Affinage

TIMP3

Metalloproteinase inhibitor 3 · UniProt P35625

Length
211 aa
Mass
24.1 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMP3 is an extracellular matrix-sequestered metalloproteinase inhibitor that serves as a master brake on protease-driven tissue remodeling, inflammation, and vascular homeostasis. It inhibits MMPs, aggrecanases (ADAMTS4/5), ADAM10, and ADAM17/TACE with sub-nanomolar potency, using its N-terminal domain for MMP and aggrecanase inhibition but requiring its full-length structure for ADAM10 blockade (PMID:11278243, PMID:10818225, PMID:18215140). By suppressing TACE activity, TIMP3 controls TNF-α shedding, EGFR ligand release, NKG2D ligand shedding, and downstream STAT1/FoxO1 signaling; its extracellular bioavailability is regulated by LRP-1-mediated endocytosis, and its loss causes spontaneous dilated cardiomyopathy, renal fibrosis, accelerated atherosclerosis, and metabolic disease through unchecked TACE and MMP activity (PMID:15262835, PMID:16294222, PMID:19406980, PMID:27476612, PMID:23401241, PMID:24943223). Mutations in TIMP3 (e.g., S156C) cause Sorsby's fundus dystrophy, linked to its unique ECM deposition in Bruch's membrane, though the S156C mutation preserves protease-inhibitory function and instead causes abnormal dimerization and ECM accumulation (PMID:9068940, PMID:12942551, PMID:18295466).

Mechanistic history

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

    Establishing the genomic architecture of TIMP3 — a TATA-less gene on chromosome 22q13.1 with Sp1-dependent basal transcription and serum-inducible upstream elements — provided the foundation for understanding its transcriptional regulation.

    Evidence Genomic cloning, somatic cell hybrid mapping, and promoter-reporter deletion analysis in cell cycle studies

    PMID:7487894

    Open questions at the time
    • Transcription factor binding to the serum-responsive element not identified
    • No chromatin-level regulation addressed
  2. 1997 High

    Demonstrating that TIMP3 protein is uniquely sequestered in the ECM (Bruch's membrane) rather than being secreted into medium explained why TIMP3 mutations cause the retinal-specific Sorsby's fundus dystrophy, unlike other TIMPs.

    Evidence RT-PCR, Northern, Western blot, and immunohistochemistry of human retina/choroid and cultured RPE cells

    PMID:9068940

    Open questions at the time
    • Molecular determinants of ECM binding not identified
    • Whether ECM sequestration differs across tissue types not resolved
  3. 2000 High

    Identifying TIMP3 as the sole TIMP capable of inhibiting both ADAM10 and TACE (ADAM17) at sub-nanomolar potency expanded its functional scope beyond MMP inhibition to regulation of ADAMs-mediated ectodomain shedding.

    Evidence Quenched fluorescent substrate assay and myelin basic protein degradation assay with recombinant ADAM10 catalytic domain

    PMID:10818225

    Open questions at the time
    • Structural basis for TIMP3 selectivity toward ADAMs not determined
    • In vivo relevance of ADAM10 inhibition not yet shown
  4. 2001 High

    Showing that the N-terminal domain of TIMP3 potently inhibits aggrecanases ADAMTS4 and ADAMTS5 (Ki < 1 nM) established TIMP3 as the first known endogenous regulator of cartilage-degrading aggrecanases.

    Evidence In vitro enzymatic inhibition assay with recombinant N-terminal TIMP3 domain

    PMID:11278243

    Open questions at the time
    • In vivo cartilage protection by endogenous TIMP3 not demonstrated
    • Aggrecanase inhibition mechanism at the structural level not resolved
  5. 2003 Medium

    Analyzing the Sorsby's fundus dystrophy S156C mutation revealed it causes TIMP3 dimerization and ECM accumulation without impairing MMP2 inhibition, redirecting pathogenic models away from simple loss of protease inhibitory function.

    Evidence Immortalized fibroblast lines from Timp3S156C/S156C mice; gelatin zymography; ECM immunoblot; turnover assays

    PMID:12942551

    Open questions at the time
    • Single lab study
    • Downstream consequence of ECM accumulation on retinal physiology not tested
    • Whether dimerization affects ADAM inhibition not assessed
  6. 2004 High

    Timp3-knockout mice developing spontaneous dilated cardiomyopathy with elevated MMP-9 and TNF-α provided the first in vivo proof that TIMP3 is indispensable for maintaining myocardial matrix homeostasis.

    Evidence Targeted Timp3-KO mice evaluated longitudinally; gelatinase bioassay; echocardiography and histology

    PMID:15262835

    Open questions at the time
    • Whether cardiomyopathy is MMP- or TACE-dependent not dissected
    • Cell-type-specific contributions within heart not determined
  7. 2005 High

    Genetic epistasis placing TIMP3 upstream of TACE/TNF-α in metabolic disease — with pharmacological TACE inhibition rescuing vascular inflammation in TIMP3-deficient mice — established the TIMP3→TACE→TNF-α axis as a central inflammatory circuit.

    Evidence Insr+/-Timp3+/- double heterozygous mice; TACE activity assays; pharmacological TACE inhibitor rescue

    PMID:16294222

    Open questions at the time
    • Contribution of other TACE substrates besides TNF-α not dissected
    • Human metabolic disease relevance not directly tested
  8. 2008 High

    Two key advances refined the inhibitory mechanism: full-length TIMP3 was shown to be required for ADAM10 inhibition (unlike for MMPs/ADAM17), and the S156C SFD mutation was found to preserve all tested protease-inhibitory and anti-angiogenic functions, suggesting SFD involves a non-protease-inhibitory mechanism.

    Evidence In vitro domain-truncation inhibition assays; Timp3S156C knock-in mice with TACE, ADAMTS, MMP, and VEGFR2-binding assays

    PMID:18215140 PMID:18295466

    Open questions at the time
    • C-terminal structural contacts with ADAM10 not mapped
    • The non-protease-inhibitory pathogenic mechanism in SFD remains unidentified
  9. 2009 High

    Double-KO epistasis (Timp3−/−/TNFα−/−) in renal obstruction proved that TIMP3 restrains kidney fibrosis via dual TACE/TNF-α and MMP-2 axes, with TNF-α deletion rescuing most inflammatory injury.

    Evidence TIMP3−/− and TIMP3−/−/TNFα−/− double-KO mice with unilateral ureteral obstruction; TACE activity; gelatin zymography

    PMID:19406980

    Open questions at the time
    • Relative contribution of TNF-dependent vs MMP-dependent fibrosis not fully quantified
    • Cell-type-specific source of renal TIMP3 not identified
  10. 2011 High

    During mammary involution, TIMP3 differentially controls apoptosis (via TNF) and inflammatory cell influx through distinct mechanisms, as shown by double-KO epistasis where TNF deletion abrogated caspase-3 activation but paradoxically increased macrophage/T-cell infiltration.

    Evidence Timp3−/− and Timp3−/−/Tnf−/− double-KO mice during mammary involution; caspase assays; flow cytometry

    PMID:22053204

    Open questions at the time
    • Identity of the TNF-independent inflammatory target protease not established
    • Whether this bifurcation applies in other tissues not tested
  11. 2012 High

    Multiple 2012 studies converged on how TIMP3 integrates into tissue-specific protease control: TACE dimerization governs TIMP3 association at the cell surface, pericyte-derived TIMP3 stabilizes capillaries via ADAMTS1 inhibition, stromal TIMP3 regulates hepatic immune populations, and TIMP3 and TIMP2 have divergent roles in renal injury.

    Evidence TACE dimerization/co-IP assays; 3D capillary tube networks with pericytes; bone marrow chimeras in Con A hepatitis; comparative TIMP2−/−/TIMP3−/− kidney models

    PMID:22323541 PMID:22383695 PMID:22550340 PMID:23760282

    Open questions at the time
    • Structural basis of TACE dimer–TIMP3 interaction unknown
    • Whether pericyte TIMP3 acts through the same TACE/TNF axis not established
  12. 2013 High

    In diabetic nephropathy, TIMP3 loss activates ADAM17 leading to elevated STAT1 that represses FoxO1 and autophagy; TIMP3 re-expression rescues this cascade, establishing TIMP3→ADAM17→STAT1→FoxO1 as a signaling axis in metabolic kidney disease.

    Evidence Diabetic Timp3−/− mice; microarray; mesangial cell re-expression; STAT1 siRNA rescue; human kidney biopsies

    PMID:23401241

    Open questions at the time
    • Which ADAM17 substrate mediates STAT1 activation not identified
    • Whether this axis operates in non-renal diabetic complications not tested
  13. 2014 High

    TIMP3's anti-inflammatory role was extended to atherosclerosis (macrophage M1 polarization in ApoE−/−Timp3−/− mice) and cardiac fibrosis (MMP-independent collagen stabilization via osteopontin/SPARC), revealing protease-independent functions.

    Evidence ApoE−/−Timp3−/− mice with en face aorta analysis and macrophage flow cytometry; TIMP3−/− mice with AngII infusion and collagen crosslinking analysis

    PMID:24692173 PMID:24943223

    Open questions at the time
    • Mechanism by which TIMP3 deficiency elevates osteopontin/SPARC not resolved
    • Direct protease target responsible for macrophage polarization not identified
  14. 2016 High

    Three breakthroughs in 2016 clarified TIMP3 bioavailability and vascular function: LRP-1 cluster II mediates TIMP3 endocytosis and a soluble minireceptor (T3TRAP) blocks this to increase extracellular TIMP3; elevated TIMP3 in CADASIL causes cerebrovascular dysfunction via ADAM17/HB-EGF/KV channel axis; and Timp3 haploinsufficiency rescues CADASIL cerebral blood flow deficits.

    Evidence Biochemical LRP-1 binding assays and MS secretome; CADASIL mouse pharmacological/genetic rescue with CBF measurement and patch-clamp electrophysiology; TgNotch3R169C × Timp3+/− mice

    PMID:26648042 PMID:27476612 PMID:27476853

    Open questions at the time
    • Whether T3TRAP is effective in vivo not demonstrated
    • Whether TIMP3 accumulation in CADASIL is the sole pathogenic mediator vs other trapped ECM proteins
    • Structural basis of LRP-1 cluster II–TIMP3 interaction not resolved
  15. 2017 High

    Hepatocyte-specific TIMP3 overexpression phenocopied hepatocyte-specific Adam17 deletion in protecting against NAFLD and hepatocarcinogenesis, confirming the TIMP3–ADAM17 axis operates cell-autonomously in hepatocytes to control lipid metabolism.

    Evidence AlbT3 and A17LKO conditional mice on HFD; metabolic assays; diethylnitrosamine tumor model

    PMID:28751722

    Open questions at the time
    • ADAM17 substrates responsible for hepatic lipid accumulation not identified
    • Whether myeloid TIMP3 has independent liver-protective roles not resolved
  16. 2018 High

    Two studies linked TIMP3 to pericyte TGF-β signaling and to LRP-1-mediated secretome remodeling: pericyte ALK5 drives TIMP3 expression to suppress perivascular MMP activity and prevent germinal matrix hemorrhage, while TIMP3 overexpression competes with other LRP-1 cargo (TIMP-1, MIF, SPARC) for endocytosis.

    Evidence Conditional pericyte Alk5-KO mice with TIMP3 rescue; MS secretome in TIMP3-overexpressing HEK293 with LRP-1 inactivation comparison

    PMID:29456135 PMID:30279425

    Open questions at the time
    • Whether TIMP3 competition for LRP-1 is physiologically relevant at endogenous expression levels
    • Downstream consequences of altered MIF/SPARC clearance not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis for TIMP3's selective inhibition of ADAMs versus MMPs; the identity of the non-protease-inhibitory function lost in Sorsby's fundus dystrophy; the cell-type-specific transcriptional and post-transcriptional regulatory network controlling TIMP3 levels in vivo; and the therapeutic potential of modulating TIMP3 bioavailability (e.g., via LRP-1 blockade) in disease.
  • No crystal structure of TIMP3 in complex with an ADAM family member
  • SFD pathogenic mechanism remains undefined despite exclusion of protease-inhibitory loss
  • In vivo therapeutic efficacy of T3TRAP or similar LRP-1-blocking strategies not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 2
Pathway
R-HSA-1474244 Extracellular matrix organization 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3
Partners
ADAM10ADAM17ADAMTS4ADAMTS5KDRLRP1MMP2MMP9

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 The N-terminal inhibitory domain of TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5), with Ki values in the subnanomolar range, establishing TIMP-3 as the first endogenous regulator of aggrecanases. In vitro enzymatic inhibition assay with recombinant N-terminal TIMP-3 domain expressed from bacterial inclusion bodies The Journal of biological chemistry High 11278243
2000 TIMP-3 (but not TIMP-2 or TIMP-4) inhibits ADAM-10 with an apparent inhibition constant of ~0.9 nM, and is the only TIMP able to inhibit both ADAM-10 and TACE (ADAM-17). Quenched fluorescent substrate assay and myelin basic protein degradation assay using recombinant ADAM-10 catalytic domain FEBS letters High 10818225
2012 Under basal conditions, TACE (ADAM17) exists predominantly as cell-surface dimers that associate efficiently with TIMP3 to suppress TACE activity; activation of ERK or p38 MAPK shifts the equilibrium toward TACE monomers, reducing TIMP3 association and increasing TACE-mediated proteolysis. Cell-surface dimerization assays, co-immunoprecipitation of TACE with TIMP3, MAPK pathway manipulation, TGF-α shedding readout Science signaling High 22550340
2005 TIMP3 deficiency leads to unchecked TACE activity, increased soluble TNF-α, and promotes diabetes and vascular inflammation; pharmacological TACE inhibition reverses these phenotypes, placing TIMP3 upstream of TACE/TNF-α signaling in metabolic disease. Genetic epistasis in Insr+/- and Insr+/-Timp3+/- double heterozygous mice; TACE activity assays; pharmacological TACE inhibition rescue experiments The Journal of clinical investigation High 16294222
2004 TIMP-3 deficiency in mice triggers spontaneous dilated cardiomyopathy with elevated MMP-9 activity and TNF-α activation, demonstrating that TIMP-3 is required to maintain myocardial matrix homeostasis and suppress proinflammatory remodeling. Targeted Timp3-knockout mice evaluated longitudinally; gelatinase bioassay for MMP activity; echocardiographic and histological analysis Circulation High 15262835
2009 TIMP3 deficiency accelerates renal tubulointerstitial fibrosis after ureteral obstruction via elevated TACE activity, increased soluble TNF-α, and enhanced MMP-2 activation; additional deletion of TNF-α markedly reduces inflammation and fibrosis, placing TIMP3 upstream of TACE/TNF-α and MMP axes in kidney injury. TIMP3-/- mice and TIMP3-/-/TNFα-/- double-KO mice with unilateral ureteral obstruction; TACE activity assays; gelatin zymography; MMP inhibitor treatment Journal of the American Society of Nephrology : JASN High 19406980
2007 TIMP-3 inhibits ADAM-10 and ADAM-17-mediated alpha-secretase cleavage of APP and ApoER2, decreases their surface levels, and thereby increases beta-secretase cleavage and Aβ production; TIMP-3 protein levels are elevated in Alzheimer's disease brain. Cell-based alpha-secretase/beta-secretase cleavage assays in neuroblastoma and COS7 cells; surface protein measurement; Aβ ELISA; brain tissue immunoblot The Journal of neuroscience : the official journal of the Society for Neuroscience High 17913923
2015 TIMP3 induces apoptosis in endothelial cells expressing VEGFR2 (KDR) through a caspase-independent mechanism involving inhibition of FAK tyrosine phosphorylation and disruption of β3 integrin/FAK/paxillin incorporation into focal adhesion contacts. Apoptosis assays in PAE/KDR vs PAE/β-R cells; caspase inhibitor experiments; FAK phosphorylation immunoblot; focal adhesion complex co-immunoprecipitation Apoptosis : an international journal on programmed cell death Medium 25558000
2016 TIMP3 acts through inhibition of the metalloprotease ADAM17 and its substrate HB-EGF to regulate cerebral arterial tone; in CADASIL mice with elevated TIMP3, exogenous ADAM17 or HB-EGF restores cerebral blood flow responses, and upregulated voltage-dependent potassium (KV) channel number in arterial myocytes is identified as a downstream effector. CADASIL mouse model; pharmacological and genetic manipulation of ADAM17/HB-EGF; cerebral blood flow measurements; patch-clamp electrophysiology of cerebral arterial myocytes eLife High 27476853
2016 Elevated TIMP3 in CADASIL mice impairs functional hyperemia and cerebrovascular reactivity; haploinsufficiency of Timp3 rescues these CBF deficits downstream of Notch3ECD deposition, demonstrating TIMP3 accumulation as a causal contributor to cerebrovascular dysfunction. TgNotch3R169C mice crossed with Timp3 haploinsufficient mice; CBF measurements; myogenic tone assays; TgBAC-TIMP3 overexpression mouse Annals of neurology High 26648042
2012 Pericyte-derived TIMP3 stabilizes capillary tube networks and inhibits ADAMTS1-mediated metalloprotease activity in endothelial cells; Timp3-/- mice show spontaneous microvascular rarefaction and exaggerated fibrosis after kidney injury. 3D capillary tube network assays with pericytes vs myofibroblasts; Timp3-/- mouse renal injury model; ADAMTS1/TIMP3 expression profiling Journal of the American Society of Nephrology : JASN High 22383695
2018 Pericyte ALK5 (TGF-β receptor) signaling upregulates TIMP3 expression; ALK5-deficient brain pericytes downregulate TIMP3, causing enhanced perivascular MMP activity, endothelial hyperproliferation, and germinal matrix hemorrhage; exogenous TIMP3 administration rescues endothelial morphogenesis. Conditional pericyte Alk5 knockout mice; immunofluorescence; gelatin zymography; TIMP3 rescue administration in vivo Developmental cell High 29456135
2008 The N-terminal domains of TIMP-1 and TIMP-3 alone are insufficient to inhibit ADAM10; full-length TIMP-3 is required, indicating that regions beyond the N-terminal inhibitory domain contribute to ADAM10 inhibition, unlike the mechanism for MMP and ADAM17 inhibition. In vitro inhibition assays comparing N-terminal domain fragments vs full-length TIMP-1 and TIMP-3 against ADAM10, ADAM17, and MMPs The Biochemical journal High 18215140
1997 TIMP-3 protein is uniquely deposited in the extracellular matrix of Bruch's membrane in the retina/choroid and is not secreted into culture medium, unlike TIMP-1 and TIMP-2, explaining why TIMP-3 mutations cause retinal-specific pathology (Sorsby's fundus dystrophy). RT-PCR, Northern analysis, Western immunoblot, immunohistochemistry of human retina/choroid and cultured RPE cells and pericytes Current eye research High 9068940
2013 Loss of TIMP3 in diabetic mice causes increased ADAM17 activity and elevated STAT1, which represses FoxO1 transcription; re-expression of TIMP3 in Timp3-/- mesangial cells rescues FoxO1 and its autophagy targets while decreasing STAT1, establishing a TIMP3→ADAM17→STAT1→FoxO1 pathway in diabetic nephropathy. Diabetic Timp3-/- mice; microarray; re-expression experiments in mesangial cells; STAT1 siRNA rescue; kidney biopsies from diabetic patients EMBO molecular medicine High 23401241
2016 TIMP3 inhibits TIMP3 internalization via LRP-1 interaction; TIMP3 extracellular levels are regulated by endocytosis through LRP-1 cluster II; a soluble minireceptor (T3TRAP) that blocks TIMP3 binding to LRP-1 selectively increases extracellular TIMP3 and inhibits ADAM10-mediated shedding of multiple cell-surface proteins. Soluble LRP-1 minireceptor binding assays, biochemical TIMP-3/LRP-1 interaction assays, mass spectrometry-based secretome analysis Matrix biology : journal of the International Society for Matrix Biology High 27476612
2018 Increased TIMP-3 expression inhibits ADAM10-mediated shedding of multiple cell-surface proteins and simultaneously increases extracellular levels of soluble proteins (TIMP-1, MIF, SPARC) by competing with them for LRP-1-mediated endocytosis. Unbiased mass spectrometry secretome analysis in TIMP-3-overexpressing HEK293 cells; LRP-1 inactivation comparison Scientific reports High 30279425
2012 TIMP3, but not TIMP2, inhibits pro-MMP2 activation in kidney; TIMP3 deficiency selectively activates TACE, caspase-3, and MAPK pathways in obstructed kidney while TIMP2 deficiency reduces MMP2 activation, demonstrating divergent and contrasting roles in renal injury. TIMP2-/- and TIMP3-/- mice with unilateral ureteral obstruction; gelatin zymography; TACE activity assays; caspase-3 assays Kidney international High 23760282
2011 TIMP3 deficiency accelerates mammary gland involution through TNF dysregulation, earlier caspase-3 activation, and mitochondrial apoptosis; TNF deficiency abrogates caspase-3 activation but increases macrophage/T-cell infiltration, demonstrating that TIMP3 differentially controls apoptosis (via TNF) and inflammatory cell influx through distinct mechanisms. Timp3-/- and Timp3-/-/Tnf-/- double-KO mice during mammary involution; caspase assays; histology; flow cytometry PloS one High 22053204
2012 Stromal (hepatocyte-derived) TIMP3 regulates basal hepatic lymphocyte populations; TIMP3 deficiency leads to spontaneous accumulation and activation of hepatic CD4+, CD8+, and NKT cells and exacerbated Th1 cytokine response dependent on TNF signaling during Con A-induced autoimmune hepatitis. Bone marrow chimeras confirmed the stromal rather than hematopoietic source of protective TIMP3. Timp3-/- mice; bone marrow chimeras; Con A hepatitis model; flow cytometry; cytokine measurements Journal of immunology (Baltimore, Md. : 1950) High 22323541
2014 TIMP3 and TIMP2 play differential roles in cardiac hypertrophy and fibrosis: TIMP3 deficiency causes excess fibrosis (via MMP-independent post-translational stabilization of collagen by osteopontin and SPARC), while TIMP2 deficiency causes hypertrophy; both independently cause diastolic dysfunction. TIMP2-/- and TIMP3-/- mice with angiotensin II infusion; echocardiography; co-culture assays; Western blot for matricellular proteins; collagen crosslinking analysis Cardiovascular research High 24692173
1995 The human TIMP-3 gene is a TATA-less, 5-exon gene mapped to chromosome 22q13.1; its promoter contains multiple Sp1 sites sufficient for basal expression, while the region between -463 and -112 bp confers serum inducibility and cell-cycle regulation. Genomic cloning, somatic cell hybrid mapping, promoter-reporter deletion analysis in cell cycle studies The Biochemical journal High 7487894
2003 The SFD mutation S156C in TIMP3 does not impair MMP2 inhibitory activity but causes the protein to form dimers and accumulate in the ECM; this accumulation is not due to altered turnover rate and does not affect MMP2 or MMP9 levels or activation in patient-derived fibroblasts. Immortalized fibroblast lines from Timp3-/- and Timp3S156C/S156C mice; gelatin zymography; ECM immunoblot; turnover assays Journal of cellular physiology Medium 12942551
2008 The SFD-associated S156C mutation in TIMP3 does not impair inhibitory activity against TACE, ADAMTS4/5, or aggrecan-cleaving MMPs, nor its anti-angiogenic properties or VEGF/VEGFR2 blocking activity, suggesting SFD pathogenesis involves loss of a distinct non-protease-inhibitory function rather than imbalanced protease activity. Timp3S156C knock-in mice; TACE, ADAMTS4/5, MMP activity assays; fibrin bead angiogenesis assay; VEGF-VEGFR2 binding assay with recombinant proteins Matrix biology : journal of the International Society for Matrix Biology High 18295466
2014 Loss of TIMP3 in ApoE-/- mice increases atherosclerosis with greater macrophage infiltration, elevated MCP-1, and polarization of macrophages toward an inflammatory M1/Gr1+ phenotype, demonstrating a role for TIMP3 in restraining macrophage inflammatory polarization during atherogenesis. ApoE-/-Timp3-/- double-KO mice; en face aorta analysis; flow cytometry of macrophage subsets; serum MCP-1 measurement Atherosclerosis High 24943223
2017 Hepatocyte-specific TIMP3 overexpression improves glucose metabolism, hepatic fatty acid oxidation, and cholesterol homeostasis during high-fat diet; hepatocyte-specific Adam17 knockout (A17LKO), but not myeloid-specific Adam17 deletion, similarly reduces hepatic steatosis, establishing TIMP3 acts through hepatocyte ADAM17 inhibition to limit NAFLD and hepatocarcinogenesis. AlbT3 (hepatocyte TIMP3 overexpression) and A17LKO/A17MKO (cell-type-specific Adam17 KO) mice on HFD; metabolic assays; diethylnitrosamine tumor model Scientific reports High 28751722
2018 TIMP3 expression is regulated by a circadian CLOCK-dependent mechanism in human keratinocytes; CLOCK knockdown reduces TIMP3 expression and inversely increases MMP-1, TNF-α, CXCL1, and IL-8 via C/EBPα; UVB exposure suppresses CLOCK and TIMP3, and TIMP3 knockdown or overexpression modulates UVB-induced TNF-α secretion. CLOCK siRNA knockdown; TIMP3 overexpression/knockdown in keratinocytes; ELISA for secreted cytokines; promoter analysis FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 29180440
2014 Human cytomegalovirus (CMV) infection downregulates TIMP3 expression through upregulated cellular and CMV-encoded microRNAs, causing increased ADAM17 and MMP14 activity and enhanced shedding of the NKG2D ligand MICA to evade NK cell recognition. CMV infection of cells; miRNA expression analysis; metalloprotease activity assays; MICA shedding ELISA; soluble MICA detection in patient serum Journal of immunology (Baltimore, Md. : 1950) Medium 24973455
2016 KDM1A (histone demethylase) represses TIMP3 transcription by removing H3K4me2 at the TIMP3 promoter; KDM1A overexpression promotes NSCLC cell invasion and migration, which is rescued by TIMP3 overexpression; TIMP3 in turn suppresses MMP2 expression and JNK phosphorylation. KDM1A KD/OE in NSCLC cells; ChIP for H3K4me2 at TIMP3 promoter; invasion/migration assays; TIMP3 rescue experiments; pharmacological inhibition Oncotarget Medium 27058897
2011 TIMP3 promotes apoptotic cell death in small cell lung cancer cells that lack functional caspase-8 (adenovirally delivered TIMP3), indicating TIMP3 can induce apoptosis through a caspase-8-independent pathway in suspension-growing tumor cells. Adenoviral TIMP3 delivery to suspension-growing SCLC cell lines SW2 and N417; apoptosis assays; caspase-8 functional analysis International journal of cancer Medium 20473894
2019 HDAC9 promotes trophoblast cell migration and invasion by repressing TIMP3 through promoter histone hypoacetylation; HDAC9 knockdown increases histone acetylation at the TIMP3 promoter (by ChIP-qPCR) and upregulates TIMP3, inhibiting trophoblast invasion in preeclampsia. HDAC9 siRNA knockdown; ChIP-qPCR for TIMP3 promoter histone acetylation; transwell migration/invasion assays American journal of hypertension Medium 30715128
2021 MSI1 (Musashi1) RNA-binding protein directly suppresses TIMP3 expression, reducing TIMP3-mediated inhibition of MMP9, thereby promoting invadopodia formation and ECM degradation in breast cancer metastasis; TIMP3 and MSI1 expression are inversely correlated in clinical specimens. MSI1 KD/OE in mammary cancer cells; invadopodia formation assays; MMP9 activity; TIMP3 rescue; clinical tissue correlation Oncogene Medium 34155343
2009 In periovulatory granulosa cells, hCG induces biphasic TIMP3 expression via PKA, PKC, MAPK, progesterone receptor, and EGF receptor pathways; siRNA knockdown of Timp3 reduces hCG-induced progesterone levels by ~20%, indicating TIMP3 regulates steroidogenesis during ovulation. Rat granulosa cell isolation; pharmacological pathway inhibitors; Timp3-specific siRNA; progesterone measurement; microarray analysis Endocrinology Medium 19389837

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 TIMP-3 is a potent inhibitor of aggrecanase 1 (ADAM-TS4) and aggrecanase 2 (ADAM-TS5). The Journal of biological chemistry 400 11278243
2000 The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS letters 334 10818225
2012 Pericyte TIMP3 and ADAMTS1 modulate vascular stability after kidney injury. Journal of the American Society of Nephrology : JASN 168 22383695
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 141 16294222
2004 TIMP-3 deficiency leads to dilated cardiomyopathy. Circulation 132 15262835
1996 A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochemistry and cell biology = Biochimie et biologie cellulaire 129 9164653
2012 TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association. Science signaling 125 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 115 32612540
2014 Differential role of TIMP2 and TIMP3 in cardiac hypertrophy, fibrosis, and diastolic dysfunction. Cardiovascular research 99 24692173
2011 Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 99 21983937
2013 Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO molecular medicine 90 23401241
2002 Matrix remodeling in experimental and human heart failure: a possible regulatory role for TIMP-3. American journal of physiology. Heart and circulatory physiology 89 12388270
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 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 76 23797704
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
2016 Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice. Annals of neurology 75 26648042
2011 TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells. Oncogene 72 21339735
1997 Exclusion of TIMP3 as a candidate locus in age-related macular degeneration. Investigative ophthalmology & visual science 71 9152225
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 66 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
2018 miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway. Clinical epigenetics 62 29796115
2016 Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. eLife 62 27476853
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
2016 Matrix metalloproteinases MMP1, MMP2, MMP9 and their tissue inhibitors TIMP1, TIMP2, TIMP3 in head and neck cancer: an immunohistochemical study. Otolaryngologia polska = The Polish otolaryngology 57 27386931
2013 TIMP2 and TIMP3 have divergent roles in early renal tubulointerstitial injury. Kidney international 55 23760282
1995 Structure of the human TIMP-3 gene and its cell cycle-regulated promoter. The Biochemical journal 55 7487894
2014 Relationship of MMP-14 and TIMP-3 expression with macrophage activation and human atherosclerotic plaque vulnerability. Mediators of inflammation 54 25301980
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 48 25065733
2017 miR-365 promotes diabetic retinopathy through inhibiting Timp3 and increasing oxidative stress. Experimental eye research 47 29196060
2014 MMP-2, MMP-3, TIMP-1, TIMP-2, and TIMP-3 protein levels in human aqueous humor: relationship with axial length. Investigative ophthalmology & visual science 46 24876280
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
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
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
1997 TIMP-3 mRNA expression is regionally increased in moderately and poorly differentiated colorectal adenocarcinoma. British journal of cancer 40 9184186
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 39 32271187
2014 Altered microRNA expression after infection with human cytomegalovirus leads to TIMP3 downregulation and increased shedding of metalloprotease substrates, including MICA. Journal of immunology (Baltimore, Md. : 1950) 39 24973455
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
2018 Pericyte ALK5/TIMP3 Axis Contributes to Endothelial Morphogenesis in the Developing Brain. Developmental cell 38 29456135
2017 MicroRNA-222 Promotes the Proliferation of Pulmonary Arterial Smooth Muscle Cells by Targeting P27 and TIMP3. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 38 28854428
2017 Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3. Cardiovascular engineering and technology 37 28236165
2014 TIMP-3 expression associates with malignant behaviors and predicts favorable survival in HCC. PloS one 37 25171061
2002 Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy. Archives of ophthalmology (Chicago, Ill. : 1960) 35 11879143
2020 MiR-770-5p facilitates podocyte apoptosis and inflammation in diabetic nephropathy by targeting TIMP3. Bioscience reports 34 32309847
2019 The Diverse Roles of TIMP-3: Insights into Degenerative Diseases of the Senescent Retina and Brain. Cells 34 31877820
2012 Heterogeneous epigenetic regulation of TIMP3 in prostate cancer. Epigenetics 34 23023649
2008 The isolated N-terminal domains of TIMP-1 and TIMP-3 are insufficient for ADAM10 inhibition. The Biochemical journal 34 18215140
2015 MiR-191 modulates malignant transformation of endometriosis through regulating TIMP3. Medical science monitor : international medical journal of experimental and clinical research 33 25819812
2017 Andrographolide Inhibits Angiogenesis by Inhibiting the Mir-21-5p/TIMP3 Signaling Pathway. International journal of biological sciences 32 28539838
2011 TIMP-3 promotes apoptosis in nonadherent small cell lung carcinoma cells lacking functional death receptor pathway. International journal of cancer 32 20473894
2019 Dysregulation of HDAC9 Represses Trophoblast Cell Migration and Invasion Through TIMP3 Activation in Preeclampsia. American journal of hypertension 31 30715128
2019 LncRNA TUG1 ameliorates diabetic nephropathy by inhibiting miR-21 to promote TIMP3-expression. International journal of clinical and experimental pathology 31 31933879
2009 Regulation and function of tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP3 in periovulatory rat granulosa cells. Endocrinology 31 19389837
2021 CircSLC7A2 protects against osteoarthritis through inhibition of the miR-4498/TIMP3 axis. Cell proliferation 30 33960555
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
2006 A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy. American journal of ophthalmology 30 16989765
2018 Indications for islet or pancreatic transplantation: Statement of the TREPID working group on behalf of the Société francophone du diabète (SFD), Société francaise d'endocrinologie (SFE), Société francophone de transplantation (SFT) and Société française de néphrologie - dialyse - transplantation (SFNDT). Diabetes & metabolism 29 30223084
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
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
2020 Disturbed balance in the expression of MMP9 and TIMP3 in cerebral amyloid angiopathy-related intracerebral haemorrhage. Acta neuropathologica communications 27 32631441
2012 Promoter hypomethylation of TIMP3 is associated with pre-eclampsia in a Chinese population. Molecular human reproduction 27 23172037
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
2017 Hepatocyte specific TIMP3 expression prevents diet dependent fatty liver disease and hepatocellular carcinoma. Scientific reports 26 28751722
2005 Alterations of the tissue inhibitor of metalloproteinase-3 (TIMP3) gene in pancreatic adenocarcinomas. Pancreas 26 15714128
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 25 30415251
2018 miR-222-3p promotes osteosarcoma cell migration and invasion through targeting TIMP3. OncoTargets and therapy 25 30584323
2017 Proteomic and metabolomic characterization of streptozotocin-induced diabetic nephropathy in TIMP3-deficient mice. Acta diabetologica 25 29134286
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
2018 Increased TIMP-3 expression alters the cellular secretome through dual inhibition of the metalloprotease ADAM10 and ligand-binding of the LRP-1 receptor. Scientific reports 24 30279425
2017 MiR-221 Exacerbate Cell Proliferation and Invasion by Targeting TIMP3 in Papillary Thyroid Carcinoma. American journal of therapeutics 24 27077469
2021 Msi1 promotes breast cancer metastasis by regulating invadopodia-mediated extracellular matrix degradation via the Timp3-Mmp9 pathway. Oncogene 23 34155343
2018 TIMP3 deficiency exacerbates iron overload-mediated cardiomyopathy and liver disease. American journal of physiology. Heart and circulatory physiology 23 29373036
2016 Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a "TRAP" to increase levels of TIMP-3 in the tissue. Matrix biology : journal of the International Society for Matrix Biology 23 27476612
2013 Ultrasound-targeted HSVtk and Timp3 gene delivery for synergistically enhanced antitumor effects in hepatoma. Cancer gene therapy 23 23598435
2011 Expression of MMP-3 and TIMP-3 in gastric cancer tissue and its clinical significance. Oncology letters 23 22848309
2023 Asiaticoside-nitric oxide promoting diabetic wound healing through the miRNA-21-5p/TGF-β1/SMAD7/TIMP3 signaling pathway. Journal of ethnopharmacology 22 37783408
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
2016 Using urinary bFGF and TIMP3 levels to predict the presence of juvenile pilocytic astrocytoma and establish a distinct biomarker signature. Journal of neurosurgery. Pediatrics 21 27314542
2018 IL-32 gamma reduces lung tumor development through upregulation of TIMP-3 overexpression and hypomethylation. Cell death & disease 20 29467412
2013 Ovarian expression, localization, and function of tissue inhibitor of metalloproteinase 3 (TIMP3) during the periovulatory period of the human menstrual cycle. Biology of reproduction 20 24048576
2020 Loss of TIMP3 expression induces inflammation, matrix degradation, and vascular ingrowth in nucleus pulposus: A new mechanism of intervertebral disc degeneration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 32107793
2003 Expression of mutant and wild-type TIMP3 in primary gingival fibroblasts from Sorsby's fundus dystrophy patients. Biochimica et biophysica acta 19 12757930
2013 A novel mutation at the N-terminal domain of the TIMP3 gene in Sorsby fundus dystrophy. Retina (Philadelphia, Pa.) 18 23023527
2007 TIMP-3 gene transfection suppresses invasive and metastatic capacity of human hepatocarcinoma cell line HCC-7721. Hepatobiliary & pancreatic diseases international : HBPD INT 18 17897911