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TIMP1

TIMP1, also known as tissue inhibitor of metalloproteinases 1, is a multifunctional glycoprotein encoded by the TIMP1 gene on the human X chromosome at locus Xp11.3, which primarily functions as an endogenous inhibitor of matrix metalloproteinases (MMPs) by forming irreversible 1:1 complexes with these enzymes to regulate extracellular matrix (ECM) degradation and tissue remodeling.^[1] The protein is broadly expressed across human tissues, with the highest levels observed in the appendix (RPKM 344.6) and gall bladder (RPKM 211.2), and its expression is highly inducible by cytokines, hormones, and growth factors such as IL-1β, TGF-β1, EGF, and IL-6.^[1]^[2] As a member of the TIMP family—comprising four proteins (TIMP1–4) with 37–51% sequence similarity—TIMP1 features a compact structure stabilized by six disulfide bridges, forming six loop regions, and includes N-linked glycosylation sites at asparagine residues 30 and 78.^[3] Its N-terminal domain is responsible for MMP inhibition, while the C-terminal domain facilitates interactions with proMMP-9, CD63, and integrins, enabling MMP-independent functions such as cytokine-like signaling that promotes cell proliferation, inhibits apoptosis, and modulates cell morphology and survival.^[3]^[2] In normal physiology, TIMP1 contributes to wound healing, neuronal protection, blood-brain barrier maintenance, oligodendrocyte differentiation, and remyelination in the central nervous system.^[3]^[2] TIMP1 plays diverse and context-dependent roles in pathophysiology, often exhibiting pleiotropic effects that can be protective or detrimental. In cancer, it is overexpressed in various malignancies and can promote tumor progression, metastasis, and chemotherapy resistance through CD63-mediated signaling and cancer-associated fibroblast accumulation, though it may also suppress invasion in certain contexts.^[3] In fibrotic diseases, such as pulmonary and myocardial fibrosis, TIMP1 enhances fibroblast activation and proliferation, contributing to excessive ECM deposition.^[3] During inflammation, it acts as a proinflammatory cytokine, influencing immune cell functions, T-cell migration in multiple sclerosis, and macrophage polarization, while in neurodegenerative conditions like Alzheimer's disease and HIV-associated dementia, it supports neuroprotection but shows dysregulated expression in chronic phases.^[3]^[2]

Overview

Discovery and Nomenclature

The tissue inhibitor of metalloproteinases 1 (TIMP1) was first identified in 1975 as a collagenase inhibitor secreted by human skin fibroblasts in culture, initially named human collagenase inhibitor (HCI).^[4] This discovery stemmed from studies on extracellular matrix remodeling, where the inhibitor was found to specifically block the activity of interstitial collagenase (now known as MMP1), highlighting its role in regulating tissue degradation.^[5] Independent reports in the same year confirmed similar inhibitory activity in rabbit synovial fibroblasts, solidifying its recognition as an endogenous regulator of collagenolytic enzymes.^[4] In 1980, TIMP1 was independently characterized for its erythroid-potentiating activity (EPA), a function that promotes the formation of erythroid colonies in bone marrow cultures, leading to its initial designation based on this hematopoietic role. This activity was observed in conditioned media from a human T-lymphoblast cell line, revealing TIMP1 as a 28 kDa glycoprotein capable of enhancing early erythroid progenitor growth independent of erythropoietin.^[6] By 1985, molecular cloning and sequencing demonstrated that the cDNA for the collagenase inhibitor (HCI) was identical to that of EPA, unifying these activities under a single protein entity.^[7] The official nomenclature as TIMP1 (Tissue Inhibitor of Metalloproteinases 1) emerged in the mid-1980s as research expanded to show its inhibition of a broader range of metalloproteinases beyond collagenases, including gelatinases and stromelysins, within the emerging TIMP family.^[5] This naming reflected the protein's conserved inhibitory function across species and its distinction from later-identified family members like TIMP2. The gene symbol is TIMP1, located on the X chromosome at Xp11.3, with historical aliases including CLGI (collagenase inhibitor), EPA, and TIMP.^[1] Key milestones include the full cDNA cloning in 1985, which enabled detailed expression studies, and structural characterizations in the 1990s that revealed its disulfide-rich fold and inhibitory mechanism through X-ray crystallography of TIMP1-MMP complexes.^[7]^[8] These advances established TIMP1 as the founding member of the TIMP family, pivotal for understanding matrix homeostasis.^[9]

Gene and Protein Structure

The TIMP1 gene is located on the X chromosome at cytogenetic band Xp11.3 and spans approximately 4.4 kb of genomic DNA, from position 47,582,408 to 47,586,789 on the GRCh38 reference assembly.^[10] The gene consists of 5 exons in its canonical transcript (ENST00000218388) and encodes a 207-amino acid preproprotein, which includes a signal peptide for secretion.^[10]^[1] The mature TIMP1 protein, following cleavage of the 23-residue signal peptide, comprises 184 amino acids and is a glycoprotein with an unglycosylated molecular mass of approximately 21 kDa, increasing to about 28-29 kDa upon post-translational modifications.^[11] As a secreted protein, it adopts a compact, disulfide-rich fold stabilized by 12 conserved cysteine residues that form six intramolecular disulfide bonds, creating a characteristic wedge-shaped structure essential for its stability.^[11]^[5] TIMP1 features two distinct structural domains: the N-terminal domain (residues 1-70), which encompasses the inhibitory region and forms a 1:1 stoichiometric complex with the active site of matrix metalloproteinases (MMPs) via key residues around the Cys1-Cys70 disulfide bond, and the C-terminal domain (residues 71-184), which participates in binding pro-MMPs and other protein interactions.^[5]^[12] The N-terminal domain adopts a beta-barrel-like fold with extended loops, while the C-terminal domain is more flexible and contributes to the overall architecture. TIMP1 undergoes N-linked glycosylation primarily at Asn30 (with a potential secondary site at Asn78), which is crucial for proper folding, secretion, and modulation of its activity and stability.^[11]^[13] The three-dimensional structure of TIMP1 was first resolved in the late 1990s through X-ray crystallography of its complex with the catalytic domain of MMP-3 (PDB: 1UEA), revealing the inhibitory mechanism at atomic resolution; subsequent structures, including the free form (PDB: 9SOQ), confirm the conserved fold across TIMPs.^[14]^[15]

Biological Functions

Inhibition of Metalloproteinases

TIMP-1 primarily functions as a potent inhibitor of matrix metalloproteinases (MMPs), which are zinc-dependent endopeptidases responsible for degrading components of the extracellular matrix (ECM). By forming tight complexes with these enzymes, TIMP-1 prevents excessive ECM breakdown, thereby maintaining tissue integrity during physiological processes such as development and repair.^[5] The inhibitory mechanism involves reversible, non-covalent 1:1 binding between the N-terminal domain of TIMP-1 and the catalytic site of MMPs. Specifically, the invariant cysteine residue at position 1 (Cys1) in the Met1-Cys1 loop coordinates the catalytic zinc ion (Zn²⁺) in the MMP active site, displacing the nucleophilic water molecule essential for peptide bond hydrolysis and thereby blocking substrate access. This interaction is further stabilized by additional contacts, including the Thr2 residue of TIMP-1 occupying the S1' specificity pocket of the MMP, which contributes to inhibitory selectivity. Structural studies of TIMP-1 in complex with MMP-3 have confirmed this mode of action, highlighting the wedge-like insertion of the TIMP-1 N-terminus into the MMP cleft.^[5] TIMP-1 exhibits broad inhibitory activity against all soluble MMPs, including interstitial collagenase (MMP-1), gelatinases A and B (MMP-2 and MMP-9), stromelysin-1 (MMP-3), matrilysin (MMP-7), and collagenase-3 (MMP-13). It also inhibits certain membrane-bound MMPs, such as MT1-MMP (MMP-14), albeit with lower affinity, and extends its action to a disintegrin and metalloproteinases like ADAM10, which are involved in ectodomain shedding. However, TIMP-1 shows reduced efficacy against other membrane-type MMPs, such as MMP-16 and MMP-24.^[5]^[16]^[17] In addition to direct inhibition, the C-terminal domain of TIMP-1 binds the hemopexin-like domains of pro-MMP-2 and pro-MMP-9 in a non-inhibitory manner, forming ternary complexes that can facilitate their activation by MT1-MMP on cell surfaces without leading to TIMP-1-mediated suppression of the activated forms. This dual role allows TIMP-1 to modulate MMP activation dynamics in localized microenvironments, such as during pericellular proteolysis.^[18]^[5] The inhibition is equimolar and characterized by high affinity, with equilibrium dissociation constants (K_i) typically ranging from 10^{-9} to 10^{-12} M, depending on the MMP target; for example, K_i values for TIMP-1 against MMP-2 and MMP-9 are in the subnanomolar range, reflecting rapid association and slow dissociation rates. This tight binding ensures efficient stoichiometric neutralization of MMP activity in vivo.^[19]^[20] Physiologically, TIMP-1's inhibition of MMPs is essential for balancing ECM degradation and synthesis in processes like tissue remodeling, wound healing, and embryonic development, where controlled proteolysis is required for cell migration and morphogenesis without pathological tissue destruction. In these contexts, TIMP-1 helps prevent untimely matrix breakdown, supporting structural homeostasis.^[16]^[5] Imbalances in TIMP-1 expression, such as deficiency, result in unchecked MMP overactivity, leading to excessive ECM degradation, enhanced inflammation, and tissue damage in conditions like arthritis and tumor invasion; conversely, adequate TIMP-1 levels mitigate these effects by restoring proteolytic equilibrium.^[5]^[16]

Receptor Interactions and Signaling

TIMP1 interacts with several cell surface receptors primarily through its C-terminal domain, which facilitates binding to tetraspanins such as CD63 and CD82, as well as β1-integrin. These interactions form supramolecular complexes that anchor TIMP1 to the plasma membrane, distinct from its N-terminal involvement in protease inhibition. Additionally, TIMP1 binds to the amyloid precursor protein (APP), with the C-terminal region enabling this association via specific docking interfaces. Structural studies, including homology modeling and mutagenesis, have identified key residues in TIMP1's C-terminal tail (e.g., 176-184) and CD63's large extracellular loop as critical for the TIMP1-CD63 complex formation.^[21]^[22]^[23] Binding of TIMP1 to the CD63/β1-integrin complex activates downstream signaling pathways, including focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), which promote cell migration, survival, and cytoskeletal reorganization. For instance, this complex enhances focal adhesion formation and F-actin dynamics in various cell types, supporting cell motility and resistance to anoikis. In monocytes, TIMP1-APP interaction triggers glucose uptake and expression of proinflammatory cytokines such as IL-6 and TNF-α, contributing to an activated phenotype. Experimental evidence from knockdown studies demonstrates that silencing CD63 or β1-integrin reduces TIMP1-mediated ERK and Akt phosphorylation, confirming the receptor dependence of these signals.^[22]^[24]^[23]^[25] Context-specific effects highlight TIMP1's role in disease-relevant processes; in cancer cells, CD63 engagement promotes invasion and metastasis by activating PI3K and MAPK pathways, as observed in melanoma models where TIMP1 overexpression correlates with enhanced colony formation. Conversely, in neurons, TIMP1 binding to CD63 enhances Akt and brain-derived neurotrophic factor (BDNF) signaling, restoring synaptic plasticity in Alzheimer's disease models and potentially modulating APP processing to mitigate amyloid-β toxicity. The TIMP1-CD82 interaction, meanwhile, inhibits migration in pancreatic ductal adenocarcinoma cells by altering actin cytoskeleton and increasing ATP levels, underscoring receptor-specific outcomes. These findings are supported by structural models of the TIMP1-CD63 complex from 2020, which inform targeted disruptions of oncogenic signaling.^[25]^[26]^[27]^[21]

Independent Cellular Roles

TIMP-1 exhibits growth-promoting effects on various cell types independent of its metalloproteinase inhibitory activity, functioning similarly to a cytokine or growth factor. In endothelial cells, TIMP-1 stimulates proliferation and enhances DNA synthesis, potentially through activation of signaling pathways such as PI3K/Akt, as demonstrated in studies using human microvascular endothelial cells where MMP-binding mutants of TIMP-1 retained this mitogenic capacity.^[28] Similarly, in epithelial cells like keratinocytes and breast epithelial cells, TIMP-1 promotes cell growth and DNA replication via receptor-independent mechanisms, with evidence from experiments showing that TIMP-1 overexpression increases cell numbers without altering MMP activity.^[29] For erythroid progenitor cells, TIMP-1 was originally identified as erythroid-potentiating activity (EPA), directly enhancing proliferation and colony formation in human bone marrow cultures through pathways involving Lyn kinase, independent of protease inhibition, as confirmed by the use of TIMP-1 variants lacking MMP-binding sites.^[30]^[31] Beyond proliferation, TIMP-1 displays potent anti-apoptotic properties in multiple cell types, particularly under stress conditions. In fibroblasts and tumor cells, such as those from lung adenocarcinoma and breast cancer, TIMP-1 inhibits caspase-3 activation and prevents Bax translocation to the mitochondria, thereby stabilizing Bcl-2 family proteins and promoting cell survival; this effect persists in MMP-knockout models and with MMP-nonbinding TIMP-1 mutants, indicating a direct intracellular signaling role via pathways like CD63/PI3K/Akt.^[32]^[33] These anti-apoptotic actions contribute to cellular resilience in inflammatory or hypoxic environments, with quantitative data showing up to 50% reduction in apoptosis rates in TIMP-1-treated fibroblasts exposed to serum deprivation.^[29] TIMP-1 also exerts other specialized effects unrelated to matrix remodeling. In adrenocortical cells, ACTH induces TIMP-1 expression, leading to inhibition of collagenase activity in bovine models.^[34] Additionally, in the central nervous system, TIMP-1 supports neuronal survival during inflammation by protecting against excitotoxic damage and promoting Bcl-xL/Bcl-2 stabilization, as observed in human neuronal cultures and astrocytic responses to CNS injury, where MMP-deficient conditions still yielded neuroprotective outcomes.^[35]^[36] Evidence for these MMP-independent roles is robustly supported by experimental models, including TIMP-1 mutants defective in MMP binding that nevertheless stimulate proliferation and inhibit apoptosis, and studies in MMP-knockout mice where TIMP-1 overexpression alone drives cellular effects like reduced neuronal loss.^[31]^[37] In pathophysiological contexts, these functions enable TIMP-1 to inhibit angiogenesis by blocking endothelial migration through PTEN activation without protease involvement, and to facilitate tumor stroma remodeling by enhancing epithelial-mesenchymal transition and stromal cell survival in cancer microenvironments.^[38] Some proliferative effects may overlap with receptor-mediated signaling, but the core mechanisms here emphasize direct cellular modulation.^[29]

Expression and Regulation

Tissue Distribution and Expression Patterns

TIMP1 exhibits broad expression across most adult human tissues, with the highest levels observed in the appendix (RPKM 344.6) and gall bladder (RPKM 211.2), and notable expression in reproductive organs such as the ovary and placenta, as well as in the liver, brain, and other reproductive tissues.^[1]^[39] In the central nervous system, expression is particularly enriched in the cerebral cortex and thalamus.^[40] This pattern reflects its role in maintaining extracellular matrix homeostasis under normal conditions, where it remains inducible in response to injury or stress.^[41] In the developing gonads, it is prominently expressed in sex cords containing Sertoli cells and primordial germ cells.^[42] These temporal patterns highlight its involvement in organogenesis, with expression levels increasing transiently to regulate matrix dynamics during critical growth phases. TIMP1 is primarily secreted by stromal cells such as fibroblasts, vascular endothelial cells, macrophages, and various tumor cells within tissues.^[43]^[44] As an X-linked gene, it displays mosaic expression patterns in females due to random X-chromosome inactivation, resulting in heterogeneous cellular expression within the same tissue.^[45] This mosaicism contributes to variability in TIMP1 distribution at the single-cell level. In healthy adults, circulating plasma levels of TIMP1 typically range from 80 to 200 ng/mL.^[46]^[47] These levels increase during pregnancy, reaching medians of approximately 555 ng/mL in early pregnancy (7-11 weeks), reflecting heightened matrix regulation demands.^[48] Detection of TIMP1 expression commonly involves reverse transcription polymerase chain reaction (RT-PCR) for mRNA quantification in tissues and enzyme-linked immunosorbent assay (ELISA) or immunohistochemistry for protein assessment in plasma and cellular contexts.^[41]^[49]

Molecular Regulatory Mechanisms

The expression of TIMP1 is tightly regulated at multiple levels, including transcriptional, hormonal, epigenetic, and post-transcriptional mechanisms, which collectively determine its levels in response to cellular and environmental cues. At the transcriptional level, the TIMP1 promoter contains binding sites for key transcription factors such as AP-1, NF-κB, and STAT3, enabling rapid induction in response to inflammatory and growth signals.^[50]^[51] Cytokines like interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) activate these sites, leading to upregulated TIMP1 transcription in various cell types, including fibroblasts and macrophages.^[52]^[53] Similarly, growth factors such as platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) stimulate TIMP1 expression through synergistic interactions with these promoter elements, often in the context of tissue remodeling.^[54]^[55] Hormonal regulation further modulates TIMP1 in a tissue-specific manner, particularly in reproductive and endocrine systems. Estrogen and progesterone upregulate TIMP1 in uterine and mammary tissues, promoting extracellular matrix stability during cyclical changes and pregnancy.^[56]^[57] In adrenal cortex cells, adrenocorticotropic hormone (ACTH) induces TIMP1 expression via the cAMP/protein kinase A (PKA) signaling pathway, which enhances transcription and inhibits collagenase activity to maintain adrenal integrity.^[58]^[34] Epigenetic modifications also play a critical role in controlling TIMP1 expression, with variability influenced by sex and disease states. As an X-linked gene, TIMP1 undergoes X-chromosome inactivation in females, resulting in expression levels comparable to those in males from the single active X chromosome, though polymorphic escape from inactivation can lead to dosage differences in certain cell types.^[59]^[45] In some cancers, such as prostate cancer, promoter hypermethylation silences TIMP1, reducing its tumor-suppressive functions.^[60] Post-transcriptional regulation fine-tunes TIMP1 levels through mRNA stability and microRNA (miRNA) interactions. The RNA-binding protein HuR stabilizes TIMP1 mRNA by binding to AU-rich elements in its 3' untranslated region (3'UTR), prolonging its half-life during inflammatory responses.^[61] Conversely, miRNAs such as miR-1293 target the TIMP1 3'UTR, repressing translation and contributing to lower expression in contexts like cancer progression.^[62] Feedback mechanisms and genetic variants add layers of complexity to TIMP1 regulation. Matrix metalloproteinases (MMPs) can indirectly upregulate TIMP1 by cleaving extracellular matrix components, releasing sequestered cytokines that activate TIMP1 transcription.^[63]^[64] Additionally, the single nucleotide polymorphism rs4898 (372 T>C) in the TIMP1 gene influences protein expression levels, with the C allele associated with higher TIMP1 production and altered disease susceptibility.^[65]^[66]

Clinical and Pathophysiological Significance

Roles in Disease Processes

TIMP1 dysregulation plays a pivotal role in cancer pathogenesis, where elevated levels often correlate with enhanced tumor progression. In breast cancer, particularly triple-negative subtypes, high TIMP1 expression is associated with aggressive disease and poor patient outcomes, promoting cell proliferation and resistance to apoptosis through non-canonical signaling pathways. Similarly, in lung cancer, TIMP1 serves as an early biomarker, with overexpression facilitating tumor invasion and metastasis by modulating the extracellular matrix and interacting with integrins on cancer cells. In colorectal cancer, upregulated TIMP1 in tumor tissues and plasma is linked to lymph node involvement, distant metastasis, and reduced survival rates, as it shifts the MMP/TIMP balance to favor stromal remodeling that supports tumor dissemination. TIMP1 also contributes to adverse prognosis in specific malignancies, such as laryngeal squamous cell carcinoma, where increased TIMP1 levels in tumor tissues predict shorter overall survival and higher recurrence risk. In melanoma, elevated circulating TIMP1 is observed in advanced stages, correlating with invasive behavior and poorer clinical outcomes, potentially through dual modulation of matrix degradation and pro-survival signals in melanoma cells. In fibrotic disorders, TIMP1 overexpression inhibits ECM degradation by binding MMPs, leading to excessive collagen accumulation and tissue stiffening. In liver fibrosis, such as that induced by chronic injury, hepatic TIMP1 upregulation exacerbates scar formation by suppressing MMP activity, resulting in persistent fibrotic foci even after injury resolution. Pulmonary fibrosis models, including those triggered by silica or bleomycin, show similar patterns, with TIMP1 derived from fibroblasts promoting alveolar remodeling and progression to irreversible lung damage. Cardiac fibrosis post-myocardial infarction or pressure overload involves elevated TIMP1 in cardiomyocytes and fibroblasts, which sustains ECM deposition and impairs ventricular function, as demonstrated in hypertensive models where TIMP1 blockade reduces scar size. TIMP1 dysregulation contributes to neuroinflammatory conditions through altered MMP/TIMP ratios that affect blood-brain barrier integrity and immune cell infiltration. In multiple sclerosis, an imbalance favoring MMPs over TIMP1 in active lesions promotes demyelination and axonal damage, while compensatory TIMP1 elevation in chronic phases may limit repair but correlates with disease progression. In stroke, elevated MMP-9/TIMP1 ratios in the acute phase exacerbate hemorrhagic transformation and neuronal loss, with TIMP1 insufficiency worsening infarct expansion. TIMP1 knockout mice exhibit heightened neuroinflammation in models of traumatic brain injury or demyelination, showing increased microglial activation and impaired myelin regeneration due to unchecked proteolytic activity. In pregnancy complications, TIMP1 dysregulation disrupts trophoblast invasion and spiral artery remodeling, essential for placental development. In preeclampsia, elevated placental and maternal TIMP1 levels inhibit MMP-mediated ECM breakdown, leading to shallow trophoblast invasion and vascular dysfunction, particularly in early-onset cases. This imbalance is also implicated in preterm birth, where altered TIMP1 expression in amniotic fluid and decidua correlates with premature rupture of membranes and reduced fetal growth, as seen in intrauterine growth restriction associated with preeclampsia. Beyond these, TIMP1 is involved in oral submucous fibrosis, a precancerous condition linked to areca nut chewing, where increased TIMP1 in subepithelial tissues inhibits collagenolysis, promoting juxta-epithelial fibrosis and trismus. In conjunctivochalasis, TIMP1 overexpression in conjunctival fibroblasts contributes to redundant tissue folding and tear film instability by limiting MMP-driven tissue turnover. TIMP1 exhibits context-dependent effects on angiogenesis: while it can inhibit vascular endothelial growth factor signaling to exert anti-angiogenic actions in some fibrotic settings, in tumors it often promotes pro-angiogenic microenvironments through cytokine-like functions, highlighting its dual role in pathology. Animal models underscore these mechanisms; TIMP1-/- mice display enhanced tumor progression in lung and colon carcinoma xenografts, with increased metastasis due to reduced matrix barriers and heightened invasive potential. Conversely, these knockouts show attenuated fibrosis in chronic injury models, such as carbon tetrachloride-induced liver damage or dextran sulfate sodium colitis, where diminished TIMP1 allows greater MMP-mediated ECM resolution and reduced scar formation.

Diagnostic and Therapeutic Implications

TIMP1 serves as a promising biomarker for various diseases due to its involvement in extracellular matrix remodeling and inflammation. Elevated serum levels of TIMP1, often exceeding 300 ng/mL as measured by enzyme-linked immunosorbent assay (ELISA), have been associated with poor prognosis in multiple cancers, including breast, endometrial, and lung carcinomas. For instance, in triple-negative breast cancer, high serum TIMP1 correlates with reduced overall survival and increased tumor aggressiveness. Similarly, in colorectal liver metastases, extravesicular TIMP1 in plasma acts as a non-invasive prognostic indicator, with higher levels predicting worse outcomes independent of other clinical factors.^[67]^[68]^[44]^[69] In fibrotic conditions, the urinary TIMP1/MMP-9 ratio provides utility for staging renal interstitial fibrosis and assessing disease progression. Studies in chronic kidney disease show a decreased MMP-9/TIMP-1 ratio in urine, reflecting imbalanced matrix degradation and accumulation, which correlates with advancing fibrosis severity. This ratio has also been elevated in acute pyelonephritis cases leading to renal scarring, highlighting TIMP1's role in early fibrotic detection. For inflammatory diseases like rheumatoid arthritis, synovial fluid and serum TIMP1 levels are significantly raised compared to healthy controls, aiding in diagnosis and monitoring joint destruction.^[70]^[71]^[72] Therapeutically, TIMP1's dual functions—both inhibiting matrix metalloproteinases to curb excessive degradation and promoting fibrosis or tumor survival—pose challenges for targeted interventions. In preclinical models of excessive MMP activity, such as inflammatory pain and arthritis-like conditions, recombinant murine TIMP1 administration has reduced hypersensitivity and tissue damage by restoring matrix balance. Conversely, anti-TIMP1 strategies aim to mitigate its pro-tumorigenic effects; for example, TIMP1 knockdown in glioma cells decreases extracellular matrix stiffness and tumor invasion via reduced tenascin C and fibronectin expression. Gene therapy approaches, including TIMP1 deficiency via genetic deletion, have attenuated fibrosis in liver and kidney models by modulating immune-related genes and inflammatory pathways.^[73]^[74]^[75]^[76] Recent advances emphasize TIMP1's integration into liquid biopsy panels for enhanced prognostic accuracy in cancer. TIMP1 mRNA in tumor-educated platelets and circulating tumor cells has emerged as a diagnostic biomarker for colorectal and breast cancers, respectively, enabling non-invasive monitoring of progression and metastasis. In glioblastoma, targeting TIMP1 through upstream regulators like Sp1 inhibition shows preclinical promise for reducing immune infiltration and tumor growth, though no phase I trials specifically for TIMP1 inhibitors were identified as of 2025. While direct clinical trials modulating TIMP1 remain limited, its inclusion in multi-analyte panels supports ongoing efforts in personalized oncology and fibrosis management.^[77]^[78]^[79]

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[39]
Tissue expression of TIMP1 - Summary - The Human Protein Atlas
The value ranges from 0 and 1, where 0 indicates identical expression across all cells/tissue types, while 1 indicates expression in a single cell/tissue type. ...Missing: review | Show results with:review<|control11|><|separator|>
[40]
Upregulated TIMP1 facilitates and coordinates myometrial ... - NIH
TIMP1 is constitutively expressed in most normal tissues, including the uterus, ovaries, brain, heart, liver, and arteries.
[41]
The TIMP protein family: diverse roles in pathophysiology
The N-terminal domain is responsible for MP-inhibition, in addition to CD74 and CD82 binding (12, 15). The C-terminal domain of TIMP1 mediates binding to ...
[42]
Whole organism profiling of the Timp gene family - PMC - NIH
We show that Timp1 expression, although present, is low in many normal tissues, supporting the idea that Timp1 is generally inducible in response to tissue ...
[43]
Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Is Differentially ...
Jun 1, 1997 · Yoav Citri, Weizmann Institute of Science, Israel) carried a 700 bp rat cDNA containing part of the 5′ untranslated region and the entire coding ...
[44]
Differential expression of tissue inhibitor of metalloproteinases type ...
May 29, 2003 · We observed that TIMP-1 expression is restricted to the developing sex cords, which contained at that time Sertoli cells and primordial germ ...
[45]
Expression of Matrix Metalloproteinases in the Microenvironment of ...
A moderate immunoreactivity against TIMP-1 was found in some tumor cells at the tumor border, whereas a strong staining was observed in endothelial cells, ...
[46]
TIMP1 is an early biomarker for detection and prognosis of lung cancer
Sep 27, 2023 · We found that TIMP1 is a tumour‐secreted protein with high sensitivity and specificity for aggressive cancer, even at early stages in mice. We ...
[47]
Polymorphic X-Chromosome Inactivation of the Human TIMP1 Gene
Direct evidence for X inactivation includes mosaic expression of X-linked gene products in heterozygous females or equal levels of gene expression in males ...
[48]
Plasma levels of tissue inhibitor of metalloproteinase-1 in patients ...
Levels of TIMP-1 in subjectively healthy controls earlier reported from our department are 92 ng/mL (range 80–103).
[49]
Changes in Plasma TIMP-1 Levels after Resection for Primary ...
The mean level was 82.0 ng/ml with RI from 59.4 ng/ml to 113.7 ng/ml. TIMP-1 levels above the upper limit of 113.7 ng/ml were considered elevated. Although we ...Missing: adults | Show results with:adults
[50]
Circulating matrix metalloproteinase MMP-9 and MMP-2/TIMP-2 ...
Jan 15, 2013 · The highest concentrations were seen in ongoing pregnancies (median 555 ng/mL), whereas in anembryonic pregnancies the TIMP-1 level was 371 ng/ ...
[51]
MMPs and TIMPs levels are correlated with anthropometric ... - Nature
Oct 8, 2021 · Our results exhibited that TIMP-1 levels were markedly and gradually increased in people with obesity as compared to overweight and non-obese ...
[52]
Signal Transducers and Activators of Transcription-3 Up-Regulates ...
Recent studies have suggested that STAT3 protein may play a role in regulating TIMP1 expression, as the promoter of the TIMP1 gene contains STAT3 binding sites.Missing: NF- | Show results with:NF-
[53]
a novel inducible system to regulate transgene expression of TIMP1
Feb 1, 2021 · NFκB regulatory elements ensure that hTIMP1 expression occurs only with inflammation, which is central to IDD development. Unlike previous ...
[54]
A novel mechanism of tissue inhibitor of metalloproteinases-1 ...
We report that IL-1 activates TIMP-1 expression via both the IKK/NF-kappaB and MEK3/6/p38/ATF-2 pathways in astrocytes.
[55]
Novel Role of TGF-β in Differential Astrocyte-TIMP-1 Regulation
Stimulating astrocytes with a combination of IL-1β and TGF-β resulted in a significant reduction in IL-1β-induced TIMP-1 activation. It is well established ...
[56]
Mechanisms of induction of human tissue inhibitor of ... - FEBS Press
Dec 25, 2001 · We have recently shown that ATRA interacts in a synergistic manner with four different growth factors, bFGF, EGF, PDGF-BB and TGF-β to stimulate ...
[57]
TIMP-1 is under regulation of the EGF signaling axis and promotes ...
We show here that EGFR signaling induces TIMP-1 expression in CRC cells, and that TIMP-1 promotes a more aggressive behavior, specifically in KRAS mutated ...Missing: PDGF | Show results with:PDGF
[58]
Expression and regulation of tissue inhibitors of metalloproteinases ...
The findings showed that TIMP1 expression increased up to 20 nM but then gradually decreased, whereas no significant effects existed among TIMP3 messenger RNA ...
[59]
Steroidal Regulation of Uterine Edema and Tissue Inhibitors of ...
Unexpectedly, we found that although estrogen and progesterone regulated TIMP-1, TIMP-2, and TIMP-3 mRNA expression in wild-type uteri through what appeared to ...
[60]
ACTH induces TIMP-1 expression and inhibits collagenase in ...
Feb 27, 2004 · TIMP-1 over-expression is associated with attenuated tumor growth, reduced metastasis and suppression of angiogenesis (Bloomston et al., 2002, ...
[61]
Polymorphic X-chromosome inactivation of the human TIMP1 gene
Expression of two alleles was detected in some female cells with previously demonstrated extreme skewing of X inactivation, indicating TIMP1 expression from the ...
[62]
[PDF] The regulation of matrix metalloproteinases and their inhibitors
Dec 24, 2007 · HDACi enhance PMA-induced TIMP1 expression but repress TGF␤-induced TIMP1 ... Recombinant HuR stabilized, whilst anti-. HuR antibody destabilized, ...
[63]
Identification of miR-1293 potential target gene: TIMP-1 - PubMed
Western blot analysis showed a significant increase of expression of the TIMP-1 gene co-transfected with the miR-1293 inhibitor, and demonstrated direct binding ...
[64]
The role of MMPs and TIMPs in regenerative medicine
Due to their ability to target ECM and ECM-associated molecules, MMPs are likely to play a key role in the release of cytokines and growth factors embedded ...
[65]
Biological role of matrix metalloproteinases: a critical balance
It has been described that TIMP-2, or TIMP-3 or TIMP-4 can interact with pro-MMP-2, and TIMP-1 or TIMP-3 with pro-MMP-9 [33]. However, except for the ...
[66]
[PDF] Tissue inhibitor matrix metalloproteinase 1 polymorphisms ...
Interestingly, a functional single-nucle- otide polymorphism (SNP) (rs4898, 372 T/C) has been reported to enhance expression of. TIMP-1 and increase the risk of ...
[67]
1 and -2 genes with chronic heart failure | Scientific Reports - Nature
Jun 21, 2018 · High levels of TIMP-1 in either the plasma or myocardium have been found in patients with hypertension, myocardial fibrosis, LV hypertrophy, ...
[68]
Higher levels of TIMP-1 expression are associated with a poor ... - NIH
In this study, we found that TIMP-1 expression was elevated in TNBC cell lines and TNBC patients compared with non-TNBC cells and non-TNBC breast cancer ...
[69]
Elevated Serum Levels of Type I Collagen Degradation Marker ICTP ...
The patients with serum levels of TIMP-1 of >300 ng/ml had unfavorable prognosis when compared with the patients with serum levels of TIMP-1 of ≤300 ng/ml (1- ...
[70]
Extravesicular TIMP-1 is a non-invasive independent prognostic ...
Feb 9, 2022 · EV-bound TIMP1 is a robust circulating biomarker for a non-invasive, preoperative risk stratification in patients with colorectal liver metastases.
[71]
Urinary metalloproteinases and tissue inhibitors of... - LWW
Our study showed increased urinary MMP-9 excretions and decreased urinary MMP-9/TIMP-1 ratio. ... TIMP-1 ratio, may become useful early biomarkers for kidney ...
[72]
Urinary matrix metalloproteinase 9 and tissue inhibitor of ...
We found that urinary MMP9 and TIMP1 levels are higher in children with acute pyelonephritis who had evidence of scar formation on a late DMSA scan, relative to ...
[73]
MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in patients with ...
Aug 6, 2025 · Serum and synovial fluid from 24 RA patients and 17 PA patients were studied to determine the levels of MMP-2 and MMP-9 proteolytic activity ...
[74]
Tissue inhibitor of metalloproteinase 1 (TIMP-1) deficiency ...
Apr 4, 2011 · In this study, we found that TIMP-1-deficient (TIMP-1-/-) mice were more susceptible to CCl4-induced liver injury and fibrosis, suggesting the ...
[75]
TIMP-1 Attenuates the Development of Inflammatory Pain Through ...
Behavioral assessment of the role of TIMP-1 in inflammatory hypersensitivity demonstrated that TIMP-1 knockout (T1KO) mice exhibited robust hypersensitivity to ...
[76]
High levels of TIMP1 are associated with increased extracellular ...
TIMP1 knockdown decreases tissue stiffness, inhibited the expression of tenascin C and fibronectin, and suppressed tumor progression.
[77]
Genetic Deletion of Tissue Inhibitor of Metalloproteinase-1/TIMP-1 ...
TIMP-1 deficiency leads to higher inflammation after acute DSS and less fibrosis after chronic DSS, and attenuated development of fibrosis.
[78]
TIMP1 mRNA in tumor-educated platelets is diagnostic biomarker for ...
These findings show that the TIMP1 mRNA in platelets is a potential independent diagnostic biomarker for colorectal cancer, and that platelets can carry RNAs ...
[79]
Circulating Tumor Cells Characterization Revealed TIMP1 as ... - MDPI
In addition, we evidenced the relevance of TIMP1 expression to promote tumor proliferation, suggesting its interest as a therapeutic target. Conclusions: ...
[80]
Sp1 induced gene TIMP1 is related to immune cell infiltration in ...
Jul 1, 2022 · Our findings suggest that the Sp1-TIMP1 axis can be a potent biomarker for evaluating immune cell infiltration at the tumor sites and therefore, the malignant ...