Affinage

ADAMTS5

A disintegrin and metalloproteinase with thrombospondin motifs 5 · UniProt Q9UNA0

Length
930 aa
Mass
101.7 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

ADAMTS5 is a secreted zinc metalloprotease that serves as the principal aggrecanase in cartilage and a major versicanase in cardiovascular, dermal, immune, and neural tissues. Its reprolysin-type catalytic domain cleaves chondroitin sulfate proteoglycans—aggrecan at multiple Glu-X bonds, versican at Glu441-Ala442 and additional sites, brevican, and biglycan—with substrate recognition requiring the C-terminal ancillary/spacer domain to dock onto chondroitin sulfate chains of the substrate (PMID:10438522, PMID:25122765, PMID:12392761, PMID:16507336). Genetic deletion of ADAMTS5 in mice prevents cartilage destruction in osteoarthritis models, impairs cardiac valve maturation through versican accumulation (rescued by Vcan haploinsufficiency), delays dermal wound healing via CD44-dependent aggrecan/versican buildup that redirects TGFβ signaling from Smad2/3 to Smad1/5/8, and compromises T cell migration during viral infection (PMID:15800624, PMID:21749862, PMID:21566131, PMID:27855162). ADAMTS5 activity is inhibited by TIMP-3 at subnanomolar affinity, cleared from the extracellular space via LRP1-mediated endocytosis, activated by syndecan-4 through direct interaction and MAPK–MMP-3 signaling, and transcriptionally controlled by NF-κB/RelA, Runx2 (regulated by WWP2-mediated ubiquitination), Sox4, and hedgehog–primary cilia mechanosensory pathways (PMID:11278243, PMID:19684582, PMID:23963448, PMID:31160553, PMID:24457103).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    The identity of aggrecanase-2 was resolved: ADAMTS5 was cloned, its multidomain architecture defined, and its ability to cleave aggrecan at the Glu373-Ala374 'aggrecanase' site demonstrated with purified recombinant protein, establishing it as a bona fide aggrecanase.

    Evidence Recombinant ADAMTS5 expression in insect cells, in vitro cleavage assay, cDNA cloning and domain mapping

    PMID:10438522 PMID:10464288

    Open questions at the time
    • Relative importance versus ADAMTS4 in vivo unknown
    • Substrate repertoire beyond aggrecan uncharacterized
    • Activation mechanism and prodomain processing not defined
  2. 2001 High

    The endogenous regulation of ADAMTS5 was established when TIMP-3 was shown to inhibit the enzyme with subnanomolar Ki, identifying the physiological inhibitor.

    Evidence In vitro enzyme inhibition assay with recombinant N-TIMP-3

    PMID:11278243

    Open questions at the time
    • Whether TIMP-3 is the sole endogenous inhibitor in vivo not established
    • Structural basis of TIMP-3–ADAMTS5 interaction unresolved
  3. 2002 High

    Detailed substrate specificity profiling revealed ADAMTS5 cleaves aggrecan at multiple Glu-X sites in the CS-2 region more readily than at Glu373-Ala374, and demonstrated a narrow substrate repertoire excluding collagens, fibronectin, and thrombospondin.

    Evidence Comprehensive in vitro substrate panel with recombinant ADAMTS5

    PMID:12392761

    Open questions at the time
    • Non-aggrecan proteoglycan substrates not yet tested
    • In vivo cleavage site hierarchy unknown
  4. 2005 High

    The long-standing question of whether ADAMTS4 or ADAMTS5 is the dominant aggrecanase in cartilage destruction was answered: ADAMTS5 catalytic-domain knockout mice were protected from surgically induced OA, establishing ADAMTS5 as the critical aggrecanase in murine cartilage.

    Evidence Genetic knockout mouse, surgical destabilization of medial meniscus OA model, histological scoring

    PMID:15800624

    Open questions at the time
    • Whether ADAMTS5 is equally dominant in human OA not proven
    • Compensatory ADAMTS4 role not fully excluded
    • Mechanism of ADAMTS5 activation in vivo unknown
  5. 2006 High

    Domain requirements for aggrecanase activity were mapped: the TSR-1 domain is necessary but not sufficient, all ADAMTS5 isoforms bind sulfated GAGs via C-terminal domains, and ADAMTS5-null chondrocytes are completely aggrecanase-inactive, confirming no functional redundancy with ADAMTS4 in this system.

    Evidence Systematic domain truncation with recombinant protein in vitro, epiphyseal chondrocyte cultures from multiple knockout mouse lines

    PMID:16406703 PMID:16507336

    Open questions at the time
    • Whether GAG binding is required for in vivo activity not tested
    • Mechanism of ancillary domain contribution to catalysis unclear
  6. 2007 High

    Crystal structures of the ADAMTS5 catalytic domain (to 1.4 Å resolution) revealed an autoinhibited closed conformation and an open inhibitor-bound form, providing atomic-level insight into the active site and explaining conformational regulation of activity.

    Evidence X-ray crystallography of recombinant ADAMTS5 catalytic domain ± inhibitor

    PMID:17991750 PMID:18042673

    Open questions at the time
    • No structure of full-length enzyme with ancillary domains
    • Structural basis of substrate recognition beyond the catalytic cleft unknown
    • Dynamics of closed-to-open transition not characterized
  7. 2009 High

    The activation mechanism in cartilage was elucidated: syndecan-4 activates ADAMTS-5 through direct interaction and through MAPK-dependent MMP-3 expression, and syndecan-4 deficiency protects from OA, linking a cell-surface proteoglycan to protease activation.

    Evidence Syndecan-4 KO mice, intra-articular antibody, surgical OA model, direct interaction studies

    PMID:19684582

    Open questions at the time
    • Structural basis of syndecan-4–ADAMTS5 interaction unknown
    • Whether syndecan-4 mechanism operates in non-cartilage tissues untested
  8. 2010 High

    Transcriptional regulation of ADAMTS5 was defined: NF-κB/RelA directly activates the ADAMTS5 promoter at two core elements, and mechanical strain induces expression via p38 MAPK–Runx2; ADAMTS5 is ~100-fold more efficient than MMP-3 at interglobular domain cleavage, explaining its dominance in aggrecan catabolism.

    Evidence Promoter-luciferase mutagenesis, ChIP, RelA conditional KO chondrocytes, cyclic tensile strain with inhibitors and Runx2 overexpression, comparative in vitro enzyme kinetics

    PMID:21055468 PMID:21094261 PMID:23963448

    Open questions at the time
    • Interplay between RelA and Runx2 pathways not dissected
    • Post-transcriptional regulation largely unexplored
  9. 2011 High

    ADAMTS5's biological roles expanded beyond cartilage: versican cleavage by ADAMTS5 was shown essential for cardiac valve maturation (rescued by Vcan haploinsufficiency) and dermal wound repair (where its loss shifts TGFβ signaling from Smad2/3 to Smad1/5/8 via aggrecan/versican accumulation).

    Evidence Adamts5 KO mice crossed with Vcan haploinsufficient or Cd44 KO mice, cardiac histology, excisional wound models, Smad phosphorylation assays

    PMID:21566131 PMID:21749862 PMID:21828051

    Open questions at the time
    • Whether versican versus aggrecan is the dominant substrate in skin unclear
    • Downstream signaling mediators between versican fragments and Smad pathway unknown
  10. 2012 Medium

    Multiple regulatory and effector mechanisms were defined: ADAMTS5 is endocytosed via LRP1, its spacer domain forms a trimolecular complex with TIMP-3 and pentosan polysulfate, and it cleaves vascular biglycan and versican to modulate LDL retention in artery walls.

    Evidence LRP1 cluster mapping and competition assays, Biacore binding of trimolecular complex with domain mutants, Adamts5-deficient mouse aortas with LDL-binding assays

    PMID:22299597 PMID:22493487 PMID:27084377

    Open questions at the time
    • LRP1-mediated clearance rate in vivo not quantified
    • Relevance of PPS trimolecular complex to endogenous GAGs uncertain
    • Human vascular studies lacking
  11. 2014 High

    The exosite mechanism for versican recognition was resolved: ADAMTS5 C-terminal ancillary domains dock onto specific chondroitin sulfate chains at Ser507/Ser525 of versican-V1, and CS modification at these sites is both necessary and sufficient for cleavage at Glu441-Ala442.

    Evidence Systematic site-directed mutagenesis of versican CS attachment sites and ADAMTS5 ancillary domain deletions, in vitro cleavage assay

    PMID:25122765

    Open questions at the time
    • Whether the same exosite mechanism applies to aggrecan recognition not shown
    • Structural visualization of docking interface lacking
  12. 2016 Medium

    ADAMTS5-mediated versican proteolysis was established as required for T cell migration during influenza infection, extending its immune function beyond ECM turnover.

    Evidence Adamts5 KO mice, influenza infection model, T cell migration assays, versican IHC

    PMID:27855162

    Open questions at the time
    • Which ADAMTS5-expressing cell type is responsible not defined
    • Whether versikine fragments have direct signaling activity in immune cells unknown
  13. 2019 High

    Upstream transcriptional circuitry was extended: WWP2 E3 ubiquitin ligase suppresses ADAMTS5 by degrading Runx2, defining a WWP2→Runx2→ADAMTS5 axis, while Sox4 directly binds and activates the ADAMTS5 promoter.

    Evidence Wwp2 KO and catalytic-dead KI mice with OA model, Runx2 ubiquitination assays; Sox4 ChIP and luciferase reporter plus adenoviral overexpression in cartilage organ culture

    PMID:30016600 PMID:31160553

    Open questions at the time
    • Cross-talk between Sox4 and Runx2 pathways not examined
    • Whether WWP2 pathway operates in non-cartilage tissues unknown
  14. 2020 High

    ADAMTS5 was identified as a downstream effector of MEKK3-KLF2/4 signaling in endothelial cells driving cerebral cavernous malformation through versican cleavage, with both gain- and loss-of-function genetics and substrate epistasis confirming the pathogenic mechanism.

    Evidence Conditional endothelial ADAMTS5 KO and OE mouse models, versican KD, CCM neonatal model

    PMID:32648916

    Open questions at the time
    • Whether versikine fragment itself is pathogenic or whether versican removal is sufficient not distinguished
    • Relevance to human CCM not confirmed
  15. 2021 High

    Quantitative proteomics expanded the ADAMTS5 cleavage map on versican and in cardiac tissue, revealing multiple novel cleavage sites with P1-Glu preference and showing that cardiac ADAMTS5 loss causes versican buildup, integrin/connexin reduction, and functional decline.

    Evidence LC-MS/MS TAILS/semi-tryptic peptide analysis of in vitro versican digestion; Adamts5ΔCat mice with angiotensin II cardiac stress model and echocardiography

    PMID:34450332 PMID:34806902

    Open questions at the time
    • Whether all identified cleavage sites are physiologically relevant unknown
    • Mechanism linking versican buildup to integrin/connexin loss not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structure of full-length ADAMTS5 with ancillary domains bound to substrate, the relative contribution of ADAMTS5 versus ADAMTS4 in human (as opposed to murine) OA, the direct signaling roles of versikine cleavage fragments, and whether the anti-angiogenic TSR1-dependent activity operates physiologically.
  • No full-length ADAMTS5 structure with substrate
  • Human genetic evidence for ADAMTS5 in OA causation lacking
  • Versikine signaling receptor/pathway unidentified
  • Catalysis-independent anti-tumor mechanism not validated in physiological settings

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 3
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 3
Pathway
R-HSA-1474244 Extracellular matrix organization 5 R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 1
Partners
ACANLRP1RUNX2SDC4TIMP3VCANWWP2

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 ADAMTS5 (then called ADAMTS11/aggrecanase-2) was cloned and shown to cleave aggrecan at the Glu373-Ala374 'aggrecanase' site; recombinant human ADAMTS5 expressed in insect cells demonstrated this cleavage activity with an inhibitor profile indistinguishable from native aggrecanase. Recombinant protein expression in insect cells, in vitro cleavage assay, inhibitor profiling The Journal of biological chemistry High 10438522
1999 ADAMTS5 domain architecture was defined: preproregion, reprolysin-type catalytic domain, disintegrin-like domain, thrombospondin type-1 module, cysteine-rich domain, spacer domain, and C-terminal TS module. It is a secreted zinc metalloprotease. cDNA cloning and sequence analysis, domain homology mapping The Journal of biological chemistry High 10464288
2001 TIMP-3 N-terminal inhibitory domain is a potent inhibitor of ADAMTS-5 (aggrecanase-2) with Ki values in the subnanomolar range, establishing TIMP-3 as the primary endogenous inhibitor of aggrecanase activity. In vitro enzyme inhibition assay with recombinant N-TIMP-3 produced by bacterial expression The Journal of biological chemistry High 11278243
2002 ADAMTS-5 cleaves aggrecan at multiple sites: Glu1480-Gly1481, Glu1667-Gly1668, Glu1771-Ala1772, Glu1871-Leu1872 more readily than at Glu373-Ala374, with an additional unique cleavage site between Gly1481 and Glu1667. ADAMTS-5 cleaves aggrecan ~2-fold slower than ADAMTS-4 and cannot cleave fibronectin, thrombospondin, collagens, casein, transferrin, or activate MMP-3 zymogen. In vitro substrate cleavage assays with recombinant human ADAMTS-5 Matrix biology : journal of the International Society for Matrix Biology High 12392761
2005 Deletion of the ADAMTS5 catalytic domain in mice prevents cartilage aggrecan degradation and significantly reduces cartilage destruction in a surgically induced osteoarthritis model, establishing ADAMTS5 as the primary aggrecanase responsible for aggrecan degradation in murine OA. Genetic knockout mouse (catalytic domain deletion), surgical destabilization of medial meniscus OA model, histological scoring Nature High 15800624
2005 ADAMTS-5 expressed by glioblastoma cells cleaves brevican at the Glu395-Ser396 bond, generating two major fragments identical to those produced by ADAMTS-4; ADAMTS-1 lacks this activity. Forced ADAMTS-5 expression in glioma cell lines stimulates cell invasion. 293T transfection/overexpression, Western blot of brevican fragments, invasion assay Acta neuropathologica Medium 16133547
2006 ADAMTS-5 C-terminal truncation studies showed that the TSR-1 domain is necessary (but not sufficient) for aggrecanase activity toward aggrecan in the interglobular domain and CS-2 region; all three ADAMTS-5 isoforms (p85, p60, p45) bind sulfated glycosaminoglycans (heparin and chondroitin sulfate) through their C-terminal domains. Recombinant protein expression (CHO cells), domain truncation analysis, in vitro aggrecanase activity assays, GAG-binding assays Biochimica et biophysica acta High 16507336
2006 ADAMTS5 is the sole aggrecanase responsible for spontaneous aggrecanolysis in murine epiphyseal chondrocyte aggregate cultures; ADAMTS5-null chondrocytes are completely aggrecanase-inactive, whereas CD44-, syndecan-1-, or MT4MMP-null chondrocytes behave as wild type, indicating CD44, syndecan-1, and MT4MMP do not control ADAMTS5 activity in this system. Epiphyseal chondrocyte cultures from knockout mice, biochemical aggrecanolysis assay, confocal immunolocalization Osteoarthritis and cartilage High 16406703
2007 Crystal structures of ADAMTS4 and ADAMTS5 catalytic domains in apo and inhibitor-bound forms reveal two distinct catalytic-site configurations: an autoinhibited closed form and an open binding-competent form, suggesting mature aggrecanases exist as an ensemble of at least two conformational isomers. X-ray crystallography of recombinant ADAMTS5 catalytic domain with and without inhibitor Protein science : a publication of the Protein Society High 18042673
2007 High-resolution crystal structure of ADAMTS-5 catalytic domain (aggrecanase-2) determined to 1.4 Å resolution in complex with an inhibitor, providing atomic-level insight into the active site architecture. X-ray crystallography of refolded/purified ADAMTS-5 catalytic domain The Journal of biological chemistry High 17991750
2007 ADAMTS5 in human OA cartilage co-localizes with hyaluronan (HA) in the pericellular matrix of chondrocytes, and a high-molecular-weight ADAMTS5-HA complex (~2×10^6 Da) can be isolated from OA cartilage, suggesting HA-dependent sequestration as a mechanism for regulating ADAMTS5 activity. Confocal immunolocalization, isotonic salt extraction, size-exclusion chromatography, Western blot Osteoarthritis and cartilage Medium 17360199
2009 Syndecan-4 controls ADAMTS-5 activation through direct interaction with the protease and through regulating MAPK-dependent synthesis of MMP-3; syndecan-4 deficiency or antibody blockade markedly decreases ADAMTS-5 activity and protects from OA cartilage damage. Syndecan-4 knockout mice, intra-articular antibody injection, OA surgical model, activity assays, direct interaction studies Nature medicine High 19684582
2010 ADAMTS5 is approximately 100-fold more efficient than MMP-3 at cleaving within the aggrecan interglobular domain, and 10-fold more efficient in the CS-2 region; MMPs show delayed activation in cartilage explants, explaining their minor contribution to aggrecan catabolism in vivo. In vitro enzyme digestion of bovine aggrecan with recombinant MMPs and ADAMTS5, Western blot analysis Matrix biology : journal of the International Society for Matrix Biology High 21055468
2010 RelA/p65 (NF-κB) is a potent transcriptional activator of ADAMTS5 in chondrocytes, binding to two core responsive elements at -896/-887 bp and -424/-415 bp in the ADAMTS5 promoter; RelA deletion in mesenchymal cells reduces cartilage aggrecanolysis. Promoter-luciferase assay, deletion/mutagenesis analysis, siRNA knockdown, Cre-mediated knockout in primary chondrocytes, ex vivo cartilage culture The Journal of biological chemistry High 23963448
2010 Mechanical stress (cyclic tensile strain) induces ADAMTS-5 expression via p38 MAPK activation of the Runx2 transcription factor; p38 MAPK inhibition blocks CTS-induced Runx2, MMP-13, and ADAMTS-5 expression, and RUNX-2 overexpression directly up-regulates ADAMTS-5. Cyclic tensile strain apparatus, siRNA knockdown, overexpression, Western blot, real-time PCR, pharmacological inhibitors Osteoarthritis and cartilage Medium 21094261
2010 The ADAMTS5 spacer domain interacts with the protein moiety (not the sulfated GAG chains) of aggrecan and is required for effective aggrecanolytic activity; an antibody to the spacer domain blocks ADAMTS5 aggrecanolysis when full-length aggrecan is substrate but not peptide substrates. Phage display antibody selection (with active-site-directed inhibitor GM6001), domain mapping, aggrecanolysis assay The Biochemical journal Medium 26303525
2011 ADAMTS5 cleaves versican and is required for cardiac valve maturation; Adamts5-deficient mice exhibit enlarged myxomatous valves with reduced versican cleavage, and genetic reduction of versican (Vcan haploinsufficiency) substantially rescues the valve anomaly, demonstrating versican as the critical ADAMTS5 substrate in this context. Adamts5 knockout mice, Vcan haploinsufficient crosses, histology, IHC for BMP2/Sox9 Developmental biology High 21749862
2011 ADAMTS5-mediated versican proteolysis in dermal fibroblast pericellular matrix regulates the fibroblast-to-myofibroblast transition; Adamts5-/- fibroblasts accumulate versican, show increased α-SMA expression, enhanced contractility and TGFβ signaling (Smad1/5/8 instead of Smad2/3). Vcan haploinsufficiency or exogenous ADAMTS5 restores normal fibroblast contractility, demonstrating versican as the mediating substrate. Adamts5-/- fibroblast cultures, Adamts5-/-;Vcan(hdf/+) double-mutant mice, 3D collagen gel contraction, Smad phosphorylation, exogenous ADAMTS5 rescue The Journal of biological chemistry High 21828051
2011 Adamts5 deletion impairs dermal wound healing through CD44-mediated aggrecan accumulation; aggrecan pericellular matrix accumulation in Adamts5-/- fibroblasts shifts TGFβ1 signaling from Smad2/3 to Smad1/5/8, and Cd44-/- / Adamts5-/- double-mutant mice recover normal dermal repair and Smad2/3 responses. Adamts5-/- and Cd44-/-/Adamts5-/- knockout mice, excisional wound model, qPCR, Smad phosphorylation assays The Journal of biological chemistry High 21566131
2012 ADAMTS5 cleaves vascular proteoglycans versican and biglycan in the aortic wall; ADAMTS5 activity reduces LDL-binding ability of biglycan and releases LDL from human aortic lesions, implicating ADAMTS5 in proteoglycan turnover and lipoprotein retention in atherosclerosis. Adamts5-deficient mouse aortas, ex vivo aortic explant culture, neoepitope ELISA, LDL-binding assay, proteoglycan quantification The Journal of biological chemistry Medium 22493487
2012 ADAMTS5 has anti-tumorigenic and anti-angiogenic activity through its first TSR domain (TSR1) independent of catalytic activity; active-site mutant E411A retains full tumor-suppression activity, and domain mapping showed TSR1 (but not TSR2) suppresses VEGF, PlGF, and PD-ECGF levels in tumor milieu. B16 melanoma mouse tumor model, catalytic mutant E411A, domain deletion constructs, overexpression, angiogenesis assays, cytokine measurements The American journal of pathology Medium 22796434
2012 Pentosan polysulfate (PPS) mediates formation of a high-affinity trimolecular complex with ADAMTS-5 and TIMP-3 through electrostatic interactions; the spacer domain of ADAMTS-5 is required for PPS binding and sensitivity to affinity increase, and PPS chains of ≥11 saccharide units are required for full effect. Binding affinity measurements (Biacore), truncated ADAMTS-5 variants, TIMP-3 mutants, salt-sensitivity experiments The Biochemical journal High 22299597
2012 ADAMTS-5 and ADAMTS-4 are both endocytosed by human chondrocytes via the endocytic receptor LRP1 (clusters II and III); LRP1 binding of MMP-13 (via its hemopexin domain) is at a distinct site within cluster II from ADAMTS-4 and ADAMTS-5, allowing co-endocytosis of all three proteases. Binding competition assays, domain deletion studies (hemopexin domain), LRP1 cluster mapping Matrix biology : journal of the International Society for Matrix Biology Medium 27084377
2014 ADAMTS5 cleavage of versican-V1 at Glu441-Ala442 requires: (1) chondroitin sulfate modification at N-terminal CS attachment sites Ser507 and Ser525 (necessary and sufficient), (2) the ADAMTS5 C-terminal ancillary domain which docks to these CS chains, and (3) intact Glu441 as the scissile bond residue. Site-directed mutagenesis of versican CS attachment sites and scissile bond, chondroitinase treatment, ADAMTS5 ancillary domain deletion mutants, in vitro cleavage assay The Journal of biological chemistry High 25122765
2014 Primary cilia-mediated hedgehog signaling activates ADAMTS-5 expression in chondrocytes downstream of mechanical strain (10% CTS); this requires a functional primary cilium and is lost at higher strains (20% CTS) due to HDAC6-mediated cilia disassembly. HDAC6 inhibition restores cilia, hedgehog signaling and ADAMTS-5 expression at 20% CTS. Cyclic tensile strain on bovine chondrocytes, Tg737(ORPK) cilia-deficient cell line, HDAC6 inhibitor, real-time PCR, confocal cilia quantification Osteoarthritis and cartilage Medium 24457103
2015 Structural mapping of inhibitory antibodies against ADAMTS-5 showed that the most potent monoclonal antibodies cross-link the catalytic and disintegrin domains; ADAMTS-5-specific mAb treatment in mice provides structural OA disease modification and associated pain behavior alleviation. Structural domain mapping of mAb epitopes, surgical OA mouse model, pain behavior assays, human OA cartilage explant ARGS neoepitope assay Osteoarthritis and cartilage Medium 25800415
2016 ADAMTS5 enzymatic activity plays a key role in influenza-specific T cell immunity; Adamts5-/- mice show delayed virus clearance, compromised T cell migration, and accumulation of versican, indicating ADAMTS5-mediated versican proteolysis is required for normal T cell migration during viral infection. Adamts5-/- mouse influenza infection model, viral clearance assays, T cell migration assays, versican immunohistochemistry PLoS biology Medium 27855162
2017 ADAMTS5 deficiency in aortas leads to versican accumulation and decreased versikine (ADAMTS-specific versican cleavage product), LRP1 reduction, and increased aortic dilation in an angiotensin II model; LRP1 silencing in smooth muscle cells reduces ADAMTS5 expression and versikine generation. ADAMTS-5 (not ADAMTS-1) is the key protease for versican regulation in murine aortas. Adamts5Δcat mice, angiotensin II infusion, proteomics, LRP1 siRNA in human aortic smooth muscle cells, echocardiography Arteriosclerosis, thrombosis, and vascular biology Medium 29622560
2019 Wwp2 (HECT-type E3 ubiquitin ligase) suppresses ADAMTS5 expression by poly-ubiquitinating and degrading Runx2; Wwp2-C838A (E3-inactive) mice show upregulation of Runx2-Adamts5 signaling and aggravated OA. This defines a Wwp2→Runx2→ADAMTS5 regulatory pathway. Wwp2 knockout and catalytic-dead knockin mice, OA surgical model, substrate identification (Runx2 ubiquitination), in vitro mRNA injection rescue Nature communications High 31160553
2019 Sox4 (and Sox11) transcription factors directly bind the ADAMTS5 gene promoter to induce ADAMTS5 expression; chromatin immunoprecipitation and luciferase reporter assays confirmed direct promoter binding, and adenoviral Sox4/Sox11 overexpression in mouse femoral head cartilage causes destruction with increased Adamts5 expression. Luciferase reporter assay, ChIP assay, adenoviral overexpression, organ culture, microarray FASEB journal Medium 30016600
2020 Endothelial ADAMTS5 expression downstream of MEKK3-KLF2/4 signaling drives cerebral cavernous malformation (CCM) formation by cleaving versican; endothelial loss of ADAMTS5 reduces CCM lesions, gain of ADAMTS5 promotes lesion formation, and lowering versican reduces CCM burden, establishing versican proteolysis (not ECM loss per se) as the pathogenic mechanism. Conditional endothelial ADAMTS5 knockout and overexpression mouse models, versican knockdown, CCM neonatal mouse model, lesion quantification The Journal of experimental medicine High 32648916
2021 Label-free quantitative proteomics (LC-MS/MS with z-score ranking) identified multiple novel ADAMTS5 cleavage sites in versican V1 beyond the canonical Glu441-Ala442, confirming a site preference for P1-Glu residues; ADAMTS5, ADAMTS1, and ADAMTS4 have overlapping but distinct cleavage-site preferences on versican. In vitro digestion of recombinant versican V1 with purified active and catalytically-inactive ADAMTS5, LC-MS/MS semi-tryptic peptide analysis, z-score statistical ranking Journal of proteomics High 34450332
2021 ADAMTS5 is required for versican degradation in the heart; Adamts5ΔCat mice show aggravated versican buildup and reduced versikine after angiotensin II infusion, accompanied by reduced integrin β1, filamin A, connexin 43, and impaired ejection fraction/global longitudinal strain. Adamts5ΔCat mice, angiotensin II infusion model, echocardiography, proteomics of cardiac ECM Circulation Medium 34806902
2024 N-terminomics (TAILS) of human OA cartilage and matched synovial fluid combined with ex vivo ADAMTS5 digestion of non-OA cartilage identified specific ADAMTS5 cleavage sites across the OA cartilage proteome, establishing a distinct ADAMTS5 cleavage signature separable from MMP13 and CMA1 activities. TAILS N-terminomics, LC-MS/MS, ex vivo ADAMTS5 digestion of cartilage, matched cartilage/synovial fluid degradomics Osteoarthritis and cartilage Medium 39293776

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 1020 15800624
1999 Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family. The Journal of biological chemistry 409 10438522
2001 TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). The Journal of biological chemistry 400 11278243
2007 Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5. Arthritis and rheumatism 333 17265492
2009 Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis. Nature medicine 262 19684582
2002 Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage. The Journal of biological chemistry 241 11956193
1999 ADAM-TS5, ADAM-TS6, and ADAM-TS7, novel members of a new family of zinc metalloproteases. General features and genomic distribution of the ADAM-TS family. The Journal of biological chemistry 171 10464288
2009 Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis. Arthritis and rheumatism 161 19565481
2008 The regulation of the ADAMTS4 and ADAMTS5 aggrecanases in osteoarthritis: a review. Clinical and experimental rheumatology 155 18328163
2016 MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1. Matrix biology : journal of the International Society for Matrix Biology 137 27084377
2010 Regulation of mechanical stress-induced MMP-13 and ADAMTS-5 expression by RUNX-2 transcriptional factor in SW1353 chondrocyte-like cells. Osteoarthritis and cartilage 124 21094261
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
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
2012 Discovery of highly potent and selective small molecule ADAMTS-5 inhibitors that inhibit human cartilage degradation via encoded library technology (ELT). Journal of medicinal chemistry 105 22891645
2015 Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification. Osteoarthritis and cartilage 103 25800415
2011 Altered versican cleavage in ADAMTS5 deficient mice; a novel etiology of myxomatous valve disease. Developmental biology 101 21749862
2001 Expression and activity of ADAMTS-5 in synovium. European journal of biochemistry 98 11231277
2005 Human glioblastomas overexpress ADAMTS-5 that degrades brevican. Acta neuropathologica 92 16133547
2019 Wwp2 maintains cartilage homeostasis through regulation of Adamts5. Nature communications 90 31160553
2008 ADAMTS-5: the story so far. European cells & materials 90 18247274
2011 Pericellular versican regulates the fibroblast-myofibroblast transition: a role for ADAMTS5 protease-mediated proteolysis. The Journal of biological chemistry 87 21828051
2006 Glycosaminoglycan-binding properties and aggrecanase activities of truncated ADAMTSs: comparative analyses with ADAMTS-5, -9, -16 and -18. Biochimica et biophysica acta 87 16507336
2007 Aggrecanolysis in human osteoarthritis: confocal localization and biochemical characterization of ADAMTS5-hyaluronan complexes in articular cartilages. Osteoarthritis and cartilage 86 17360199
2014 Primary cilia disassembly down-regulates mechanosensitive hedgehog signalling: a feedback mechanism controlling ADAMTS-5 expression in chondrocytes. Osteoarthritis and cartilage 85 24457103
2021 ADAMTS5 in Osteoarthritis: Biological Functions, Regulatory Network, and Potential Targeting Therapies. Frontiers in molecular biosciences 83 34434966
2012 Novel role of ADAMTS-5 protein in proteoglycan turnover and lipoprotein retention in atherosclerosis. The Journal of biological chemistry 80 22493487
2017 Effect of inhibiting MMP13 and ADAMTS5 by intra-articular injection of small interfering RNA in a surgically induced osteoarthritis model of mice. Cell and tissue research 77 28120109
2009 Adamts5, the gene encoding a proteoglycan-degrading metalloprotease, is expressed by specific cell lineages during mouse embryonic development and in adult tissues. Gene expression patterns : GEP 75 19250981
2021 Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling. Circulation 74 34806902
2009 Effect of small interference RNA (siRNA) for ADAMTS5 on intervertebral disc degeneration in the rabbit anular needle-puncture model. Arthritis research & therapy 72 19889209
2018 Role of ADAMTS-5 in Aortic Dilatation and Extracellular Matrix Remodeling. Arteriosclerosis, thrombosis, and vascular biology 71 29622560
2013 Transcriptional induction of ADAMTS5 protein by nuclear factor-κB (NF-κB) family member RelA/p65 in chondrocytes during osteoarthritis development. The Journal of biological chemistry 69 23963448
2012 Regulated proteolytic processing of Reelin through interplay of tissue plasminogen activator (tPA), ADAMTS-4, ADAMTS-5, and their modulators. PloS one 68 23082219
2012 ADAMTS5 functions as an anti-angiogenic and anti-tumorigenic protein independent of its proteoglycanase activity. The American journal of pathology 65 22796434
2017 Epigallocatechin-3-O-gallate modulates global microRNA expression in interleukin-1β-stimulated human osteoarthritis chondrocytes: potential role of EGCG on negative co-regulation of microRNA-140-3p and ADAMTS5. European journal of nutrition 64 28110479
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
2007 High resolution crystal structure of the catalytic domain of ADAMTS-5 (aggrecanase-2). The Journal of biological chemistry 64 17991750
2011 Adamts5 deletion blocks murine dermal repair through CD44-mediated aggrecan accumulation and modulation of transforming growth factor β1 (TGFβ1) signaling. The Journal of biological chemistry 63 21566131
2010 MMPs are less efficient than ADAMTS5 in cleaving aggrecan core protein. Matrix biology : journal of the International Society for Matrix Biology 59 21055468
2020 ADAMTS-5: A difficult teenager turning 20. International journal of experimental pathology 58 32219922
2013 Transcriptomics of wild-type mice and mice lacking ADAMTS-5 activity identifies genes involved in osteoarthritis initiation and cartilage destruction. Arthritis and rheumatism 56 23436205
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
2019 LncRNA MALAT1/MiR-145 Adjusts IL-1β-Induced Chondrocytes Viability and Cartilage Matrix Degradation by Regulating ADAMTS5 in Human Osteoarthritis. Yonsei medical journal 54 31637891
2010 ADAMTS-5 and intervertebral disc degeneration: the results of tissue immunohistochemistry and in vitro cell culture. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 53 21437951
2007 Characterization of the human ADAMTS-5 (aggrecanase-2) gene promoter. Molecular biology reports 53 17211519
2014 Determinants of versican-V1 proteoglycan processing by the metalloproteinase ADAMTS5. The Journal of biological chemistry 51 25122765
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
2016 Resistin Promotes Intervertebral Disc Degeneration by Upregulation of ADAMTS-5 Through p38 MAPK Signaling Pathway. Spine 47 26974833
2013 Polymorphic variation within the ADAMTS2, ADAMTS14, ADAMTS5, ADAM12 and TIMP2 genes and the risk of Achilles tendon pathology: a genetic association study. Journal of science and medicine in sport 47 23491141
2013 Targeting of ADAMTS5's ancillary domain with the recombinant mAb CRB0017 ameliorates disease progression in a spontaneous murine model of osteoarthritis. Osteoarthritis and cartilage 47 23954517
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
2016 ADAMTS5 Is a Critical Regulator of Virus-Specific T Cell Immunity. PLoS biology 41 27855162
2015 Antibody-based exosite inhibitors of ADAMTS-5 (aggrecanase-2). The Biochemical journal 41 26303525
2014 Expression of ADAMTs-5 and TIMP-3 in the condylar cartilage of rats induced by experimentally created osteoarthritis. Archives of oral biology 41 24632095
2016 microRNA -140-5p inhibits colorectal cancer invasion and metastasis by targeting ADAMTS5 and IGFBP5. Stem cell research & therapy 40 27906093
2020 Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican. The Journal of experimental medicine 39 32648916
2011 Biochemical identification and immunolocalizaton of aggrecan, ADAMTS5 and inter-alpha-trypsin-inhibitor in equine degenerative suspensory ligament desmitis. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 39 21246622
2019 Adamts5-/- Mice Exhibit Altered Aggrecan Proteolytic Profiles That Correlate With Ascending Aortic Anomalies. Arteriosclerosis, thrombosis, and vascular biology 38 31366218
2005 Metalloproteinase ADAMTS-1 but not ADAMTS-5 is manifold overexpressed in neurodegenerative disorders as Down syndrome, Alzheimer's and Pick's disease. Brain research. Molecular brain research 38 15661359
2021 LncRNA MIR22HG promotes osteoarthritis progression via regulating miR-9-3p/ADAMTS5 pathway. Bioengineered 37 34187303
2013 ADAMTS1, ADAMTS5, ADAMTS9 and aggrecanase-generated proteoglycan fragments are induced following spinal cord injury in mouse. Neuroscience letters 37 23562508
2021 Identification of novel ADAMTS1, ADAMTS4 and ADAMTS5 cleavage sites in versican using a label-free quantitative proteomics approach. Journal of proteomics 36 34450332
2019 Degrading products of chondroitin sulfate can induce hypertrophy-like changes and MMP-13/ADAMTS5 production in chondrocytes. Scientific reports 36 31676809
2017 The noncoding RNA linc-ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression. Clinical science (London, England : 1979) 36 28341660
2016 Clinical significance of ADAMTS1, ADAMTS5, ADAMTS9 aggrecanases and IL-17A, IL-23, IL-33 cytokines in polycystic ovary syndrome. Journal of endocrinological investigation 35 27146815
2018 Fibrin-hyaluronic acid hydrogel-based delivery of antisense oligonucleotides for ADAMTS5 inhibition in co-delivered and resident joint cells in osteoarthritis. Journal of controlled release : official journal of the Controlled Release Society 34 30572032
2017 ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells. Arteriosclerosis, thrombosis, and vascular biology 34 28546218
2012 Pentosan polysulfate increases affinity between ADAMTS-5 and TIMP-3 through formation of an electrostatically driven trimolecular complex. The Biochemical journal 34 22299597
2018 ADAMTS5 acts as a tumor suppressor by inhibiting migration, invasion and angiogenesis in human gastric cancer. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 32 30105548
2017 MiR-132-3p regulates ADAMTS-5 expression and promotes chondrogenic differentiation of rat mesenchymal stem cells. Journal of cellular biochemistry 30 28980719
2008 The first but not the second thrombospondin type 1 repeat of ADAMTS5 functions as an angiogenesis inhibitor. Biochemical and biophysical research communications 29 18433719
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
2017 Long non-coding RNA HOTAIR promotes expression of ADAMTS-5 in human osteoarthritic articular chondrocytes. Die Pharmazie 28 29441864
2011 Involvement of ADAMTS5 and hyaluronidase in aggrecan degradation and release from OSM-stimulated cartilage. European cells & materials 28 21225593
2006 ADAMTS5-mediated aggrecanolysis in murine epiphyseal chondrocyte cultures. Osteoarthritis and cartilage 27 16406703
2017 Association between COL11A1 (rs1337185) and ADAMTS5 (rs162509) gene polymorphisms and lumbar spine pathologies in Chinese Han population: an observational study. BMJ open 26 28583914
2015 Hsa-miR-15a exerts protective effects against osteoarthritis by targeting aggrecanase-2 (ADAMTS5) in human chondrocytes. International journal of molecular medicine 26 26707794
2017 ADAMTS5 Deficiency Protects Mice From Chronic Tobacco Smoking-induced Intervertebral Disc Degeneration. Spine 25 28570296
2009 Co-culture of mechanically injured cartilage with joint capsule tissue alters chondrocyte expression patterns and increases ADAMTS5 production. Archives of biochemistry and biophysics 25 19607802
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
2021 Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5. Osteoarthritis and cartilage 24 34626798
2017 Loss of ADAMTS5 enhances brown adipose tissue mass and promotes browning of white adipose tissue via CREB signaling. Molecular metabolism 24 28702327
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
2008 A transcriptional enhancer from the coding region of ADAMTS5. PloS one 21 18478108
2016 Overexpression of ADAMTS5 can regulate the migration and invasion of non-small cell lung cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 20 26738863
2016 ADAMTS5 deficiency protects against non-alcoholic steatohepatitis in obesity. Liver international : official journal of the International Association for the Study of the Liver 20 27254774
2015 Deletion of ADAMTS5 does not affect aggrecan or versican degradation but promotes glucose uptake and proteoglycan synthesis in murine adipose derived stromal cells. Matrix biology : journal of the International Society for Matrix Biology 20 25840345
2020 Periostin Mediates Condylar Resorption via the NF-κB-ADAMTS5 Pathway. Inflammation 19 31840212
2012 Expression of ADAMTS-1, ADAMTS-4, ADAMTS-5 and TIMP3 by hepatocellular carcinoma cell lines. International journal of oncology 19 22735305
2016 High expression of ADAMTS5 is a potent marker for lymphatic invasion and lymph node metastasis in colorectal cancer. Molecular and clinical oncology 18 28123746
2011 Adamts5 (aggrecanase-2) is widely expressed in the mouse musculoskeletal system and is induced in specific regions of knee joint explants by inflammatory cytokines. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 18 21800360
2013 ADAMTS5 is required for biomechanically-stimulated healing of murine tendinopathy. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 17 23754494
2024 Degradomics defines proteolysis information flow from human knee osteoarthritis cartilage to matched synovial fluid and the contributions of secreted proteases ADAMTS5, MMP13 and CMA1 to articular cartilage breakdown. Osteoarthritis and cartilage 16 39293776
2019 Genetic variation of aggrecanase-2 (ADAMTS5) in susceptibility to osteoarthritis. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 16 30652828
2013 Osteoprotegerin promotes the proliferation of chondrocytes and affects the expression of ADAMTS-5 and TIMP-4 through MEK/ERK signaling. Molecular medicine reports 16 24126801
2019 ADAMTS-9 in Mouse Cartilage Has Aggrecanase Activity That Is Distinct from ADAMTS-4 and ADAMTS-5. International journal of molecular sciences 15 30699963
2018 ADAMTS1 and ADAMTS5 metalloproteases produced by Sertoli cells: a potential diagnostic marker in azoospermia. Systems biology in reproductive medicine 15 29737873
2015 Development of human neutralizing antibody to ADAMTS4 (aggrecanase-1) and ADAMTS5 (aggrecanase-2). Biochemical and biophysical research communications 15 26612259
2007 Natural chondroitin sulphates increase aggregation of proteoglycan complexes and decrease ADAMTS-5 expression in interleukin 1 beta-treated chondrocytes. Annals of the rheumatic diseases 15 17901089