Affinage

TIMP3

Metalloproteinase inhibitor 3 · UniProt P35625

Length
211 aa
Mass
24.1 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMP3 is an extracellular-matrix-bound metalloproteinase inhibitor that maintains vascular, renal, cardiac, hepatic, and metabolic homeostasis primarily by restraining the sheddase ADAM17/TACE and matrix metalloproteinases (PMID:16294222, PMID:19406980, PMID:18295466). Unlike other TIMPs, TIMP3 is sequestered exclusively in the ECM rather than secreted into the medium, accumulating in basement membranes near RPE and endothelial cells (PMID:9068940). A central function is direct inhibition of TACE, silencing TNF-alpha shedding: TACE exists as cell-surface dimers whose cytoplasmic-domain-dependent dimerization enables stable TIMP3 association, and MAPK-driven dimer-to-monomer conversion releases TIMP3 to permit ectodomain shedding (PMID:22550340). Through this TACE-TNF-alpha axis, TIMP3 limits inflammation and downstream MMP2 activation in renal injury, atherosclerosis, autoimmune hepatitis, and diabetic kidney disease, where loss of TIMP3 elevates TACE activity and engages a STAT1-FoxO1 autophagy pathway (PMID:16294222, PMID:19406980, PMID:23401241, PMID:22323541, PMID:24943223). TIMP3 also broadly restricts metalloproteolysis (MMP2, ADAMs, ADAMTSs) to stabilize the microvasculature and ECM: pericyte-derived, ALK5-induced TIMP3 maintains capillary integrity and prevents fibrosis, microvascular rarefaction, aneurysm, and germinal-matrix hemorrhage (PMID:22383695, PMID:23144462, PMID:29456135). Beyond protease inhibition, TIMP3 drives caspase-independent endothelial apoptosis requiring VEGFR2 (KDR) by blocking matrix-induced FAK phosphorylation and disrupting focal-adhesion assembly (PMID:25558000). TIMP3 expression is itself tightly controlled at multiple levels — by the circadian factor CLOCK (PMID:29180440), by chromatin writers/erasers acting at its promoter (KDM1A, HDAC9, MLL1) (PMID:27058897, PMID:30715128, PMID:33653378), and post-transcriptionally by the m6A demethylase ALKBH5 (PMID:31927006). The Sorsby fundus dystrophy S156C mutation does not impair TIMP3's inhibitory activities but causes pathological ECM accumulation that alters cellular morphology (PMID:12942551, PMID:18295466).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1995 High

    Defining the TIMP3 gene architecture and promoter established how its expression is set, including serum-inducible cell-cycle regulation, framing later studies of its transcriptional control.

    Evidence Genomic cloning, chromosomal mapping, and promoter-reporter deletion assays in growth-arrested cells

    PMID:7487894

    Open questions at the time
    • Did not identify the trans-acting factors mediating serum inducibility
    • No link yet to protein function or substrate spectrum
  2. 1997 High

    Showing that TIMP3, unlike TIMP-1/-2, is bound exclusively in the ECM and not the medium established its distinctive spatial mode of action as a matrix-tethered inhibitor.

    Evidence ECM-vs-medium fractionation, immunoblot, and IHC in RPE, pericytes, and endothelial cells

    PMID:9068940

    Open questions at the time
    • Molecular basis of ECM retention not defined
    • Functional consequence of matrix tethering not yet tested
  3. 2003 Medium

    Testing the SFD S156C mutation addressed whether disease arises from loss of protease inhibition; it showed the mutant retains MMP-inhibitory activity but abnormally accumulates in ECM and alters cell morphology.

    Evidence MMP activity assays, ECM fractionation, and pulse-chase in S156C knock-in and Timp3-/- fibroblasts

    PMID:12942551

    Open questions at the time
    • Mechanism linking ECM accumulation to morphology change unresolved
    • Single lab; not extended to retinal phenotype in vivo
  4. 2005 High

    Placing TIMP3 upstream of TACE-mediated TNF-alpha shedding answered how a protease inhibitor governs metabolic inflammation, linking TIMP3 loss to diabetes and vascular inflammation.

    Evidence Insr+/-, Timp3+/-, double-heterozygote mice with TACE activity assays and pharmacological TACE inhibition

    PMID:16294222

    Open questions at the time
    • Did not resolve the structural basis of TIMP3-TACE binding
    • Tissue-specific contributions not dissected
  5. 2007 Medium

    Extending TIMP3 inhibition to ADAM-10/17 in APP processing and to cardiac remodeling broadened its substrate-spectrum and physiological reach to neuronal shedding and post-MI dysfunction.

    Evidence Recombinant TIMP3 with APP fragment/surface-biotinylation analysis (neural cells); Timp3-/- coronary ligation with echocardiography and zymography

    PMID:17913923 PMID:17945252

    Open questions at the time
    • APP study single-lab, Medium confidence
    • Direct contribution to human Alzheimer pathology not established
  6. 2009 High

    Double-knockout epistasis established the TACE-TNF-alpha-MMP2 cascade as the mechanistic chain through which TIMP3 protects the injured kidney.

    Evidence TIMP3-/- and TIMP3-/-/TNFalpha-/- mice, ureteral obstruction, TACE assay, MMP zymography, MMP inhibitor

    PMID:19406980

    Open questions at the time
    • Did not address why MMP2 but not MMP9 is selectively activated
    • Cell-type source of protective TIMP3 not defined here
  7. 2012 High

    Dissecting TACE dimerization revealed how TIMP3 inhibition is gated: TIMP3 silences only dimeric TACE, and MAPK-driven monomerization releases the inhibitor to permit shedding.

    Evidence Cell-surface dimerization assays, TIMP3-TACE co-IP, MAPK modulation, TGF-alpha shedding, cytoplasmic-domain mutagenesis

    PMID:22550340

    Open questions at the time
    • Atomic structure of the dimer-TIMP3 complex not resolved
    • In vivo relevance of dimer state not tested
  8. 2012 High

    A series of in vivo models established TIMP3 as a tissue-protective regulator across microvascular stability, diabetic kidney injury, aortic aneurysm, and hepatic immune tolerance, often via TACE/MMP2 control.

    Evidence Pericyte 3D tube assays and Timp3-/- kidney injury; Timp3-/-/Akita diabetic mice; Timp3-/-/Mmp2-/- Ang II aneurysm with bone-marrow chimeras; Timp3-/- ConA hepatitis chimeras

    PMID:22323541 PMID:22383695 PMID:22896043 PMID:23144462

    Open questions at the time
    • Organ-selective vulnerability (e.g., kidney vs heart in diabetes) not mechanistically explained
    • Relative weighting of TACE vs MMP2 contributions varies by tissue
  9. 2013 High

    Comparative knockouts and a STAT1-FoxO1 rescue defined divergent TIMP roles (TIMP3 protective, TIMP2 injurious) and a transcriptional autophagy arm downstream of TIMP3 in diabetic kidney disease.

    Evidence Timp2-/- vs Timp3-/- ureteral obstruction; diabetic Timp3-/- mice with TIMP3 re-expression, STAT1 knockdown, and human biopsy validation

    PMID:23401241 PMID:23760282

    Open questions at the time
    • How extracellular TIMP3 controls intracellular STAT1/FoxO1 not mechanistically connected
    • TIMP2 opposing mechanism not fully resolved
  10. 2014 High

    Studies of cardiac fibrosis, atherosclerosis, and hepatocellular carcinoma revealed context-dependent outcomes of TIMP3 loss, including MMP-independent fibrosis, macrophage M1 polarization, and paradoxical tumor protection via senescence.

    Evidence Timp3-/- Ang II hearts with osteopontin/SPARC analysis; ApoE-/-/Timp3-/- atherosclerosis with FACS; Timp3-/- DEN hepatocarcinogenesis with p53/p38/Notch and TNF epistasis

    PMID:24692173 PMID:24943223 PMID:25347747

    Open questions at the time
    • Mechanism switching TIMP3 between protective and tumor-promoting roles unresolved
    • MMP-independent fibrotic mechanism only partially defined
  11. 2015 High

    Establishing a caspase-independent, VEGFR2-dependent FAK-disruption mechanism showed TIMP3 drives endothelial apoptosis separately from its protease-inhibitory function.

    Evidence VEGFR2-expressing vs control cell lines, recombinant TIMP3, FAK phosphorylation, FAK/paxillin co-IP, caspase inhibition, in vivo tumor assay

    PMID:25558000

    Open questions at the time
    • How matrix-bound TIMP3 transduces signal through VEGFR2 to FAK not defined
    • Direct TIMP3-VEGFR2 binding interface not mapped
  12. 2016 High

    CADASIL models identified excess TIMP3 as a direct, dose-dependent cause of cerebrovascular dysfunction through ADAM17/HB-EGF inhibition and KV channel upregulation, and a histone demethylase (KDM1A) was shown to silence TIMP3 to enable cancer metastasis.

    Evidence TgNotch3(R169C) and TgBAC-TIMP3 mice with Timp3 haploinsufficiency rescue, patch-clamp, ADAM17/HB-EGF treatment; KDM1A KD/OE with ChIP-qPCR for H3K4me2 and invasion assays

    PMID:26648042 PMID:27058897 PMID:27476853

    Open questions at the time
    • KDM1A regulation is Medium confidence, single lab
    • How TIMP3 accumulates in CADASIL not fully explained
  13. 2017 High

    Hepatocyte-specific TIMP3 gain and ADAM17 loss demonstrated cell-autonomous metabolic protection, placing TIMP3 upstream of hepatocyte ADAM17 in NAFLD, tumorigenesis, and iron handling.

    Evidence AlbT3, hepatocyte and myeloid Adam17 KO mice under HFD, DEN, and iron-overload models with metabolic and ferroportin/MMP readouts

    PMID:28751722 PMID:29373036

    Open questions at the time
    • Mechanism by which TIMP3 controls ferroportin not defined
    • Iron-overload study Medium confidence, single lab
  14. 2018 High

    Identifying TIMP3 as both an ALK5-induced effector in brain vascular morphogenesis and a CLOCK-dependent circadian gene linked its expression control to developmental signaling and diurnal rhythm.

    Evidence Pericyte-specific Alk5 conditional KO with in vivo TIMP3 rescue; CLOCK and TIMP3 KD/OE in UVB-treated keratinocytes

    PMID:29180440 PMID:29456135

    Open questions at the time
    • Circadian regulation Medium confidence, in vitro only
    • Direct CLOCK occupancy at the TIMP3 locus not shown
  15. 2019 Medium

    Biochemical and epigenetic studies refined how TIMP3 activity and expression are tuned: glycosaminoglycans modulate MMP2/TIMP3 complex formation, while HDAC9 represses TIMP3 transcription in trophoblasts.

    Evidence MMP2/TIMP3 complex assays with sulfated hyaluronan/heparin and molecular dynamics; ChIP-qPCR for histone acetylation with HDAC9 knockdown/rescue and invasion assays

    PMID:30715128 PMID:30894640

    Open questions at the time
    • GAG study lacks mutagenesis validation
    • HDAC9 axis single lab; preeclampsia causality not established
  16. 2020 Medium

    Post-transcriptional and lncRNA-guided chromatin mechanisms (ALKBH5 m6A demethylation and lncRNA ROR-MLL1-H3K4me3) were shown to control TIMP3 levels in cancer, expanding its regulatory layers.

    Evidence RIP-Seq, mRNA stability assays, and xenografts for ALKBH5; RIP, RNA pull-down, ChIP, and xenografts for lncRNA ROR-MLL1

    PMID:31927006 PMID:33653378

    Open questions at the time
    • Both single-lab studies
    • Specific m6A sites and their functional weight not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How matrix-tethered, extracellular TIMP3 transmits signals to intracellular effectors (STAT1/FoxO1, FAK, VEGFR2) and what governs its context-dependent switch between tissue protection and tumor promotion remains unresolved.
  • No structural model of TIMP3 engaging cell-surface receptors
  • Mechanism integrating its protease-inhibitory and protease-independent functions unclear
  • Determinants of opposing roles across tissues undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0031012 extracellular matrix 2 GO:0005576 extracellular region 1
Pathway
R-HSA-1474244 Extracellular matrix organization 4 R-HSA-168256 Immune System 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9909396 Circadian clock 1
Partners
ADAM10ADAM17KDRMMP2

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 TIMP3 directly inhibits TACE (ADAM17), the TNF-alpha-converting enzyme. In insulin receptor heterozygous (Insr+/-) mice, TIMP3 deficiency led to unchecked TACE activity, increased soluble TNF-alpha, and subsequent diabetes and vascular inflammation. Pharmacological TACE inhibition reduced hyperglycemia, and Tace+/- mice showed increased insulin sensitivity, placing TIMP3 upstream of TACE-mediated TNF-alpha shedding in a metabolic/inflammatory pathway. Genetic mouse models (Insr+/-, Timp3+/-, double heterozygotes), TACE activity assays, TNF-alpha measurement, pharmacological TACE inhibition The Journal of clinical investigation High 16294222
2012 TACE (ADAM17) exists predominantly as dimers at the cell surface under basal conditions; dimerization requires its cytoplasmic domain and enables efficient association with TIMP3, which silences TACE activity. Upon ERK or p38 MAPK activation, the dimer-to-monomer shift decreases TIMP3 association and increases TACE-mediated ectodomain shedding of TGF-alpha, establishing TIMP3 as a dimer-dependent inhibitor of TACE. Cell-surface TACE dimerization assays, co-immunoprecipitation of TIMP3 with TACE, MAPK pathway activation/inhibition, TGF-alpha shedding assays, cytoplasmic domain mutagenesis Science signaling High 22550340
2007 TIMP3 inhibits alpha-secretase cleavage of amyloid precursor protein (APP) and ApoER2 by blocking ADAM-10 and ADAM-17. TIMP3 decreased surface levels of ADAM-10, APP, and ApoER2, increased APP beta-CTF and Abeta production, and directed APP toward endocytosis and beta-secretase cleavage rather than alpha-secretase cleavage. Recombinant TIMP3 treatment, ADAM-10/17 activity assays, Western blot for APP processing fragments, surface biotinylation, cell transfection in neuroblastoma/glia/COS7 cells The Journal of neuroscience Medium 17913923
2009 TIMP3 deficiency in mice leads to accelerated TACE activity and elevated soluble TNF-alpha after ureteral obstruction, followed by enhanced MMP2 (but not MMP9) activation, increased fibrosis, and apoptosis. Additional deletion of TNF-alpha in TIMP3-/- mice markedly reduced inflammation and MMP induction, placing TIMP3 upstream of TACE-TNF-alpha-MMP signaling in renal injury. Genetic knockout mice (TIMP3-/-, TIMP3-/-/TNFalpha-/-), unilateral ureteral obstruction model, TACE activity assay, MMP zymography, histopathology, MMP inhibitor treatment Journal of the American Society of Nephrology : JASN High 19406980
2012 TIMP3 stabilizes capillary tube networks and inhibits metalloproteolytic activity and angiogenic signaling in endothelial cells; this function is lost when pericytes transition to myofibroblasts. Pericyte-derived TIMP3 (in contrast to ADAMTS1) maintains microvascular stability, and Timp3-/- mice have spontaneous microvascular rarefaction and exaggerated fibrotic response to injury. 3D capillary tube assays, Timp3-/- mice, in vivo kidney injury models, pericyte-myofibroblast differentiation assays, metalloproteolytic activity assays Journal of the American Society of Nephrology : JASN High 22383695
2012 Loss of TIMP3 in the Akita diabetic mouse background selectively exacerbates diabetic renal injury (albuminuria, mesangial expansion, kidney hypertrophy) with elevated TACE activity, increased reactive oxygen species, NADPH oxidase activity, and PKCbeta1 elevation; cardiac function was unaffected, demonstrating a kidney-selective protective role of TIMP3 in diabetes. Double-mutant mice (TIMP3-/-/Akita), albuminuria measurement, TACE activity assay, ROS/NADPH oxidase assays, Western blot for PKC isoforms and signaling molecules American journal of physiology. Renal physiology High 22896043
2012 Timp3 deficiency in Ang II-infused mice causes abdominal aortic aneurysm (AAA) with reduced collagen and elastin proteins (not mRNA), elevated MMP2 and broad proteolytic activities. Additional deletion of Mmp2 exacerbated AAA and rupture; bone marrow reconstitution with WT cells in Timp3-/-/Mmp2-/- mice reduced inflammation and prevented AAA, identifying an MMP-dependent and bone marrow inflammatory component downstream of TIMP3. Timp3-/- mice, Ang II infusion, Mmp2-/- double knockout, bone marrow transplantation, MMP inhibitor (PD166793) treatment, zymography, protein/mRNA analysis The Journal of biological chemistry High 23144462
2013 TIMP3 deficiency in diabetic mice leads to reduced FoxO1 expression and its autophagy-related targets, with increased STAT1. Re-expression of TIMP3 in Timp3-/- mesangial cells rescued FoxO1 and its targets and decreased STAT1, establishing a TIMP3 → STAT1 → FoxO1 pathway in diabetic kidney disease. Diabetic Timp3-/- mice, microarray profiling, TIMP3 re-expression in mesangial cells, qPCR/Western blot for FoxO1, STAT1 knockdown rescue experiments, human kidney biopsy validation EMBO molecular medicine High 23401241
2013 In renal injury after ureteral obstruction, TIMP3 deficiency (but not TIMP2 deficiency) increases MMP2 activation, TACE activity, caspase-3 activity, and fibrosis through collagen I/III, CTGF, TGF-beta/Smad2/3 pathway activation. TIMP2 deficiency blocks MMP2 activation and reduces fibrosis, demonstrating divergent and opposing roles: TIMP3 protects from damage while TIMP2 promotes injury through MMP2 activation. Timp2-/- and Timp3-/- mice, unilateral ureteral obstruction, gene microarray, zymography for MMP2 activation, TACE activity assay, caspase assay, histopathology Kidney international High 23760282
2014 In Ang II-infused mice, TIMP3 deficiency produces excess fibrosis (without hypertrophy) involving post-translational stabilization and deposition of collagen by matricellular proteins osteopontin and SPARC, increased inflammation, and elevated TACE activity; this is distinct from TIMP2 deficiency effects and appears independent of canonical MMP-inhibitory function. TIMP2-/- and TIMP3-/- mice, Ang II infusion, adult cardiomyocyte/fibroblast co-culture, cyclic stretch assays, Western blot for osteopontin and SPARC, collagen quantification, TACE activity assay Cardiovascular research High 24692173
2007 TIMP3 deficiency accelerates maladaptive cardiac remodeling after myocardial infarction, with greater left ventricular dilation, increased gelatinase MMP activity, elevated TNF-alpha levels, increased blood vessel density, cell proliferation, apoptosis in infarct area, and reduced collagen in remote myocardium, resulting in accelerated systolic dysfunction and higher mortality. Timp3-/- mice, coronary artery ligation, echocardiography, pressure-volume measurements, MMP zymography, histopathology, ELISA for TNF-alpha Journal of molecular and cellular cardiology High 17945252
2015 TIMP3 promotes apoptosis in endothelial cells via a caspase-independent mechanism. The apoptotic activity is independent of MMP inhibitory activity and requires KDR (VEGFR2) expression. TIMP3 inhibits matrix-induced focal adhesion kinase (FAK) tyrosine phosphorylation, disrupts FAK association with paxillin, and prevents incorporation of beta3 integrin, FAK, and paxillin into focal adhesion contacts, an effect not reversed by caspase inhibitors. PAE/KDR vs PAE/beta-R cell lines, recombinant TIMP3 treatment, caspase inhibitor treatment, FAK phosphorylation assay, co-immunoprecipitation of FAK/paxillin, immunofluorescence of focal adhesions, in vivo tumor assay with TIMP3-overexpressing breast carcinoma cells Apoptosis : an international journal on programmed cell death High 25558000
2016 TIMP3 accumulation in CADASIL acts through inhibition of ADAM17 and HB-EGF to regulate cerebral arterial tone and blood flow responses. In CADASIL mice, exogenous ADAM17 or HB-EGF restored cerebrovascular responses. Upregulated voltage-dependent potassium channel (KV) number in cerebral arterial myocytes was identified as a downstream effector of TIMP3-induced cerebrovascular deficits. TgNotch3(R169C) CADASIL mouse model, TgBAC-TIMP3 overexpressing mice, Timp3 haploinsufficiency rescue, cerebral blood flow measurements, ex vivo arterial tone assays, patch-clamp for KV channels, ADAM17/HB-EGF exogenous treatment eLife High 27476853
2016 In CADASIL mice, elevated TIMP3 (but not Notch3 ECD deposition) impairs cerebral blood flow autoregulation and functional hyperemia. Haploinsufficiency of Timp3 rescues cerebrovascular reactivity deficits. A separate TgBAC-TIMP3 overexpressing mouse also displays attenuated myogenic responses of brain arteries, confirming TIMP3 level as a direct determinant of cerebrovascular function. TgNotch3(R169C) mice with Timp3 haploinsufficiency, TgBAC-TIMP3 transgenic mice, cerebral blood flow measurements (laser Doppler), ex vivo pressurized artery myogenic response assays Annals of neurology High 26648042
2018 Pericyte ALK5 (TGF-beta receptor) signaling upregulates TIMP3 expression; pericyte-specific ALK5 knockout in embryonic mice downregulates TIMP3, leading to germinal matrix hemorrhage with abnormal microvessel dilation, reduced pericyte coverage, EC hyperproliferation, and enhanced perivascular MMP activity. Exogenous TIMP3 administration to ALK5-mutant embryos improved endothelial morphogenesis and attenuated hemorrhage, placing TIMP3 downstream of pericyte ALK5 in brain vascular morphogenesis. Pericyte-specific Alk5 conditional knockout mice, TIMP3 protein administration in vivo, histopathology, MMP activity assays, quantification of vascular phenotypes Developmental cell High 29456135
1997 TIMP3 is expressed and secreted by retinal pigment epithelium (RPE), choroidal microcapillary endothelium, and pericytes. Unlike TIMP-1 and -2 (which are secreted into culture medium), TIMP3 localizes exclusively to the extracellular matrix and is not found in conditioned medium. In vivo, TIMP3 immunostaining is pronounced in Bruch's membrane, particularly near RPE and endothelial basement membranes. RT-PCR, Northern analysis, Western immunoblot of conditioned medium vs ECM fractions, immunohistochemistry of retina/choroid sections, cultured RPE/pericyte/endothelial cells Current eye research High 9068940
1995 The human TIMP3 gene is TATA-less, initiates transcription at one major site, consists of five exons and four introns spanning ~30 kb, maps to chromosome 22q13.1, and gives rise to three distinct mRNAs via alternative polyadenylation. The first 112 bases of the promoter (containing multiple Sp1 sites) confer high basal expression; the region from -463 to -112 is a major determinant of serum inducibility, conferring cell cycle regulation. Genomic cloning and sequencing, somatic cell hybrid mapping, promoter-reporter deletion assays, serum stimulation of growth-arrested cells The Biochemical journal High 7487894
2003 The SFD-associated S156C mutation in TIMP3 does not affect MMP inhibitory activity or metalloproteinase homeostasis in fibroblasts derived from mutant mice. Instead, mutant TIMP3(S156C) accumulates in the ECM (not due to altered turnover rate) and this accumulation alters cellular morphology. Loss of TIMP3 function in determining cellular morphology (not protease inhibition) is proposed as the pathogenic mechanism. Immortalized fibroblasts from Timp3-/- and Timp3(S156C/S156C) mice, MMP activity assays, ECM fractionation, pulse-chase for turnover rates, phenotypic analysis Journal of cellular physiology Medium 12942551
2008 The S156C SFD mutation does not impair TIMP3's inhibitory activities toward TACE, ADAMTS4/5, aggrecan-cleaving MMPs, or its anti-angiogenic properties in fibrin bead assays. TIMP3 S156C blocks VEGF binding to VEGFR2 to the same extent as wild-type TIMP3. In contrast, Timp3-/- tissue shows significantly enhanced TACE activity (but not ADAMTS4/5 or MMP activity), suggesting compensatory inhibitors for the latter enzymes. Timp3 S156C knock-in and Timp3-/- mice, TACE/ADAMTS4/5/MMP activity assays from tissue extracts, fibrin bead angiogenesis assay, VEGF-VEGFR2 binding assay with recombinant proteins, rescue with recombinant TIMP3 Matrix biology : journal of the International Society for Matrix Biology High 18295466
2012 TIMP3 deficiency leads to spontaneous accumulation and activation of hepatic CD4+, CD8+, and NKT cells. In Con A-induced autoimmune hepatitis, Timp3-/- mice have a greatly enhanced Th1 cytokine response and acute liver failure that mechanistically depends on TNF signaling. Bone marrow chimera experiments established that hepatic stromal (not hematopoietic) TIMP3 provides protection, with hepatocytes identified as the major source of Timp3 in resting liver. Timp3-/- mice, Con A model, bone marrow chimeras, flow cytometry of liver lymphocyte populations, Tnf genetic crosses, in situ hybridization/immunostaining for cell-type-specific Timp3 expression Journal of immunology (Baltimore, Md. : 1950) High 22323541
2011 TIMP3 deficiency leads to TNF dysregulation, earlier caspase activation, accelerated mitochondrial apoptosis, faster loss of STAT3 and TGFbeta3, E-cadherin fragmentation, accelerated adipogenesis, and greater macrophage/T-cell infiltration during mammary gland involution. Crossing in Tnf deficiency abrogated caspase-3 activation but paradoxically heightened macrophage/T-cell influx, showing that TIMP3 differentially controls apoptosis (TNF-dependent) and inflammatory cell infiltration (TNF-independent) during involution. Timp3-/- and Timp3-/-/Tnf-/- mice, mammary gland involution model, caspase activity assays, Western blot for signaling molecules, flow cytometry/histopathology for immune cells PloS one High 22053204
2014 TIMP3 loss in ApoE-/- mice increases atherosclerosis with greater macrophage plaque infiltration, elevated serum MCP-1, and expansion of inflammatory (M1) Gr1+ macrophages in circulation and aortic tissue, establishing TIMP3 as a regulator of macrophage inflammatory polarization in atherosclerosis. ApoE-/-/Timp3-/- double-knockout mice, en face aorta analysis, aortic root histology, FACS for macrophage subsets, serum MCP-1 ELISA, metabolomics Atherosclerosis High 24943223
2014 Genetic loss of Timp3 protects mice from carcinogen-induced hepatocellular carcinoma (HCC): all WT mice developed HCC by 12 months, while only 33% of Timp3-/- mice did. Protection occurs through precocious activation of p53, p38, and Notch pathways, leading to hepatocyte senescence rather than apoptosis; TNF signaling was dispensable for this protection. Timp3-/- mice, diethylnitrosamine carcinogen model, immunohistochemistry and Western blot for p53/p38/Notch, senescence assays (SA-beta-Gal), apoptosis assays, Timp3-/-/Tnf-/- epistasis, Timp3-/- mouse embryo fibroblasts Oncogene High 25347747
2015 In MMTV-PyMT and MMTV-Neu breast cancer models, Timp3 loss delays tumor onset and some mice remain tumor-free. The tumor-suppression in Timp3-null mice requires TNFR1 signaling. Transplantation experiments showed that Timp3 deficiency in the host stroma (not tumor cells) is sufficient to delay early but not advanced tumor growth. MMTV-PyMT/Timp3-/- and MMTV-Neu/Timp3-/- mice, Tnfr1 genetic crosses (epistasis), tumor cell transplantation into Timp3-/- hosts, tumor onset/incidence measurement PloS one High 25807548
2017 Hepatocyte-specific TIMP3 overexpression (AlbT3 mice) improved glucose metabolism, hepatic fatty acid oxidation, and cholesterol homeostasis during high-fat diet. This was linked to regulation of ADAM17: hepatocyte-specific Adam17 knockout (A17LKO, but not myeloid Adam17 KO) similarly improved liver steatosis, placing TIMP3 upstream of hepatocyte ADAM17 in NAFLD protection. Both AlbT3 and A17LKO mice showed reduced hepatic tumorigenesis. Hepatocyte-specific TIMP3 transgenic (AlbT3), hepatocyte-specific Adam17 KO (A17LKO), myeloid-specific Adam17 KO (A17MKO) mice, HFD model, diethylnitrosamine tumor model, metabolic phenotyping, gene expression analysis Scientific reports High 28751722
2018 TIMP3 is a CLOCK-dependent diurnal gene in human keratinocytes: CLOCK knockdown reduces TIMP3 expression rhythmically, and TIMP3 inversely regulates MMP-1 and inflammatory cytokines (TNF-alpha, CXCL1, IL-8). UVB exposure downregulates both CLOCK and TIMP3, increasing TNF-alpha secretion and CXCL1/IL-8 transcription via C/EBP-alpha. TIMP3 overexpression decreases, and knockdown increases, UVB-induced TNF-alpha secretion. CLOCK knockdown in keratinocytes, TIMP3 KD/OE, UVB irradiation, MMP-1 activity assay, ELISA for TNF-alpha, qPCR/Western blot for cytokines, circadian rhythm monitoring FASEB journal Medium 29180440
2019 Glycosaminoglycans (specifically sulfated hyaluronan and heparin) influence MMP2/TIMP3 complex formation and MMP2 inhibition. Sulfated hyaluronan supports fibrillar co-alignment of MMP2 and TIMP3, stabilizing interactions between MMP2 hemopexin domain and TIMP3 C-terminal tail. Molecular modeling indicates that GAG can either support or preclude TIMP3-mediated MMP2 inhibition depending on the sequential order of complex formation. In vitro MMP2 activity assays with bone marrow stromal cells, MMP2/TIMP3 complex formation assays, in silico docking and molecular dynamics simulations, immunofluorescence imaging of fibrillar structures Scientific reports Medium 30894640
2016 KDM1A (histone demethylase) promotes lung cancer metastasis by silencing TIMP3 through H3K4me2 demethylation at the TIMP3 promoter. KDM1A knockdown increases TIMP3, which in turn inhibits MMP2 expression and JNK phosphorylation. Restoring TIMP3 expression in KDM1A-deficient cells inhibits invasion/migration, and TIMP3 knockdown in KDM1A-deficient cells rescues metastatic capability. KDM1A KD/OE in NSCLC cells, ChIP-qPCR for H3K4me2 at TIMP3 promoter, TIMP3 KD rescue experiment, MMP2 activity assay, JNK phosphorylation assay, Transwell invasion assay, pharmacological inhibition Oncotarget Medium 27058897
2017 Hepatocyte-specific TIMP3 overexpression or Adam17 deletion protected against iron overload-mediated cardiac dysfunction and liver injury. In Timp3-/- mice with iron overload, constituently lower ferroportin levels led to twofold higher hepatic iron accumulation, increased MMP-2 activation, and greater hepatic inflammatory cytokine and MMP-12/13 expression. Timp3-/- mice, chronic iron overload model, echocardiography, hepatic iron quantification, ferroportin Western blot, MMP zymography, gelatinase activity assay, histopathology American journal of physiology. Heart and circulatory physiology Medium 29373036
2019 HDAC9 promotes trophoblast cell migration and invasion by repressing TIMP3 transcription through promoter histone hypoacetylation. In preeclampsia, HDAC9 is downregulated in syncytiotrophoblasts; HDAC9 knockdown increases histone acetylation at the TIMP3 promoter (confirmed by ChIP-qPCR), elevates TIMP3 expression, and inhibits cell migration and invasion in HTR-8/SVneo cells. ChIP-qPCR for histone acetylation at TIMP3 promoter, HDAC9 siRNA knockdown and rescue, Transwell migration/invasion assays, RT-qPCR and Western blot, immunohistochemistry in human placentas American journal of hypertension Medium 30715128
2020 ALKBH5 (an m6A RNA demethylase) represses TIMP3 mRNA stability and protein production in non-small cell lung cancer. RIP-Seq identified TIMP3 mRNA as an ALKBH5-bound target; ALKBH5 knockdown increased TIMP3 expression and reduced tumor growth in vivo, establishing an ALKBH5-mediated m6A modification as a post-transcriptional regulator of TIMP3. RNA immunoprecipitation sequencing (RIP-Seq), ALKBH5 KD/OE, mRNA stability assay, Western blot, in vivo xenograft, RT-qPCR Gene Medium 31927006
2021 LncRNA ROR recruits histone methyltransferase MLL1 to promote H3K4 trimethylation at the TIMP3 locus, enhancing TIMP3 transcription and breast cancer progression. RIP, RNA pull-down, and ChIP assays confirmed lncRNA ROR-MLL1-H3K4me3-TIMP3 axis; lncRNA ROR knockdown inhibited breast cancer cell invasion and tumor growth through downregulation of TIMP3. RIP assay, RNA pull-down, ChIP for H3K4me3 at TIMP3, lncRNA ROR KD/OE, Transwell invasion assay, in vivo xenograft Journal of translational medicine Medium 33653378

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Pericyte TIMP3 and ADAMTS1 modulate vascular stability after kidney injury. Journal of the American Society of Nephrology : JASN 169 22383695
2013 Both mature miR-17-5p and passenger strand miR-17-3p target TIMP3 and induce prostate tumor growth and invasion. Nucleic acids research 158 23990326
2016 MicroRNA-181b Controls Atherosclerosis and Aneurysms Through Regulation of TIMP-3 and Elastin. Circulation research 147 27756793
2005 Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. The Journal of clinical investigation 143 16294222
2012 TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association. Science signaling 126 22550340
2009 Loss of TIMP3 enhances interstitial nephritis and fibrosis. Journal of the American Society of Nephrology : JASN 119 19406980
2020 Biology of Tissue Inhibitor of Metalloproteinase 3 (TIMP3), and Its Therapeutic Implications in Cardiovascular Pathology. Frontiers in physiology 116 32612540
2014 Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction. Cardiovascular research 100 24692173
2013 Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO molecular medicine 90 23401241
2005 The expression and regulation of ADAMTS-1, -4, -5, -9, and -15, and TIMP-3 by TGFbeta1 in prostate cells: relevance to the accumulation of versican. The Prostate 87 15599946
2020 CircFNDC3B sequestrates miR-937-5p to derepress TIMP3 and inhibit colorectal cancer progression. Molecular oncology 83 32896063
2020 N6-methyladenosine ALKBH5 promotes non-small cell lung cancer progress by regulating TIMP3 stability. Gene 79 31927006
2016 Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice. Annals of neurology 77 26648042
2016 The Angiogenic Effect of microRNA-21 Targeting TIMP3 through the Regulation of MMP2 and MMP9. PloS one 77 26872030
2013 Regulation of TIMP3 in diabetic nephropathy: a role for microRNAs. Acta diabetologica 77 23797704
2001 Upregulation and differential expression of matrilysin (MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett's oesophageal adenocarcinoma. British journal of cancer 77 11487270
2003 Expression of ADAMs (a disintegrin and metalloproteases) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinomas. International journal of oncology 76 14532978
2004 TIMP3 checks inflammation. Nature genetics 71 15340428
2003 Expression profiling reveals that methylation of TIMP3 is involved in uveal melanoma development. International journal of cancer 70 12845640
2007 The metalloprotease inhibitor TIMP-3 regulates amyloid precursor protein and apolipoprotein E receptor proteolysis. The Journal of neuroscience : the official journal of the Society for Neuroscience 68 17913923
2019 Loss of TIMP3 by promoter methylation of Sp1 binding site promotes oral cancer metastasis. Cell death & disease 67 31624299
2018 TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome. PLoS genetics 67 30281655
2015 Tissue inhibitor of metalloproteinase-3 (TIMP3) promotes endothelial apoptosis via a caspase-independent mechanism. Apoptosis : an international journal on programmed cell death 66 25558000
2009 Hypermethylation and transcriptional downregulation of the TIMP3 gene is associated with allelic loss on 22q12.3 and malignancy in meningiomas. Brain pathology (Zurich, Switzerland) 65 19922547
2016 Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. eLife 63 27476853
2018 miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway. Clinical epigenetics 62 29796115
2019 Promoter Hypermethylation of Tumor-Suppressor Genes p16INK4a,RASSF1A,TIMP3, and PCQAP/MED15 in Salivary DNA as a Quadruple Biomarker Panel for Early Detection of Oral and Oropharyngeal Cancers. Biomolecules 61 31013839
2013 MiR-21 down-regulation suppresses cell growth, invasion and induces cell apoptosis by targeting FASL, TIMP3, and RECK genes in esophageal carcinoma. Digestive diseases and sciences 61 23504349
2012 Loss of Timp3 gene leads to abdominal aortic aneurysm formation in response to angiotensin II. The Journal of biological chemistry 60 23144462
2010 Overexpression of TACE and TIMP3 mRNA in head and neck cancer: association with tumour development and progression. British journal of cancer 59 21102583
2016 Smad2/3/4 Pathway Contributes to TGF-β-Induced MiRNA-181b Expression to Promote Gastric Cancer Metastasis by Targeting Timp3. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 58 27383203
2013 TIMP2 and TIMP3 have divergent roles in early renal tubulointerstitial injury. Kidney international 56 23760282
2014 Relationship of MMP-14 and TIMP-3 expression with macrophage activation and human atherosclerotic plaque vulnerability. Mediators of inflammation 55 25301980
1995 Structure of the human TIMP-3 gene and its cell cycle-regulated promoter. The Biochemical journal 55 7487894
2012 Correlation between BRAF mutation and promoter methylation of TIMP3, RARβ2 and RASSF1A in thyroid cancer. Epigenetics 53 22694820
2013 Promoter methylation and expression of TIMP3 gene in gastric cancer. Diagnostic pathology 52 23819566
2009 Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia. American journal of physiology. Gastrointestinal and liver physiology 52 19299578
2007 TIMP-3 deficiency accelerates cardiac remodeling after myocardial infarction. Journal of molecular and cellular cardiology 52 17945252
1997 Discrete expression and distribution pattern of TIMP-3 in the human retina and choroid. Current eye research 51 9068940
2017 MicroRNA-21 promotes proliferation, migration, and invasion of cervical cancer through targeting TIMP3. Archives of gynecology and obstetrics 49 29177591
2014 HPV-positive oropharyngeal squamous cell carcinoma is associated with TIMP3 and CADM1 promoter hypermethylation. Cancer medicine 49 25065733
2010 Loss of expression of TIMP3 in clear cell renal cell carcinoma. European journal of cancer (Oxford, England : 1990) 49 20194016
2017 miR-365 promotes diabetic retinopathy through inhibiting Timp3 and increasing oxidative stress. Experimental eye research 47 29196060
2014 Loss of TIMP3 exacerbates atherosclerosis in ApoE null mice. Atherosclerosis 44 24943223
2012 Loss of TIMP3 selectively exacerbates diabetic nephropathy. American journal of physiology. Renal physiology 42 22896043
2020 Pregnancy-associated Inflammatory Myofibroblastic Tumors of the Uterus Are Clinically Distinct and Highly Enriched for TIMP3-ALK and THBS1-ALK Fusions. The American journal of surgical pathology 40 32271187
2020 Curcumin Inhibits Hepatocellular Carcinoma via Regulating miR-21/TIMP3 Axis. Evidence-based complementary and alternative medicine : eCAM 40 32724322
2016 KDM1A promotes tumor cell invasion by silencing TIMP3 in non-small cell lung cancer cells. Oncotarget 40 27058897
2018 Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain. Developmental cell 39 29456135
2017 Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition. Oncotarget 39 28404876
2005 DNA hypermethylation of TIMP3 gene in invasive breast ductal carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 39 16507410
2022 Exosomal miR-452-5p Induce M2 Macrophage Polarization to Accelerate Hepatocellular Carcinoma Progression by Targeting TIMP3. Journal of immunology research 38 36164322
2014 TIMP-3 expression associates with malignant behaviors and predicts favorable survival in HCC. PloS one 38 25171061
2013 Differential TIMP3 expression affects tumor progression and angiogenesis in melanomas through regulation of directionally persistent endothelial cell migration. Angiogenesis 38 24221409
2017 Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3. Cardiovascular engineering and technology 37 28236165
2013 TIMP3 and CCNA1 hypermethylation in HNSCC is associated with an increased incidence of second primary tumors. Journal of translational medicine 36 24359512
2019 The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain. Cells 35 31877820
2002 Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy. Archives of ophthalmology (Chicago, Ill. : 1960) 35 11879143
1994 Expression of TIMP3 mRNA is elevated in retinas affected by simplex retinitis pigmentosa. FEBS letters 35 7925969
2020 MiR-770-5p facilitates podocyte apoptosis and inflammation in diabetic nephropathy by targeting TIMP3. Bioscience reports 34 32309847
2015 MiR-191 modulates malignant transformation of endometriosis through regulating TIMP3. Medical science monitor : international medical journal of experimental and clinical research 34 25819812
2019 Dysregulation of HDAC9 Represses Trophoblast Cell Migration and Invasion Through TIMP3 Activation in Preeclampsia. American journal of hypertension 32 30715128
2017 Andrographolide Inhibits Angiogenesis by Inhibiting the Mir-21-5p/TIMP3 Signaling Pathway. International journal of biological sciences 32 28539838
2021 CircSLC7A2 protects against osteoarthritis through inhibition of the miR-4498/TIMP3 axis. Cell proliferation 31 33960555
2019 LncRNA TUG1 ameliorates diabetic nephropathy by inhibiting miR-21 to promote TIMP3-expression. International journal of clinical and experimental pathology 31 31933879
2015 The imbalance between TIMP3 and matrix-degrading enzymes plays an important role in intervertebral disc degeneration. Biochemical and biophysical research communications 31 26686417
2020 Disturbed balance in the expression of MMP9 and TIMP3 in cerebral amyloid angiopathy-related intracerebral haemorrhage. Acta neuropathologica communications 30 32631441
2016 TIMP3 regulates osteosarcoma cell migration, invasion, and chemotherapeutic resistances. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 30 26749283
2015 MicroRNA-373 promotes migration and invasion in human esophageal squamous cell carcinoma by inhibiting TIMP3 expression. American journal of cancer research 30 27073718
2006 A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy. American journal of ophthalmology 30 16989765
2021 Long non-coding RNA ROR recruits histone transmethylase MLL1 to up-regulate TIMP3 expression and promote breast cancer progression. Journal of translational medicine 29 33653378
2012 Stromal TIMP3 regulates liver lymphocyte populations and provides protection against Th1 T cell-driven autoimmune hepatitis. Journal of immunology (Baltimore, Md. : 1950) 29 22323541
2012 Promoter hypomethylation of TIMP3 is associated with pre-eclampsia in a Chinese population. Molecular human reproduction 28 23172037
2006 Expression of ADAMTS-1, -4, -5 and TIMP-3 in normal and multiple sclerosis CNS white matter. Multiple sclerosis (Houndmills, Basingstoke, England) 28 16900752
2003 Sorsby fundus dystrophy mutation Timp3(S156C) affects the morphological and biochemical phenotype but not metalloproteinase homeostasis. Journal of cellular physiology 28 12942551
2021 A circular RNA, circSMARCA5, inhibits prostate cancer proliferative, migrative, and invasive capabilities via the miR-181b-5p/miR-17-3p-TIMP3 axis. Aging 27 34390329
2018 MicroRNA-323a-3p Promotes Pressure Overload-Induced Cardiac Fibrosis by Targeting TIMP3. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 27 30415251
2016 Tissue inhibitor of metalloproteinase-3 (TIMP3) expression decreases during melanoma progression and inhibits melanoma cell migration. European journal of cancer (Oxford, England : 1990) 27 27522248
2009 Hypomethylation and expression of BEX2, IGSF4 and TIMP3 indicative of MLL translocations in acute myeloid leukemia. Molecular cancer 27 19835597
2018 TIMP3 is a CLOCK-dependent diurnal gene that inhibits the expression of UVB-induced inflammatory cytokines in human keratinocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 29180440
2018 miR-222-3p promotes osteosarcoma cell migration and invasion through targeting TIMP3. OncoTargets and therapy 26 30584323
2017 Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma. Scientific reports 26 28751722
2011 Decreased IRS2 and TIMP3 expression in monocytes from offspring of type 2 diabetic patients is correlated with insulin resistance and increased intima-media thickness. Diabetes 26 21984580
2005 Alterations of the tissue inhibitor of metalloproteinase-3 (TIMP3) gene in pancreatic adenocarcinomas. Pancreas 26 15714128
2005 TIMP3 mutation in Sorsby's fundus dystrophy: molecular insights. Expert reviews in molecular medicine 26 16259644
2014 TIMP3 controls cell fate to confer hepatocellular carcinoma resistance. Oncogene 25 25347747
2023 Asiaticoside-nitric oxide promoting diabetic wound healing through the miRNA-21-5p/TGF-β1/SMAD7/TIMP3 signaling pathway. Journal of ethnopharmacology 24 37783408
2019 Glycosaminoglycans influence enzyme activity of MMP2 and MMP2/TIMP3 complex formation - Insights at cellular and molecular level. Scientific reports 24 30894640
2019 A Strong Decrease in TIMP3 Expression Mediated by the Presence of miR-17 and 20a Enables Extracellular Matrix Remodeling in the NSCLC Lesion Surroundings. Frontiers in oncology 24 31921636
2017 MiR-221 Exacerbate Cell Proliferation and Invasion by Targeting TIMP3 in Papillary Thyroid Carcinoma. American journal of therapeutics 24 27077469
2015 Timp3 deficient mice show resistance to developing breast cancer. PloS one 24 25807548
2013 Ultrasound-targeted HSVtk and Timp3 gene delivery for synergistically enhanced antitumor effects in hepatoma. Cancer gene therapy 24 23598435
2018 TIMP3 deficiency exacerbates iron overload-mediated cardiomyopathy and liver disease. American journal of physiology. Heart and circulatory physiology 23 29373036
2011 Expression of MMP-3 and TIMP-3 in gastric cancer tissue and its clinical significance. Oncology letters 23 22848309
2016 Expression and inhibitory role of TIMP-3 in hepatocellular carcinoma. Oncology reports 22 27222429
2011 TIMP3 regulates mammary epithelial apoptosis with immune cell recruitment through differential TNF dependence. PloS one 22 22053204
2008 Molecular dissection of TIMP3 mutation S156C associated with Sorsby fundus dystrophy. Matrix biology : journal of the International Society for Matrix Biology 22 18295466
2021 CircCSNK1G3 up-regulates miR-181b to promote growth and metastasis via TIMP3-mediated epithelial to mesenchymal transitions in renal cell carcinoma. Journal of cellular and molecular medicine 21 33560588
2018 MicroRNA-21 up-regulates metalloprotease by down-regulating TIMP3 during cumulus cell-oocyte complex in vitro maturation. Molecular and cellular endocrinology 21 29775626
2012 Expression of ADAMTS-1, ADAMTS-4, ADAMTS-5 and TIMP3 by hepatocellular carcinoma cell lines. International journal of oncology 20 22735305

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