GPI synthesis, but not by serine or cysteine protease inhibitors. Stable transfection of human chondrosarcoma cells with full-length ADAMTS4; domain-specific antisera Western analysis; preparative SDS-PAGE isolation of individual forms with activity assays; pharmacological inhibition studies The Journal of biological chemistry High 11796708
2002 Full-length ADAMTS4 undergoes autocatalytic C-terminal truncation to generate ~53 kDa and ~40 kDa isoforms with reduced affinity for sulfated GAGs; the cysteine-rich and spacer domains contain additional GAG-binding sites beyond the thrombospondin motif, as demonstrated by competition with synthetic peptides mimicking GAG-binding consensus sequences. C-terminal sequencing and mass analysis of autocatalytic fragments; GAG-binding competition assays with deglycosylated aggrecan and synthetic peptides The Journal of biological chemistry High 12202483
2002 ADAMTS4 also cleaves the Asn341-Phe342 MMP site in aggrecan interglobular domain (secondarily to the Glu373-Ala374 aggrecanase site); this secondary cleavage is inhibited by TIMP-3 but not TIMP-1 or TIMP-2, distinguishing it from MMP activity. In vitro digestion of native human aggrecan and recombinant G1-G2 constructs with purified ADAMTS4; inhibitor studies with TIMP-1, TIMP-2, TIMP-3 The Journal of biological chemistry High 11854269
2003 The non-catalytic C-terminal spacer domain of ADAMTS4 masks its general proteolytic activity; deletion of the spacer domain generates a more promiscuous enzyme with enhanced activity against the Glu373-Ala374 IGD bond, Cm-Tf, fibromodulin, and decorin, while removal of the cysteine-rich domain reduces aggrecanase activity by 80%; the full-length 70 kDa form is the most effective aggrecanase but shows little IGD activity and binds to the pericellular matrix, whereas spacer-deleted ADAMTS4 is released from the matrix. Expression of domain deletion mutants in mammalian cells; aggrecanase activity assays; general proteinase substrate (Cm-Tf) assays; Western analysis with domain-specific antisera The Journal of biological chemistry High 14662755
2003 Proprotein convertase furin cleaves the prodomain of pro-ADAMTS4 in the trans-Golgi network at multiple sites (RPRR206-209, RAKR209-212, or KR211-212), and the pro-form (but not the mature form) physically co-precipitates with furin; processing is blocked by brefeldin A and furin-specific inhibitors; a furin-independent activation pathway also exists. Co-localization by confocal microscopy; co-immunoprecipitation; RNA interference of furin; furin-specific inhibitor treatment; brefeldin A treatment The Journal of biological chemistry High 14744861
2003 C-terminal truncation of ADAMTS4 from p68 to p53 (required for activation of IGD cleavage) is mediated by GPI-anchored MT4-MMP (MMP-17) on the cell surface; co-transfection with active MT4-MMP enhanced truncation, while inactive MT4-MMP mutant was ineffective; activated p53 ADAMTS4 remains associated with cell surface syndecan-1 through both chondroitin sulfate and heparan sulfate chains. Co-transfection of ADAMTS4 with active/inactive MT4-MMP; phosphatidylinositol-specific phospholipase C treatment; glycosaminoglycan lyase digestions with FACE analysis; immunoprecipitation with anti-syndecan-1 The Journal of biological chemistry High 14701864
2004 ADAMTS4 binds to the C-terminal domain of fibronectin through its spacer domain; this interaction inhibits aggrecanase activity of ADAMTS4 (IC50 ~110 nM for full-length fibronectin; ~170 nM for 40-kDa C-terminal fibronectin fragment); ADAMTS4 lacking the spacer domain is not inhibited by fibronectin and does not co-localize with fibronectin on cell surfaces. Yeast two-hybrid screening; chemical cross-linking; solid-phase binding assay; confocal microscopy co-localization; aggrecanase activity assay with inhibition by fibronectin The Journal of biological chemistry High 15161923
2004 ADAMTS4 cleaves versican V2 at Glu405-Gln406 to generate the brain protein GHAP (glial hyaluronate binding protein), as demonstrated by immunological analysis of purified human GHAP with anti-neoepitope antiserum and in vitro digestion of human cerebellum proteoglycans with ADAMTS4. Anti-neoepitope antiserum immunological analysis; in vitro digestion of human cerebellum proteoglycans with ADAMTS4; Western analysis The Biochemical journal Medium 14561220
2005 Pro-ADAMTS4 is not capable of autocatalytic prodomain removal under physiological conditions (mercuric compounds, temperatures 22-65°C, ionic strengths 0.1-1M, neutral/acidic pH do not trigger autocatalysis); proprotein convertases furin, PACE4, and PC5/6 efficiently remove the prodomain at Arg212/Phe213 to generate active enzyme; MMP-9 and trypsin can also remove the prodomain; autocatalysis occurs only at basic pH 8-10. In vitro incubation of pro-ADAMTS4 with diverse proteases and conditions; activity assays; N-terminal sequencing Archives of biochemistry and biophysics High 16289022
2005 MT4-MMP plays a central role in IL-1-induced cartilage aggrecanolysis by activating ADAMTS4; IL-1 treatment causes loss of p68 ADAMTS4 from cartilage and appearance of p53 in medium; blocking MT4-MMP (via ManN or EST) nearly completely prevented p68 loss, p53 formation, and aggrecan degradation; increased ADAMTS4/5 mRNA by IL-1 was not accompanied by increased total enzyme protein, indicating that activation rather than new synthesis drives aggrecanolysis. Western analysis of aggrecan fragments and ADAMTS4 species in cartilage explants; real-time PCR; pharmacological inhibition with ManN (GPI synthesis inhibitor) and EST (MMP expression inhibitor) Osteoarthritis and cartilage Medium 15780640
2006 The spacer domain of ADAMTS4 is critical for its localization in the extracellular matrix, whereas for ADAMTS5 the cysteine-rich domain is more influential; sequential inclusion of C-terminal ancillary domains of ADAMTS4 progressively enhances activity against aggrecan, Cm-Tf, fibromodulin, decorin, biglycan, and fibronectin; very little proteolytic activity is detected with the catalytic domain alone. Expression of domain deletion mutants; activity assays against multiple substrates; ECM localization assays The Journal of biological chemistry High 17430884
2006 The NFATp and Runx2 transcription factors regulate ADAMTS4 promoter activity in chondrocytes; the NFI binding site (-441 to -429) acts as a negative regulator of the ADAMTS4 promoter specifically in chondrocytes; the region -383 to +10 is necessary for full basal promoter activity and contains Sp1 and AP2 sites. Reporter gene (promoter-luciferase) assays with deletion variants; mRNA analysis in porcine chondrocytes and NIH3T3 cells Biochemical and biophysical research communications Medium 11254106 16677612
2007 TIMP-3 inhibition of ADAMTS4 is enhanced in the presence of aggrecan through binding of chondroitin 6-sulfate GAGs to the thrombospondin type 1 motif and spacer domains of ADAMTS4, forming a complex with improved TIMP-3 binding affinity over free ADAMTS4. FRET peptide assay; aggrecan-binding competition experiments; solid-phase binding assays The Journal of biological chemistry Medium 17470431
2007 Crystal structures of ADAMTS4 reveal two distinct catalytic site configurations: a closed autoinhibited non-binding form and an open binding-competent form; mature aggrecanases exist as an ensemble of at least two isomers, only one of which is proteolytically active. X-ray crystallography of human ADAMTS4 in apo and inhibitor-bound forms Protein science High 18042673
2007 Aggrecan cleavage by ADAMTS4 proceeds via an exosite mechanism: substrate initially binds at an exosite (reflected in the apparent Km), then the peptide sequence binds at the active site; an active-site inhibitor (SC81956, hydroxamic acid, Ki=23 nM) is non-competitive with aggrecan but competitive with low-molecular-weight peptide substrates, consistent with inability to compete with the final Michaelis complex. Enzyme kinetics with native aggrecan and fluorogenic peptide substrates; inhibition kinetics with varying substrate concentrations Biochemistry Medium 17487981
2008 Calcium pentosan polysulfate (CaPPS) directly inhibits the aggrecanase activity of ADAMTS4 by interacting with its C-terminal ancillary domains (thrombospondin type 1 repeat, cysteine-rich, and spacer domains), without affecting mRNA expression of ADAMTS species. Aggrecanase activity assay in IL-1α-stimulated OA chondrocytes; synthetic peptide competition of CaPPS binding; mRNA expression analysis FEBS letters Medium 18671975
2009 ADAMTS4 processes the matricellular protein hevin in mouse brain; in vitro digestion of hevin with ADAMTS4 produced fragments similar to those present in brain lysates; a SPARC-like fragment generated from hevin co-localizes with ADAMTS4 in vivo in mouse cerebellum, and this proteolysis contributes to normal cerebellar development. In vitro digestion of hevin with recombinant ADAMTS4; co-localization by confocal microscopy with monoclonal antibodies; comparison of brain lysate fragments The Journal of biological chemistry Medium 20018883
2012 ADAMTS4 is endocytosed and degraded by chondrocytes via LRP1; the cysteine-rich and spacer domains of ADAMTS4 are responsible for binding to LRP1 clusters II and IV (KD,app ~98 nM and ~73 nM, respectively); the half-life of ADAMTS4 endocytosis is ~220 min, slower than ADAMTS5 (~100 min) due to 13-fold lower affinity for LRP1; ADAMTS5 competitively inhibits ADAMTS4 endocytosis but not vice versa. Domain deletion mutagenesis; soluble LRP1 cluster binding assays; endocytosis kinetics; competitive inhibition assays The Journal of biological chemistry High 24474687
2012 ADAMTS4 degrades brevican, neurocan, and phosphacan core proteins and reverses their inhibition of neurite outgrowth; local administration of ADAMTS4 protein promoted motor function recovery and enhanced axonal regeneration/sprouting after spinal cord contusion injury in mice. In vitro CSPG degradation assay; neurite outgrowth assay; in vivo spinal cord contusion model with local ADAMTS4 administration and behavioral assessment Journal of neuroinflammation Medium 22420304
2012 ADAMTS4 and ADAMTS5 participate in regulated proteolytic processing of Reelin; both enzymes cleave Reelin in vitro, and TIMP-3, α-2-Macroglobulin, serpins, and MMP-9 modulate this cleavage; ADAMTS4 and Reelin expression levels largely overlap in murine hippocampus. In vitro cleavage assay with recombinant enzymes and Reelin; inhibitor studies with TIMPs and serpins; immunolocalization in murine hippocampus PloS one Medium 23082219
2013 TNF-α and IL-1β regulate ADAMTS4 expression in nucleus pulposus cells through MAPK (ERK1, p38α, p38β2, p38γ) and NF-κB signaling; p65 induces ADAMTS4 promoter activity while p50 blocks it; silencing of NF-κB components (p65, p52, IKK-α, IKK-β) decreased ADAMTS-4 and -5 levels and aggrecan degradation; both ADAMTS-4 and ADAMTS-5 contribute non-redundantly to aggrecan degradation in human NP cells. Transient transfection promoter assays; MAPK/NF-κB inhibitors; gain/loss-of-function studies; lentiviral shRNA silencing; Western blotting; aggrecan degradation assays The American journal of pathology Medium 23602832
2013 IL-1β-induced upregulation of ADAMTS4 in human OA chondrocytes is suppressed by miR-125b overexpression; luciferase reporter assay with mutated miR-125b binding site in the ADAMTS4 3'UTR confirmed direct interaction, establishing miR-125b as a direct post-transcriptional regulator of ADAMTS4. miR-125b overexpression; luciferase reporter assay with wild-type and mutant ADAMTS4 3'UTR; quantitative RT-PCR; Western blotting Arthritis research & therapy Medium 23406982
2015 CCN1 (Cyr61) binds specifically to the cysteine-rich domain of ADAMTS4 and inhibits its aggrecanase activity; CCN1 co-purifies with ADAMTS4-transfected chondrocytic cells (identified by LC-MS/MS), and the interaction was confirmed by immunoprecipitation and solid-phase binding assay; in TGFβ-treated chondrocytes, CCN1 knockdown reveals latent ADAMTS4 aggrecanase activity. LC-MS/MS identification of co-purified proteins; immunoprecipitation; solid-phase binding assay; aggrecan digestion assay; siRNA knockdown; immunohistochemistry Arthritis & rheumatology Medium 25709087
2017 ADAMTS4 translocates to the nucleus in smooth muscle cells (SMCs) under stress and directly cleaves and degrades poly ADP ribose polymerase-1 (PARP-1), leading to SMC apoptosis; ADAMTS4 deficiency in mice significantly reduced angiotensin II/high-fat diet-induced aortic aneurysm formation, elastic fiber destruction, versican degradation, macrophage infiltration, and apoptosis. Adamts4-/- mouse model of sporadic AAD (angiotensin II + high fat diet); nuclear translocation demonstrated by imaging of apoptotic SMCs; direct PARP-1 cleavage assay; aortic phenotyping (diameter, histology) Scientific reports Medium 28955046
2018 ADAMTS4 cleaves APP/Aβ to generate N-truncated Aβ4-x peptides; a recognition site for ADAMTS4 was identified in the Aβ sequence; inducible overexpression of ADAMTS4 in HEK293 cells increased secretion of Aβ4-40; in ADAMTS4-/- mice (5xFAD background) Aβ4-40 levels were reduced; ADAMTS4 is exclusively expressed in oligodendrocytes in adult mouse brain, and ADAMTS4-/- oligodendrocyte cultures do not produce Aβ4-40. ADAMTS4 recognition site identification; inducible overexpression in HEK293 cells with Aβ ELISA; ADAMTS4-/- mouse model; primary oligodendrocyte cultures from ADAMTS4-/- mice; immunofluorescence co-localization Acta neuropathologica High 30426203
2018 Sox4 (and Sox11) directly bind to the ADAMTS4 promoter and upregulate ADAMTS4 and ADAMTS5 gene expression; demonstrated by luciferase reporter assay and chromatin immunoprecipitation; Sox4 overexpression in mouse femoral head cartilage organ cultures caused cartilage destruction associated with increased aggrecanase expression. Luciferase reporter assay; chromatin immunoprecipitation (ChIP); adenoviral overexpression in mouse femoral head organ cultures; quantitative RT-PCR FASEB journal Medium 30016600
2020 Damage-responsive lung fibroblasts produce ADAMTS4 during severe respiratory viral infection; ADAMTS4 ECM protease activity modifies the lung microenvironment to promote immune cell infiltration; ADAMTS4 levels in lower respiratory tract samples correlated with severity of influenza infection in three human cohorts. Single-cell transcriptomics identifying fibroblast activation states; mouse influenza model with fibroblast characterization; measurement of ADAMTS4 in human BALF from influenza patients Nature Medium 33116313
2021 ADAMTS4 (along with ADAMTS1 and ADAMTS5) cleaves versican V1 at multiple sites beyond the known Glu441-Ala442 bond; 21 novel cleavage sites were identified using LC-MS/MS label-free proteomics with z-score ranking; ADAMTS4 shows a substrate site preference for P1-Glu residue. In vitro digestion of recombinant versican V1 with recombinant full-length ADAMTS4 vs. catalytically inactive mutant; LC-MS/MS label-free quantitative proteomics with z-score analysis Journal of proteomics Medium 34450332
2011 Adamts4 and Adamts1 play redundant roles in perinatal kidney development; Adamts4 single-knockout mice are phenotypically normal, but >95% of Adamts1-/-;Adamts4-/- double-knockout mice die within 72 hours of birth with marked thinning of the renal medulla, a defect not observed in embryos. Gene targeting to generate Adamts4-/- mice; genetic cross with Adamts1-/- mice; histological analysis of renal medulla Developmental dynamics Medium 21584905
2007 IL-1β induction of ADAMTS4 expression in human OA chondrocytes requires PKCζ (an atypical PKC); PKCζ mediates IL-1β-induced NF-κB activation (phosphorylation of IKKαβ and IκBα); pharmacological inhibition or siRNA/shRNA knockdown of PKCζ suppressed IL-1β-induced ADAMTS4 mRNA upregulation and aggrecanase activity. Pharmacological inhibitors of atypical PKCs; siRNA and shRNA knockdown of PKCζ; Western blotting for NF-κB pathway phosphorylation; quantitative PCR for ADAMTS4 mRNA; aggrecanase activity assay Arthritis and rheumatism Medium 18050214
2009 IL-1β induction of ADAMTS4 in chondrocytes requires MyD88, IRAK1, and TRAF6 adaptor proteins (each individually required but partial); Ras-mediated ROS production synergizes with these adaptors; combined knockdown of Ras and individual adaptors strongly blocked NF-κB activation (IKKαβ, IκBα phosphorylation) and ADAMTS4 induction. siRNA-mediated knockdown of MyD88, IRAK1, TRAF6, and Ras; antioxidant treatment; Western blotting for NF-κB pathway; ADAMTS4 mRNA quantitation Journal of immunology Medium 19342688
2016 ADAMTS4 exerts anti-inflammatory effects in microglia and astrocytes; recombinant ADAMTS4 pretreatment of primary microglia and astrocytes decreased LPS-induced NO production and pro-inflammatory cytokine synthesis/release (NOS2, CCL2, TNF-α, IL-1β, MMP-9); siRNA silencing of ADAMTS4 increased these pro-inflammatory markers; in vivo, ADAMTS4 treatment decreased astrogliosis, macrophage infiltration, and increased M2 microglia after middle cerebral artery occlusion. Recombinant ADAMTS4 treatment of primary microglia/astrocyte cultures; siRNA silencing of ADAMTS4; NO and cytokine measurement; mouse middle cerebral artery occlusion model with ADAMTS4 treatment; immunohistochemistry Glia Medium 27301579
2013 ADAMTS4 contributes to aggrecan degradation in human osteoarthritic nucleus pulposus cells non-redundantly with ADAMTS5; silencing either enzyme individually reduced TNF-α-dependent aggrecan degradation. Lentiviral shRNA silencing of ADAMTS-4 or ADAMTS-5 in human NP cells; Western blotting; aggrecan degradation assay The American journal of pathology Medium 23602832

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 404 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 334 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
2020 Exuberant fibroblast activity compromises lung function via ADAMTS4. Nature 176 33116313
2003 Altered proteolytic activities of ADAMTS-4 expressed by C-terminal processing. The Journal of biological chemistry 176 14662755
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 166 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
2001 Cloning and characterization of ADAMTS-14, a novel ADAMTS displaying high homology with ADAMTS-2 and ADAMTS-3. The Journal of biological chemistry 154 11741898
2002 Activation of the proteolytic activity of ADAMTS4 (aggrecanase-1) by C-terminal truncation. The Journal of biological chemistry 153 11796708
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 120 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 111 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
2008 Expression of ADAMTS-4 by chondrocytes in the surface zone of human osteoarthritic cartilage is regulated by epigenetic DNA de-methylation. Rheumatology international 90 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 90 16046392
2003 Transforming growth factor-beta induces secretion of activated ADAMTS-2. A procollagen III N-proteinase. The Journal of biological chemistry 90 12646579
2013 MicroRNA-125b regulates the expression of aggrecanase-1 (ADAMTS-4) in human osteoarthritic chondrocytes. Arthritis research & therapy 89 23406982
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
2012 The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury. Journal of neuroinflammation 77 22420304
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 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 69 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
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 65 25045124
2015 Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT). ACS medicinal chemistry letters 64 26288689
2013 Tumor necrosis factor-α induces ADAMTS-4 expression in human osteoarthritis chondrocytes. Molecular medicine reports 59 24126638
2010 ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity. Cellular and molecular life sciences : CMLS 59 20574651
2004 ADAMTS4 (aggrecanase-1) interaction with the C-terminal domain of fibronectin inhibits proteolysis of aggrecan. The Journal of biological chemistry 59 15161923
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 57 17470431
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
2006 Regulation of the human ADAMTS-4 promoter by transcription factors and cytokines. Biochemical and biophysical research communications 52 16677612
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 51 30426203
2016 Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice. Scientific reports 51 27491335
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 49 30016600
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
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
2021 Identification of novel ADAMTS1, ADAMTS4 and ADAMTS5 cleavage sites in versican using a label-free quantitative proteomics approach. Journal of proteomics 38 34450332
2016 Anti-inflammatory effects of ADAMTS-4 in a mouse model of ischemic stroke. Glia 38 27301579
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
2020 Astrocyte-selective AAV-ADAMTS4 gene therapy combined with hindlimb rehabilitation promotes functional recovery after spinal cord injury. Experimental neurology 34 32044329
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
2011 Interleukin-6 upregulates expression of ADAMTS-4 in fibroblast-like synoviocytes from patients with rheumatoid arthritis. International journal of rheumatic diseases 32 22324945
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
2009 Cell death-associated ADAMTS4 and versican degradation in vascular tissue. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 29 19506088
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
2020 MiR-126a-5p limits the formation of abdominal aortic aneurysm in mice and decreases ADAMTS-4 expression. Journal of cellular and molecular medicine 28 32469162
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
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
2016 ADAMTS-4 promotes neurodegeneration in a mouse model of amyotrophic lateral sclerosis. Molecular neurodegeneration 27 26809777
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
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 26 29694979
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 25 24752352
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
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 24 33350314
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
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
2018 IL-1β-induced miR-34a up-regulation inhibits Cyr61 to modulate osteoarthritis chondrocyte proliferation through ADAMTS-4. Journal of cellular biochemistry 21 29236314
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
2016 The impact of parathyroidectomy on serum ADAMTS1, ADAMTS4 levels, insulin resistance, and subclinical cardiovascular disease in primary hyperparathyroidism. Endocrine 20 27844209
2012 Expression of ADAMTS-1, ADAMTS-4, ADAMTS-5 and TIMP3 by hepatocellular carcinoma cell lines. International journal of oncology 20 22735305
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
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 19 36403758
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
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

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