Affinage

TIMP4

Metalloproteinase inhibitor 4 · UniProt Q99727

Length
224 aa
Mass
25.5 kDa
Annotated
2026-06-10
65 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMP4 is a secreted tissue inhibitor of metalloproteinases that restrains MMP-driven extracellular matrix turnover across cardiovascular, vascular, reproductive, and ocular tissues (PMID:9252358, PMID:20516072). It is a broad-spectrum, high-affinity inhibitor of soluble MMPs (MMP-1, -2, -3, -7, -9) with low-nanomolar potency (PMID:9252358, PMID:12475252), and binds the C-terminal hemopexin-like domain of pro-MMP-2 at a site overlapping that of TIMP-2 (PMID:9182583, PMID:12475252). Despite being an efficient MT1-MMP inhibitor, TIMP-4 cannot assemble the TIMP-2-like ternary MT1-MMP·TIMP·pro-MMP-2 complex needed for cell-surface pro-MMP-2 activation, and instead competes with TIMP-2 to suppress this activation step (PMID:10998420, PMID:11178970, PMID:11437402). The inhibitory repertoire is domain-partitioned: only the N-terminal domain inhibits TACE/ADAM-17, an activity suppressed by the C-terminal domain and tunable by AB-loop residues (PMID:15713681). In the heart, TIMP4 is essential after myocardial infarction, where its loss causes lethal ventricular rupture that is rescued by Mmp2 deletion, establishing MMP-2 inhibition as its core protective mechanism (PMID:20516072). Its expression is governed by an Sp1/initiator-driven TATA-less promoter (PMID:11988080) and is dynamically controlled by epigenetic silencing through promoter CpG methylation and EZH2/H3K27me3 (PMID:35996686, PMID:27396717), by miRNA repression (PMID:34643044, PMID:27396717), by suppression downstream of TGF-β1 (PMID:25971370), and by mRNA stabilization through AKAP1 (PMID:39965635); downstream, TIMP-4 modulates NFκB signaling in vascular smooth muscle cells and during adipogenesis (PMID:25999146, PMID:39965635). Beyond MMP inhibition, TIMP4 controls vascular smooth muscle cell migration and neointimal formation after injury (PMID:10082471, PMID:12947565), regulates CD36 proteolytic processing in enterocytes to enable lipid absorption (PMID:28740132), and maintains ocular ECM homeostasis, with heterozygous loss-of-function variants linked to early-onset high myopia (PMID:38069250).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1997 High

    Established that TIMP-4 is a functional MMP inhibitor and defined its physical interaction with pro-MMP-2, answering whether the protein behaves like other TIMPs.

    Evidence Recombinant binding/competition assays with MMP-2 domains and enzymatic inhibition assays plus a Matrigel invasion readout

    PMID:9182583 PMID:9252358

    Open questions at the time
    • Inhibitory profile against membrane-type MMPs not yet tested
    • No in vivo confirmation of inhibitory function
  2. 2000 High

    Resolved why TIMP-4 differs functionally from TIMP-2 despite similar binding, showing it inhibits MT1-MMP but cannot support ternary-complex-dependent pro-MMP-2 activation.

    Evidence Cell-based pro-MMP-2 activation assays in Timp2-null cells with MT1-MMP/TIMP coexpression

    PMID:10998420 PMID:11178970 PMID:11437402

    Open questions at the time
    • Structural basis for the failure to form the ternary complex not defined
    • Competition with TIMP-2 quantified only in overexpression systems
  3. 2002 High

    Provided rigorous kinetic constants and a two-site binding model, and identified platelets as a major physiological compartment for TIMP-4.

    Evidence Progress-curve kinetics and biosensor analysis with recombinant proteins; platelet biochemistry, electron microscopy and aggregometry

    PMID:12466243 PMID:12475252

    Open questions at the time
    • Physiological relevance of the acidic-pH reactivity not established
    • Mechanism of TIMP-4 effect on platelet aggregation beyond MMP inhibition unclear
  4. 2002 High

    Defined the cis-elements controlling TIMP4 transcription, answering how the gene is constitutively expressed.

    Evidence Promoter deletion/point-mutant reporter assays and transcription start site mapping in fibroblasts

    PMID:11988080

    Open questions at the time
    • Trans-acting factors beyond Sp1 not identified
    • No link yet to tissue-specific or signal-driven regulation
  5. 2005 High

    Mapped the domain determinants of TIMP-4 target specificity, showing the N-terminal domain alone inhibits TACE and that the C-terminal domain suppresses this.

    Evidence Kinetic inhibition assays of N-TIMP-4 versus full-length TIMP-4 against TACE with AB/EF-loop mutagenesis

    PMID:15713681

    Open questions at the time
    • Physiological relevance of TACE inhibition by an N-terminal fragment in vivo unknown
    • Whether full-length TIMP-4 ever exposes this activity in tissue not addressed
  6. 2010 High

    Demonstrated the essential, MMP-2-specific cardioprotective role of TIMP4 in vivo through genetic epistasis, the strongest causal anchor for its function.

    Evidence Timp4 knockout mice in MI and pressure-overload models with pharmacological and Mmp2-deletion rescue; primary cardiomyocyte contractility assays

    PMID:20422465 PMID:20516072

    Open questions at the time
    • Whether other tissues show MMP-2-specific dependence not tested
    • Compensation by TIMP-2 leaves the unique role outside the heart unclear
  7. 2016 Medium

    Established that TIMP4 expression is dynamically silenced in cardiac and vascular disease through layered epigenetic and post-transcriptional mechanisms.

    Evidence Methylation-specific PCR, bisulfite sequencing, ChIP for H3K27me3, miRNA profiling and EZH2 gain/loss-of-function in heart-failure and atrial-fibroblast models

    PMID:25971370 PMID:27396717 PMID:34643044 PMID:35996686

    Open questions at the time
    • Causal hierarchy among methylation, EZH2, and miRNAs not resolved
    • Most mechanisms shown in single labs and rodent models
  8. 2017 Medium

    Extended TIMP4 function beyond MMP inhibition to metabolic physiology, showing it is required for CD36 proteolytic processing and intestinal lipid absorption.

    Evidence Timp4 knockout mice on high-fat diet with CD36 protein/mRNA dissociation and lipid absorption measurements

    PMID:28740132

    Open questions at the time
    • The specific metalloproteinase mediating CD36 processing not identified
    • Direct enzymatic mechanism linking TIMP-4 to CD36 not reconstituted
  9. 2019 Medium

    Identified a direct protein partner (CRN2) linking TIMP-4 and MT1-MMP at the invasive front, suggesting spatial coordination of inhibitor and protease.

    Evidence Reciprocal Co-IP/pull-down, enzyme activity assays and co-localization in glioblastoma cells with a CRN2 knockout model

    PMID:31677819

    Open questions at the time
    • Single lab; reciprocal validation not extended to other systems
    • Functional consequence of the CRN2-TIMP4 interaction on inhibitory activity unclear
  10. 2023 Medium

    Connected TIMP4 to a human Mendelian-like phenotype, establishing a causal role in ocular ECM homeostasis.

    Evidence Whole-exome sequencing of high-myopia patients plus dose-dependent Timp4-deficient rat ocular phenotyping

    PMID:38069250

    Open questions at the time
    • Molecular target whose dysregulation drives scleral/retinal collagen loss not defined
    • Human variants are heterozygous; full penetrance and mechanism not established
  11. 2025 Medium

    Defined an mRNA-stabilizing upstream regulator (AKAP1) and placed TIMP-4 as a node suppressing NFκB-driven vascular injury responses.

    Evidence RNA immunoprecipitation, mRNA stability assays and TIMP-4 gain/loss-of-function with NFκB pathway readouts in VSMCs

    PMID:39965635

    Open questions at the time
    • Direct mechanism of NFκB suppression by TIMP-4 not resolved
    • Single lab; in vivo confirmation of the AKAP1-TIMP4 axis lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TIMP-4's varied non-canonical activities (CD36 processing, NFκB modulation, platelet and ocular roles) connect mechanistically to its core metalloproteinase-inhibitory function remains unresolved.
  • No structural model explaining ternary-complex failure versus TIMP-2
  • Tissue-specific MMP substrates downstream of TIMP-4 largely uncharacterized
  • Whether NFκB and metabolic effects are protease-dependent unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-1474244 Extracellular matrix organization 2 R-HSA-162582 Signal Transduction 2 R-HSA-1430728 Metabolism 1
Partners
ADAM17AKAP1CRN2MMP14MMP2MMP9TIMP2

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 TIMP-4 binds specifically and with high affinity to the C-terminal hemopexin-like domain (C domain) of human progelatinase A (MMP-2), but not to the fibronectin type II-like collagen-binding domain. This interaction is similar to TIMP-2 binding to progelatinase A, and TIMP-2 and TIMP-4 compete for a common or overlapping binding site on the C domain. Microwell protein binding assay, affinity chromatography, competition binding assay with recombinant domains The Journal of biological chemistry High 9182583
1997 Recombinant TIMP-4 inhibits MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9 enzymatic activity with IC50 values of 19, 3, 45, 8, and 83 nM, respectively, and inhibits invasion of breast cancer cells across reconstituted basement membranes. Enzymatic kinetic inhibition assays with purified recombinant TIMP-4; Matrigel invasion assay The Journal of biological chemistry High 9252358
2000 TIMP-4, unlike TIMP-2, does not support MT1-MMP-dependent activation of pro-MMP-2 on the cell surface, even though it is an efficient MT1-MMP inhibitor. TIMP-4 lacks the ability to form the TIMP-2-like ternary complex (MT1-MMP·TIMP·pro-MMP-2) required for pro-MMP-2 activation. Cell-based pro-MMP-2 activation assay; Timp2-null cell reconstitution; coexpression of MT1-MMP with TIMP-4 or TIMP-2 The Journal of biological chemistry High 10998420 11178970
2001 TIMP-4 binds to MT1-MMP and inhibits its autocatalytic turnover/processing on the cell surface. When coexpressed with TIMP-2, TIMP-4 competitively reduces pro-MMP-2 activation by MT1-MMP, suggesting TIMP-4 competes with TIMP-2 for binding to MT1-MMP. Coexpression of MT1-MMP with TIMP-4 and/or TIMP-2 in cells; assessment of MT1-MMP autocatalytic processing and pro-MMP-2 activation by zymography/Western blot Biochemical and biophysical research communications Medium 11178970
2001 TIMP-4 blocks MT1-MMP-mediated activation of pro-MMP-2 (progelatinase A) in human umbilical vein endothelial cells, whereas TIMP-1 does not. TIMP-4 also reduces invasion of U251 glioma cells through Matrigel. Cell-based pro-MMP-2 activation assay with recombinant TIMP-4; Matrigel invasion assay with U87 cells overexpressing TIMP-4 British journal of cancer Medium 11437402
2002 Kinetic analysis shows TIMP-4 inhibits MMPs with association rate constants (~10^5 M^-1 s^-1) and Ki values (10^-9 to 10^-12 M) similar to TIMP-1 and TIMP-2. TIMP-4 retains higher inhibitory reactivity with MMPs at acidic pH compared to TIMP-1 and TIMP-2. Biosensor analysis reveals that both pro-MMP-2 and active MMP-2 (with blocked active site) have essentially identical affinities for TIMP-4 via a hemopexin domain site, while active MMP-2 also engages a second lower-affinity site through the catalytic domain. Progress curve kinetic analysis; alpha2-macroglobulin dissociation assay; IAsys biosensor analysis Biochemistry High 12475252
2002 TIMP-4 is the major MMP inhibitor in human platelets (12–16 ng per 10^8 platelets), co-localizes with MMP-2 in resting platelets, and is released upon platelet aggregation induced by collagen and thrombin. Recombinant TIMP-4 (but not TIMP-1) partially inhibits platelet aggregation and recruitment, and this inhibition is potentiated by NO donor GSNO. Western blot, reverse zymography, immunogold electron microscopy, aggregometry, flow cytometry, serotonin release assay British journal of pharmacology High 12466243
2002 The Timp-4 promoter contains an initiator-like element and an Sp1 motif that are essential for expression; mutation of either element almost completely abolishes reporter expression. An inverted CCAAT box acts as a modest repressor (2-fold increase when mutated). The TATA-less promoter is non-inducible by serum. Transient transfection reporter assays with promoter deletion and point mutants in C3H10T1/2 fibroblasts; RACE and RNase protection for transcription start site mapping The Biochemical journal High 11988080
1999 TIMP-4 protein accumulates in the adventitia and neointima of rat carotid arteries after balloon injury, and recombinant TIMP-4 reduces invasion of rat vascular smooth muscle cells through matrix-coated membranes by 53%, implicating TIMP-4 in controlling smooth muscle cell migration and collagen deposition after vascular injury. In situ hybridization, immunohistochemistry, Western blot of injured arteries; in vitro Boyden chamber invasion assay with recombinant TIMP-4 Circulation research Medium 10082471
2003 Adenoviral gene transfer of TIMP-4 into rat carotid arteries after balloon injury inhibits vascular smooth muscle cell migration in vitro and reduces neointimal hyperplasia by 66.5% compared to controls at 28 days. Adenovirus-mediated gene transfer in vivo; monolayer scrape migration assay in vitro; morphometric analysis of neointima/media ratio Beijing da xue xue bao. Yi xue ban Medium 12947565
2005 The N-terminal domain of TIMP-4 (N-TIMP-4) is a slow tight-binding inhibitor of TACE (ADAM-17) with low nanomolar affinity, whereas full-length TIMP-4 has negligible activity against TACE. Transplantation of three residues (Pro-Phe-Gly) from TIMP-3's AB-loop onto N-TIMP-4 enhanced TACE inhibition 10-fold, indicating the C-terminal domain suppresses and specific AB-loop residues determine TACE activity. Kinetic inhibition assays with recombinant N-TIMP-4 and full-length TIMP-4 against TACE; site-directed mutagenesis of AB-loop and EF-loop The Journal of biological chemistry High 15713681
2010 Timp4-deficient mice (Timp4−/−) generated by homologous recombination show significantly increased post-myocardial infarction mortality primarily due to left ventricular rupture. This enhanced mortality is rescued by a synthetic MMP inhibitor or by genetic deletion of Mmp2, demonstrating that TIMP4 functions as an MMP inhibitor (specifically MMP-2) after myocardial infarction. After cardiac pressure overload, Timp4-deficiency is compensated by increased Timp2 expression with no survival difference. Homologous recombination knockout; myocardial infarction model; aortic banding model; synthetic MMP inhibitor treatment; genetic cross with Mmp2-/- mice; cardiac function assessment The Journal of biological chemistry High 20516072
2010 MMP-9 treatment of primary cardiomyocytes attenuates voltage-induced contraction and reduces Ca2+ transients; TIMP-4 (an MMP-9 inhibitor) reverses this inhibition, and this MMP-9 effect is mediated through PAR-1 signaling. MMP-9 knockout cardiomyocytes contract more rapidly and release more Ca2+ than controls, associated with induction of serca-2a. Primary cardiomyocyte isolation; video-edge detection contractility assay; Fura-2-AM calcium imaging; MMP-9 KO mice; PAR-1 antagonist; recombinant TIMP-4 treatment Cell biochemistry and biophysics Medium 20422465
2013 Hypoxia upregulates TIMP-4 (and TIMP-3) in fetal rat hearts and H9c2 cardiomyocytes. Knockdown of TIMP-4 completely abrogates hypoxia-mediated inhibition of cardiomyocyte proliferation (Ki-67, BrdU, cyclin D2), while having no significant effect on basal proliferation, establishing a causal role for TIMP-4 in hypoxia-induced inhibition of cardiomyocyte proliferation. siRNA knockdown of TIMP-4 in H9c2 cells; Ki-67 immunostaining; BrdU incorporation; Western blot for cyclin D2 and p27; ex vivo fetal heart hypoxia model American journal of physiology. Regulatory, integrative and comparative physiology Medium 23427085
2015 TIMP-4 overexpression in cervical cancer cells enriches the tumor progenitor cell (TPC) population and accelerates xenograft tumor growth. Genome-wide expression analysis shows hrTIMP-4 treatment activates NFκB signaling pathway globally, modulating cell survival, proliferation, inflammation, and EMT networks. Stable TIMP-4 overexpression; xenograft limiting dilution assay; recombinant TIMP-4 treatment; microarray gene expression; in silico pathway analysis; NFκB pathway validation Molecular carcinogenesis Medium 26618609
2015 TIMP-4 knockdown in 3T3-L1 preadipocytes accelerates differentiation into mature adipocytes, associated with decreased NFκB activity during adipogenesis, suggesting TIMP-4 acts as a negative regulator of adipogenesis via NFκB modulation. Stable shRNA knockdown in 3T3-L1 cells; adipocyte differentiation assay; microarray gene expression; NFκB activity assay Experimental cell research Medium 25999146
2016 LOX (lysyl oxidase) transcriptionally activates the SNAI2 promoter, and LOX/SNAI2 depletion reduces TIMP4 secretion in cancer cell lines. LOX binds to the SNAI2 promoter as shown by chromatin immunoprecipitation, placing TIMP4 downstream of a LOX-SNAI2 axis. Chromatin immunoprecipitation (ChIP); promoter luciferase assay; siRNA knockdown; protein array for MMPs/TIMPs; in vivo metastatic mouse model Clinical cancer research Medium 27029493
2016 Recombinant TIMP-4 treatment of MCF7 breast cancer cells activates ER-α signaling (increases ER-α protein levels) and enriches for ER-α binding sites in promoters of TIMP4-upregulated genes. TIMP-4 also modulates HIF1A and TGF-β signaling while downregulating FOXO3 signaling. Recombinant TIMP-4 treatment; RNASeq; RT-PCR validation; network pathway analysis Folia biologica Low 27187039
2017 Absence of TIMP4 in knockout mice impairs lipid absorption on high-fat diet by preventing proteolytic processing of CD36 protein in intestinal enterocytes. HFD increases CD36 protein (not mRNA) in WT but not Timp4-/- intestinal enterocytes, indicating TIMP4 regulates CD36 post-translationally through metalloproteinase-dependent mechanisms. Timp4 knockout mice; high-fat diet model; CD36 protein and mRNA quantification in intestinal enterocytes; lipid absorption (fecal free fatty acid); body composition analysis Scientific reports Medium 28740132
2019 CRN2 (an actin filament binding protein) directly binds TIMP4 and MMP14 (MT1-MMP) as novel binding partners; all three proteins co-localize at lamellipodia fronts. CRN2 increases TIMP4 secretion and enhances MMP14 catalytic activity, promoting perivascular invasion of glioblastoma cells. Immunoprecipitation; pull-down assays; enzyme activity assay; immunofluorescence co-localization; CRN2 knockout mouse model; transplanted glioblastoma cell assay European journal of cell biology Medium 31677819
2015 TGF-β1 stimulation of isolated human atrial fibroblasts directly suppresses TIMP-4 protein levels as shown by Western blot. In patients with atrial fibrillation secondary to rheumatic heart disease, TIMP-4 expression is inversely correlated with TGF-β1 levels (r = -0.98), and lower TIMP-4 correlates with increased MMP-2, collagen I, and collagen III. In vitro recombinant TGF-β1 stimulation of primary atrial fibroblasts; Western blot; patient tissue Western blot and qRT-PCR; Masson staining Molecular and cellular biochemistry Medium 25971370
2022 EZH2 suppresses Timp4 gene transcription by catalyzing H3K27me3 modifications in the Timp4 promoter region. Knockdown of Ezh2 increases Timp4 expression and accelerates replicative senescence of atrial fibroblasts; Ezh2 overexpression reduces senescence. A functional balance between TIMP4 and MMP8 in atrial fibroblasts is disrupted by Ezh2 level changes. ChIP assay for H3K27me3 at Timp4 promoter; siRNA knockdown and overexpression of Ezh2; senescence assays; RNA-seq; GSK-126 and GSK-343 methyltransferase inhibitors Journal of inflammation research Medium 35996686
2021 miR-146b-5p directly targets and represses TIMP4 in atrial cardiomyocytes; reduced TIMP4 increases MMP9 activity and collagen synthesis. Inhibition of miR-146b-5p in a MI mouse model increases TIMP4 expression and reduces cardiac fibrosis markers (MMP9, TGFB1, COL1A1). miR-146b-5p transfection in hiPSC-aCMs-fibroblast co-culture; antagomiR-146 treatment in MI mouse model; Western blot and qRT-PCR for TIMP4/MMP9/TGFB1/COL1A1 Journal of cellular and molecular medicine Medium 34643044
2023 Loss of TIMP4 does not exacerbate thoracic or abdominal aortic aneurysm severity compared to wild-type mice, whereas loss of TIMP3 significantly worsens both. In vitro, Timp4 knockdown does not significantly compromise endothelial monolayer permeability compared to Timp3 knockdown. Timp4-/- and Timp3-/- mouse aortic aneurysm models (elastase); histology; proteinase activity; EC monolayer permeability assay Journal of molecular and cellular cardiology Medium 37844423
2016 TIMP4 promoter CpG islands undergo methylation during heart failure progression (created by AV fistula), leading to epigenetic silencing of TIMP4 expression. Upregulation of miR-122a also contributes to TIMP4 regulation. Consequent MMP9 upregulation drives cardiac remodeling. Methylation-specific PCR; high-resolution melting; bisulfite sequencing; ChIP for histone modifications; miRNA expression analysis; AV fistula heart failure mouse model; echocardiography Journal of cellular and molecular medicine Medium 27396717
2025 AKAP1 (RNA binding protein) stabilizes TIMP-4 mRNA to maintain TIMP-4 expression. TIMP-4 upregulation suppresses Ang-II-induced NF-κB pathway activation, oxidative stress, inflammation, and MMP9 expression in vascular smooth muscle cells. TIMP-4 reduction partially abrogates AKAP1's suppressive effects, placing TIMP-4 downstream of AKAP1 in protection against VSMC injury. RNA immunoprecipitation (RIP); mRNA stability analysis; TIMP-4 overexpression and knockdown in VSMCs; Western blot for NF-κB signaling; oxidative stress and inflammation assays; GSE7084 and GSE140947 dataset analysis Shock (Augusta, Ga.) Medium 39965635
2023 TIMP4 heterozygous loss-of-function variants (c.528C>A and c.234_235insAA) are enriched in early-onset high myopia patients. Timp4-deficient rats show axial length elongation, reduced retinal and scleral collagen content, and reduced retinal thickness in a dose-dependent manner (Timp4-/- < Timp4+/- < Timp4+/+), establishing a causal role for TIMP4 in maintaining ocular ECM homeostasis and normal ocular development. Whole exome sequencing; Timp4 gene-editing rat model; ocular morphology and axial length measurement; electroretinogram; HE and immunofluorescence staining; collagen quantification; form deprivation myopia model International journal of molecular sciences Medium 38069250
2006 In human endometrium, TIMP-4 mRNA is exclusively produced in stromal cells, while TIMP-4 protein is taken up by epithelial cells, accumulates in apical granules, and is secreted into uterine fluid. TIMP-4 is the main TIMP present in uterine fluid. This stromal-to-epithelial transcytosis pathway establishes compartment-specific regulation of MMP-26 activity. In situ hybridization; immunohistochemistry; real-time PCR on separated stromal and epithelial cells; Western blot of uterine fluid Molecular human reproduction Medium 16809379
2013 Osteoprotegerin (OPG) upregulates TIMP-4 expression while downregulating ADAMTS-5 in chondrocytes via MEK/ERK signaling; suppression of ERK by PD098059 blocks OPG-induced TIMP-4 upregulation. OPG had no effect on TIMP-1, TIMP-2, or TIMP-3 expression, showing specificity for TIMP-4. Primary rat chondrocyte culture; OPG treatment; MEK/ERK inhibitors (U0126, PD098059); Western blot; qPCR Molecular medicine reports Medium 24126801

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues. FEBS letters 167 9013889
1997 Specific, high affinity binding of tissue inhibitor of metalloproteinases-4 (TIMP-4) to the COOH-terminal hemopexin-like domain of human gelatinase A. TIMP-4 binds progelatinase A and the COOH-terminal domain in a similar manner to TIMP-2. The Journal of biological chemistry 129 9182583
2000 Tissue inhibitor of metalloproteinase (TIMP)-2 acts synergistically with synthetic matrix metalloproteinase (MMP) inhibitors but not with TIMP-4 to enhance the (Membrane type 1)-MMP-dependent activation of pro-MMP-2. The Journal of biological chemistry 109 10998420
1997 Preparation and characterization of recombinant tissue inhibitor of metalloproteinase 4 (TIMP-4). The Journal of biological chemistry 105 9252358
2010 Mice with tissue inhibitor of metalloproteinases 4 (Timp4) deletion succumb to induced myocardial infarction but not to cardiac pressure overload. The Journal of biological chemistry 73 20516072
2001 Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas. British journal of cancer 73 11437402
2001 Differential roles of TIMP-4 and TIMP-2 in pro-MMP-2 activation by MT1-MMP. Biochemical and biophysical research communications 69 11178970
2006 Tissue inhibitor of metalloproteinases 4 (TIMP4) is involved in inflammatory processes of human cardiovascular pathology. Histochemistry and cell biology 66 16521002
2002 Identification, regulation and role of tissue inhibitor of metalloproteinases-4 (TIMP-4) in human platelets. British journal of pharmacology 66 12466243
2002 E. coli expression of TIMP-4 and comparative kinetic studies with TIMP-1 and TIMP-2: insights into the interactions of TIMPs and matrix metalloproteinase 2 (gelatinase A). Biochemistry 60 12475252
2016 Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 58 27029493
2002 Identification of an initiator-like element essential for the expression of the tissue inhibitor of metalloproteinases-4 (Timp-4) gene. The Biochemical journal 56 11988080
1999 TIMP-4 is regulated by vascular injury in rats. Circulation research 55 10082471
2005 Total conversion of tissue inhibitor of metalloproteinase (TIMP) for specific metalloproteinase targeting: fine-tuning TIMP-4 for optimal inhibition of tumor necrosis factor-{alpha}-converting enzyme. The Journal of biological chemistry 49 15713681
2007 Increased expression of matrix metalloproteinases-21 and -26 and TIMP-4 in pancreatic adenocarcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 41 17873896
2006 Coordinated peak expression of MMP-26 and TIMP-4 in preinvasive human prostate tumor. Cell research 39 16940965
2010 MMP-9 gene ablation and TIMP-4 mitigate PAR-1-mediated cardiomyocyte dysfunction: a plausible role of dicer and miRNA. Cell biochemistry and biophysics 37 20422465
2019 Upregulated long noncoding RNA Linc00261 in pre-eclampsia and its effect on trophoblast invasion and migration via regulating miR-558/TIMP4 signaling pathway. Journal of cellular biochemistry 36 30891826
2017 Absence of Tissue Inhibitor of Metalloproteinase-4 (TIMP4) ameliorates high fat diet-induced obesity in mice due to defective lipid absorption. Scientific reports 35 28740132
2021 MicroRNA-146b-5p promotes atrial fibrosis in atrial fibrillation by repressing TIMP4. Journal of cellular and molecular medicine 32 34643044
2013 Hypoxia inhibits cardiomyocyte proliferation in fetal rat hearts via upregulating TIMP-4. American journal of physiology. Regulatory, integrative and comparative physiology 31 23427085
2011 Heterogeneity and degree of TIMP4, GATA4, SOX18, and EGFL7 gene promoter methylation in non-small cell lung cancer and surrounding tissues. Cancer genetics 29 22018271
2002 Characterization of the murine Timp4 gene, localization within intron 5 of the synapsin 2 gene and tissue distribution of the mRNA. Biochimica et biophysica acta 29 12151094
1998 Cloning of the human tissue inhibitor of metalloproteinase-4 gene (TIMP4) and localization of the TIMP4 and Timp4 genes to human chromosome 3p25 and mouse chromosome 6, respectively. Genomics 27 9693046
2015 Tissue inhibitor of metalloproteinases-4 (TIMP-4) regulates stemness in cervical cancer cells. Molecular carcinogenesis 25 26618609
2019 Expressions of MMP-12, TIMP-4, and Neutrophil Elastase in PBMCs and Exhaled Breath Condensate in Patients with COPD and Their Relationships with Disease Severity and Acute Exacerbations. Journal of immunology research 23 31143784
2015 TGF-β1 and TIMP-4 regulate atrial fibrosis in atrial fibrillation secondary to rheumatic heart disease. Molecular and cellular biochemistry 23 25971370
2011 Matrix metalloproteinase-1 expression enhances tumorigenicity as well as tumor-related angiogenesis and is inversely associated with TIMP-4 expression in a model of glioblastoma. Journal of neuro-oncology 21 21858729
2004 Endometrial TIMP-4 mRNA is high at midcycle and in hyperplasia, but down-regulated in malignant tumours. Coordinated expression with MMP-26. Molecular human reproduction 20 15273280
2022 Ezh2 Inhibits Replicative Senescence of Atrial Fibroblasts Through Promotion of H3K27me3 in the Promoter Regions of CDKN2a and Timp4 Genes. Journal of inflammation research 19 35996686
2016 Epigenetic silencing of TIMP4 in heart failure. Journal of cellular and molecular medicine 18 27396717
2016 TIMP4 expression is regulated by miR-200b-3p in prostate cancer cells. APMIS : acta pathologica, microbiologica, et immunologica Scandinavica 18 28028835
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
2022 Targeting interleukin-21 inhibits stress overload-induced cardiac remodelling via the TIMP4/MMP9 signalling pathway. European journal of pharmacology 15 36587888
2014 TIMP-3 -1296 T>C and TIMP-4 -55 T>C gene polymorphisms play a role in the susceptibility of hepatocellular carcinoma among women. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 13 24903383
2008 Promoter polymorphism (rs3755724, -55C/T) of tissue inhibitor of metalloproteinase 4 (TIMP4) as a risk factor for Kawasaki disease with coronary artery lesions in a Korean population. Pediatric cardiology 13 19048177
2008 Association of TIMP-4 gene polymorphism with the risk of osteoarthritis in the Korean population. Rheumatology international 12 18301898
2020 Zingerone Attenuates Pi-induced Vascular Calcification via AMPK-mediated TIMP4 Expression. Journal of lipid and atherosclerosis 11 33537254
2019 CRN2 binds to TIMP4 and MMP14 and promotes perivascular invasion of glioblastoma cells. European journal of cell biology 11 31677819
2015 Tissue inhibitor of metalloproteases-4 (TIMP-4) modulates adipocyte differentiation in vitro. Experimental cell research 11 25999146
2006 Endometrial TIMP-4 mRNA is expressed in the stroma, while TIMP-4 protein accumulates in the epithelium and is released to the uterine fluid. Molecular human reproduction 11 16809379
2021 CD24 gene inhibition and TIMP-4 gene upregulation by Imperata cylindrica's root extract prevents metastasis of CaSki cells via inhibiting PI3K/Akt/snail signaling pathway and blocking EMT. Journal of ethnopharmacology 10 33848610
2006 Endometrial expression of the estrogen-sensitive genes MMP-26 and TIMP-4 is altered by a substitution protocol without down-regulation in IVF patients. Human reproduction (Oxford, England) 9 17012332
2023 Defect of TIMP4 Is Associated with High Myopia and Participates in Rat Ocular Development in a Dose-Dependent Manner. International journal of molecular sciences 8 38069250
2024 Expression of Tissue Inhibitors of Metalloproteinases (TIMP-1, TIMP-2, TIMP-3, TIMP-4) in Blood Serum of Patients with Keratoconus. Journal of clinical medicine 7 38398480
2017 Higher levels of circulating TIMP-4 in preeclampsia is strongly associated with clinical parameters and microRNA. Clinical and experimental hypertension (New York, N.Y. : 1993) 7 29231756
2024 Altered brain expression and cerebrospinal fluid levels of TIMP4 in cerebral amyloid angiopathy. Acta neuropathologica communications 6 38915119
2023 Loss of TIMP3, but not TIMP4, exacerbates thoracic and abdominal aortic aneurysm. Journal of molecular and cellular cardiology 6 37844423
2022 Colorectal Cancer Chemotherapy Drug Bevacizumab May Induce Muscle Atrophy Through CDKN1A and TIMP4. Frontiers in oncology 6 35847900
2005 Expression of tissue inhibitor of metalloproteinase-4 (TIMP-4) in endometrium and placenta of rhesus monkey (Macaca mulatta) during early pregnancy. Life sciences 6 16375928
2023 Aloperine Prevents Migration, Invasion, and Adhesion by Upregulating TIMP-4 in Human Bladder Cancer Cells. Protein and peptide letters 5 36734907
2012 Assessment of the correlation between TIMP4 SNPs and schizophrenia and autism spectrum disorders. Molecular medicine reports 4 23229788
2019 Association of TIMP4 gene variants with steroid-induced osteonecrosis of the femoral head in the population of northern China. PeerJ 3 30697482
2016 TIMP4 Modulates ER-α Signalling in MCF7 Breast Cancer Cells. Folia biologica 3 27187039
2014 Contribution of TIMP4 rs3755724 polymorphism to susceptibility to focal epilepsy in Malaysian Chinese. Journal of neuroimmunology 3 25595263
2025 An integrated machine learning model of transcriptomic genes in multi-center chronic obstructive pulmonary disease reveals the causal role of TIMP4 in airway epithelial cell. Respiratory research 2 40269868
2025 TIMP4 as a Potential Complementary Biomarker and Therapeutic Target in Membranous Nephropathy: A Multi-Omics Investigation with Clinical Validation. Journal of inflammation research 2 41169458
2018 Divergent changes in the content and activity of MMP-26 and TIMP-4 in human umbilical cord tissues associated with preeclampsia. European journal of obstetrics, gynecology, and reproductive biology 2 30321788
2013 [Expression and significance of MMP-26, TIMP-4 and MMP-9 in diffuse large B-cell lymphoma cells]. Zhongguo shi yan xue ye xue za zhi 2 24156427
2025 AKAP1-STABILIZED TIMP-4 ATTENUATES ANG-II-INDUCED OXIDATIVE STRESS AND INFLAMMATION IN VASCULAR SMOOTH MUSCLE CELLS BY INACTIVATING THE NF-ΚB SIGNALING. Shock (Augusta, Ga.) 1 39965635
2025 Exosomal TIMP4 from Myocardial Cell Relieves Heart Failure by Influencing Th17/Treg Balance. Cardiology 1 40418920
2010 Development of a monoclonal antibody that specifically detects tissue inhibitor of metalloproteinase-4 (TIMP-4) in formalin-fixed, paraffin-embedded human tissues. Journal of cellular biochemistry 1 20564221
2008 [Changing trends of the expression of TIMP-4 in mouse ovary during pregnant and postpartum period]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 1 21141538
2003 [Adenovirus-mediated transfer of TIMP-4 gene inhibits neointimal formation after balloon injury]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 1 12947565
2025 Decreased serum TIMP4 levels in patients with rheumatoid arthritis. Open life sciences 0 40291774

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