Affinage

MMP13

Collagenase 3 · UniProt P45452

Length
471 aa
Mass
53.8 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

MMP13 (collagenase-3) is a zinc-dependent matrix metalloproteinase that cleaves fibrillar collagens—with marked preference for type II collagen at Gly775-Leu776—using its hemopexin domain for triple-helical substrate recognition and its catalytic domain for hydrolysis, thereby remodeling extracellular matrix in bone, cartilage, vasculature, and wound repair (PMID:25008319, PMID:23298463, PMID:31700695). Transcription of MMP13 is driven by a promoter containing functional AP-1, RUNX2/OSE-2, Lef1/β-catenin, and Smad-responsive elements, integrating signals from MEK-ERK (via RUNX2 phosphorylation, FGF23-FGFR1, mechanical strain), p38α-JNK-NF-κB (via Rac1, IL-1β), Wnt/β-catenin (via Lef1), TGF-β-Smad3, and direct binding of ATF3 and ETV4; transcriptional repression is mediated by ANKRD1-nucleolin at the AP-1 site, Hsp90β/p130Cas at the AGRE element, p38γ antagonism, and HA-CD44-DUSP10 axis suppressing MAPK (PMID:9119388, PMID:15564063, PMID:17971297, PMID:27956552, PMID:24515436, PMID:20633667, PMID:27101204). Post-translationally, nitric oxide–driven nitration of Tyr338 releases MMP13 from caveolin-1 storage in endothelial cells, controlling its secretion during wound healing (PMID:18495757). In vivo, osteocyte-derived MMP13 maintains perilacunar/canalicular remodeling and cartilage integrity, chondrocyte MMP13 drives osteoarthritis cartilage destruction, macrophage-expressed MMP13 promotes lung fibrosis resolution, and stromal/tumor-derived MMP13 facilitates angiogenesis via FAK-ERK activation and VEGF-A release and enables tumor extravasation and metastasis (PMID:31700695, PMID:23298463, PMID:30785343, PMID:22992737, PMID:25880591).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 High

    Defining the transcriptional architecture of MMP13 established that its inducibility is controlled through a modular promoter with AP-1, OSE-2, PEA-3, and TGF-β-inhibitory elements, providing the framework for understanding how diverse stimuli converge on MMP13 expression.

    Evidence Genomic cloning, CAT reporter assays, and EMSA with nuclear extracts in multiple cell lines

    PMID:9119388

    Open questions at the time
    • Relative contribution of each promoter element in physiological contexts was not resolved
    • Chromatin-level regulation not addressed
    • No in vivo promoter validation
  2. 2004 High

    Demonstrating that mechanical strain and growth factor (FGF2) signals converge on MEK-ERK to activate MMP13 transcription—via RUNX2 phosphorylation in chondrocytes and direct transcriptional induction in osteoblasts—established the ERK-MAPK axis as a central upstream regulator of MMP13.

    Evidence RUNX2 overexpression with promoter assays, MEK inhibitors (PD98059), dominant-negative MEK1/2, biaxial strain in osteoblastic cells

    PMID:15044466 PMID:15564063

    Open questions at the time
    • Identity of ERK substrates directly binding the MMP13 promoter beyond RUNX2 not resolved
    • Relative contributions of RUNX2-dependent vs. -independent ERK targets unclear
  3. 2006 High

    Showing that TGF-β/Smad3 signaling drives MMP13 expression and invasion in squamous carcinoma cells revealed a second major transcriptional axis (independent of MEK-ERK) through which MMP13 promotes cancer cell invasiveness.

    Evidence Dominant-negative Smad3, Smad7 overexpression, kinase-defective ALK-5, Matrigel invasion assays, xenografts

    PMID:16407850

    Open questions at the time
    • Direct Smad3 occupancy of MMP13 promoter not shown by ChIP
    • Cross-talk between Smad and AP-1 pathways at MMP13 not addressed
  4. 2007 High

    Identification of a functional Lef1/β-catenin binding site and ChIP-confirmed occupancy at the MMP13 locus established the Wnt pathway as a direct transcriptional activator of MMP13, later reinforced by evidence that β-catenin nuclear translocation (regulated by SENP2/TBL1) controls MMP13 in cancer cells.

    Evidence ChIP, EMSA, siRNA knockdown of Lef1 in chondrocytes; SENP2/TBL1 SUMOylation assays and β-catenin translocation in bladder cancer cells

    PMID:17971297 PMID:26369384

    Open questions at the time
    • Whether Lef1 and RUNX2 cooperate or compete at the MMP13 promoter is unknown
    • Wnt ligand specificity for MMP13 induction in vivo not established
  5. 2008 High

    Discovery that NO-mediated Tyr338 nitration dissociates MMP13 from caveolin-1, promoting its secretion from endothelial cells during wound healing, revealed the first post-translational mechanism controlling MMP13 release rather than transcription.

    Evidence Y338 mutagenesis, Co-IP of MMP13/caveolin-1, iNOS-KO and caveolin-1-KO mice with wound healing assays

    PMID:18495757

    Open questions at the time
    • Whether Y338 nitration affects catalytic activity in addition to secretion is unknown
    • Applicability beyond endothelial cells not tested
  6. 2008 High

    Parallel studies revealed additional MAPK route diversity: ultrasound-induced MMP13 in osteoblasts depends on p38/JNK (not ERK), and angiotensin II activates MMP13 in atherosclerotic plaques, expanding the pathophysiological contexts of MMP13 regulation beyond cartilage and bone.

    Evidence Dominant-negative p38/JNK with AP-1 reporters in osteoblasts; ATII infusion in ApoE-KO carotid model with MMP13 IHC

    PMID:17941091 PMID:19233360

    Open questions at the time
    • Stimulus-specific selection of p38/JNK vs. ERK at the MMP13 promoter not mechanistically explained
    • ATII-MMP13 link not validated by genetic ablation
  7. 2009 High

    MMP13-knockout host mice showed impaired melanoma growth, reduced metastasis, and decreased angiogenesis, establishing that stroma-derived MMP13 is functionally required for tumor vascularization and organ-specific metastatic colonization.

    Evidence Intradermal melanoma injection in global Mmp13-KO mice, MRI vessel permeability, IHC

    PMID:19516266

    Open questions at the time
    • Specific MMP13 substrates mediating vascular permeability not identified
    • Tumor-cell-autonomous vs. stromal MMP13 not dissected in this model
  8. 2010 High

    Demonstrating that p38γ opposes p38α in suppressing MMP13 output in chondrocytes established isoform-specific MAPK antagonism as a fine-tuning mechanism, explaining why global p38 inhibitors do not simply reduce MMP13.

    Evidence Constitutively active and dominant-negative p38γ constructs, isoform-selective inhibitors, ELISA in chondrocytes

    PMID:20633667

    Open questions at the time
    • Direct p38γ phosphorylation targets that mediate MMP13 suppression not identified
    • In vivo relevance of p38γ-mediated MMP13 regulation not shown
  9. 2012 High

    Recombinant MMP13 directly activates FAK and ERK in endothelial cells to promote tube formation and indirectly stimulates VEGF-A secretion, defining a dual (direct + indirect) pro-angiogenic mechanism that explains the vascular phenotype of MMP13-KO tumors.

    Evidence Recombinant MMP13 treatment, FAK/ERK phosphorylation, capillary tube assays in vitro and in vivo

    PMID:22992737

    Open questions at the time
    • The MMP13 substrate(s) that generate FAK-activating ligands in endothelial cells are unidentified
    • Whether catalytic activity or protein-protein interaction drives FAK activation is unclear
  10. 2012 High

    Osterix physically interacts with RUNX2 (by Co-IP) and cooperates to drive MMP13 during endochondral ossification; adenoviral MMP13 rescue of Osterix-KO cells restores matrix calcification, placing MMP13 as a critical RUNX2/Osterix effector in skeletal development.

    Evidence Global and conditional Osterix-KO mice, Co-IP, adenoviral MMP13 rescue in limb bud cells

    PMID:22869368

    Open questions at the time
    • Whether Osterix directly contacts the MMP13 promoter or acts solely through RUNX2 is unresolved
    • Osterix-RUNX2 binding interface not structurally characterized
  11. 2013 High

    Chondrocyte-specific Mmp13 deletion decelerates osteoarthritis progression (preserving collagen II and proteoglycan and reducing apoptosis), directly establishing MMP13 as a disease-driving collagenase in OA cartilage and validating it as a therapeutic target.

    Evidence Conditional Col2CreER Mmp13 KO, meniscal-ligamentous OA model, pharmacological validation with CL82198, histomorphometry

    PMID:23298463

    Open questions at the time
    • Whether MMP13 inhibition is sufficient long-term or whether compensatory collagenases emerge is unknown
    • Anti-apoptotic effect could be indirect via ECM preservation
  12. 2014 High

    Biochemical dissection with triple-helical peptide toolkits showed MMP13 preferentially binds collagen II over collagens I/III through its hemopexin domain recognizing specific triple-helical motifs, with canonical cleavage at Gly775-Leu776, resolving the structural basis for substrate selectivity.

    Evidence Solid-phase binding with Collagen Toolkit peptide libraries, proteolysis assays with recombinant domains

    PMID:25008319

    Open questions at the time
    • Full-length collagen II–MMP13 co-crystal structure unavailable
    • How collagen cross-linking or post-translational modifications affect recognition unknown
  13. 2014 High

    Identification of ANKRD1-nucleolin as a repressive complex at the MMP13 AP-1 site (by yeast two-hybrid, Co-IP, and ChIP) and of Hsp90β/p130Cas as repressors at the AGRE element revealed dedicated negative regulatory mechanisms that are relieved by cytokine stimulation.

    Evidence Yeast two-hybrid, Co-IP, ChIP showing increased c-Jun binding in Ankrd1-KO; mass spectrometry, siRNA of Hsp90β/p130Cas in chondrocytes

    PMID:18593760 PMID:24515436

    Open questions at the time
    • Whether ANKRD1-nucleolin and Hsp90β/p130Cas interact or regulate independently is unknown
    • Structural basis for ANKRD1 displacement of c-Jun not resolved
  14. 2015 High

    Using MMP13-deficient hosts and tumor-cell-specific knockdown in a liver metastasis model, both stromal and tumor-derived MMP13 were shown to promote colorectal cancer extravasation, extending MMP13's metastatic role beyond melanoma to epithelial cancers with tissue-specific effects.

    Evidence Splenic injection model in Mmp13-KO mice, stable shRNA in tumor cells, whole-organ confocal imaging

    PMID:25880591

    Open questions at the time
    • MMP13 substrates facilitating trans-endothelial migration not identified
    • Whether MMP13 acts on endothelial junctions or basement membrane in this context is unclear
  15. 2016 High

    ChIP-based temporal mapping revealed that ATF3 (not c-Fos) is the sustained direct occupant of the MMP13 AP-1 site after stimulation, with ETV4 independently shown to directly activate MMP13 transcription in breast epithelial cells, diversifying the set of known direct transcriptional activators.

    Evidence Time-resolved ChIP for ATF3/cFOS occupancy with siRNA in chondrocytes; ETV4 gain/loss-of-function with MMP13 promoter reporters in mammary cells

    PMID:27956552 PMID:29996935

    Open questions at the time
    • Whether ATF3 and ETV4 cooperate in any shared cell type is unknown
    • Genome-wide enhancer elements driving MMP13 beyond the proximal promoter not mapped
  16. 2016 High

    FGF23 was shown to drive MMP13 in chondrocytes through FGFR1 (Klotho-independent) predominantly via MEK/ERK, and HA-CD44-DUSP10/MKP5 axis was identified as suppressing MMP13 by dephosphorylating p38/JNK, adding receptor-level specificity to both inductive and suppressive arms of MMP13 regulation.

    Evidence FGFR1/Klotho siRNA with phosphoprotein arrays; CD44 blocking antibody, DUSP10 expression analysis in chondrocytes

    PMID:27101204 PMID:27307356

    Open questions at the time
    • Relative in vivo importance of FGF23 vs. FGF2 in OA-associated MMP13 upregulation not established
    • Whether DUSP10 directly dephosphorylates p38α at the MMP13 promoter complex is unresolved
  17. 2019 High

    Osteocyte-specific Mmp13 ablation (DMP1-Cre) impaired perilacunar/canalicular remodeling and secondarily degraded cartilage homeostasis, establishing that osteocyte-derived MMP13 maintains the bone-cartilage unit through subchondral matrix turnover.

    Evidence Conditional DMP1-Cre Mmp13 KO mice, histomorphometry, IHC of bone and cartilage

    PMID:31700695

    Open questions at the time
    • Molecular signals from osteocytes to chondrocytes disrupted by PLR failure are unknown
    • Whether lactation-induced PLR also requires MMP13 not tested
  18. 2019 High

    Mmp13-null mice showed exacerbated bleomycin-induced lung fibrosis with reduced collagenolytic activity, revealing an anti-fibrotic role for macrophage-derived MMP13 in fibrosis resolution—opposite to its cartilage-destructive role in OA.

    Evidence Global Mmp13-KO, bleomycin model, BAL cytokine array, gelatinase activity assays

    PMID:30785343

    Open questions at the time
    • Whether MMP13 directly cleaves lung collagen or acts through activation of other MMPs is not resolved
    • Specific macrophage subtype expressing MMP13 not identified
  19. 2021 High

    MMP13 cleavage of type I collagen exposes cryptic integrin α3 ligands that activate FAK-RUNX2, which in turn transactivates MMP13, establishing a self-amplifying positive feedback loop (MMP13→ITGA3→FAK→RUNX2→MMP13) in osteogenic differentiation.

    Evidence Recombinant MMP13 pre-treatment of collagen matrix, ITGA3 analysis, RUNX2 ChIP on MMP13 promoter, in vivo bone formation

    PMID:33677160

    Open questions at the time
    • Specific cryptic collagen I peptide sequences recognized by ITGA3 not identified
    • Whether this feedback loop operates in pathological bone remodeling (e.g., metastatic lesions) is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for MMP13 hemopexin domain recognition of collagen II triple helix, the identity of MMP13-generated fragments that activate endothelial FAK during angiogenesis, how tissue context (cartilage vs. lung vs. tumor stroma) determines whether MMP13 activity is destructive or protective, and whether therapeutic MMP13 inhibition can achieve tissue-selective effects.
  • No co-crystal structure of MMP13 hemopexin domain with collagen II
  • Angiogenic substrate fragments not identified biochemically
  • No systems-level model integrating transcriptional, post-translational, and feedback regulation of MMP13 across tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005576 extracellular region 8 GO:0031012 extracellular matrix 4
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1474244 Extracellular matrix organization 7 R-HSA-1643685 Disease 4
Partners
ANKRD1ATF3CAV1CTNNB1LEF1NCLRUNX2SP7

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 The MMP13 gene is composed of 10 exons and 9 introns spanning over 12.5 kb. Its promoter contains a functional AP-1 site responsible for inducibility by tumor promoter TPA, an OSE-2 (osteoblast-specific element), a PEA-3 consensus sequence, and a TGF-β inhibitory element. DNA binding analysis confirmed formation of specific complexes between MMP13 promoter AP-1 sequences and nuclear proteins. Genomic cloning, nucleotide sequencing, transient transfection with CAT reporter constructs, DNA binding/EMSA with nuclear extracts Genomics High 9119388
2004 RUNX2 overexpression in articular chondrocytes increases MMP-13 promoter activity and protein expression; FGF2 activates RUNX2 via MEK/ERK phosphorylation (~2-fold increase in RUNX2 phosphorylation), synergistically upregulating MMP-13. MEK/ERK inhibitors (PD98059) block this upregulation. RUNX2 overexpression, MMP-13 promoter activity assays, MEK/ERK inhibitor treatment, immunohistochemistry, Western blotting Osteoarthritis and cartilage High 15564063
2004 Mechanical strain induces MMP-13 expression in osteoblastic cells through MEK-ERK1/2 signaling. The strain-induced MMP-13 mRNA expression does not require de novo protein synthesis. Dominant-negative MEK1/2 mutants block this induction. Biaxial strain application, Western blotting, RT-PCR, zymography, pharmacological inhibitors (PD98059, SB203580, SP600125), dominant-negative MEK1/2 transfection The Journal of biological chemistry High 15044466
2006 TGF-β activates Smad2/3 in head-and-neck SCC cells, and Smad3 signaling (including basal activation) drives MMP-13 expression and invasion. Disruption of Smad signaling by dominant-negative constructs or Smad7 overexpression suppresses MMP-13 expression and invasion through Matrigel and collagen I. Adenoviral delivery of Smad7, dominant-negative Smad3, kinase-defective ALK-5; Matrigel invasion assays; xenograft models Oncogene High 16407850
2007 Lef1 and β-catenin synergistically upregulate MMP13 transcription in chondrocytes. A Lef1 binding site was mapped to the 3′ region of the MMP13 genomic locus; Lef1/β-catenin binding was confirmed by ChIP and EMSA. Lef1 siRNA knockdown suppressed IL-1β-mediated MMP13 expression. siRNA knockdown, ChIP, EMSA, MMP13 promoter reporter assays, plasmid transfection Biochemical and biophysical research communications High 17971297
2008 Nitric oxide (NO) causes tyrosine nitration of MMP-13 at residue Y338, which dissociates MMP-13 from caveolin-1, promoting its release from endothelial cells. In iNOS knockout mice, less MMP-13 is released and wound healing is slower; in caveolin-1 KO mice, increased MMP-13 nitration and accelerated wound healing are observed. Mutagenesis (Y338 identification), Co-IP (MMP-13/caveolin-1 association), iNOS and caveolin-1 knockout mouse models, wound healing assays FASEB journal High 18495757
2008 Ultrasound stimulation induces MMP-13 expression in osteoblasts via p38 and JNK signaling pathways (but not ERK). c-Fos and c-Jun bind to the AP-1 element on the MMP-13 promoter in response to ultrasound, enhancing AP-1 luciferase activity. Dominant-negative p38 or JNK mutants block this induction. Zymography, RT-PCR, AP-1 luciferase reporter assay, dominant-negative p38/JNK transfection, SB203580/SP600125 pharmacological inhibitors Journal of cellular physiology High 17941091
2009 Stroma-derived MMP-13 is required for melanoma tumor growth and organ-specific metastasis. Tumor growth was significantly impaired in mmp-13−/− mice, and metastasis to lungs, liver, and heart was substantially reduced. Decreased tumor growth correlated with reduced blood vessel density and decreased blood vessel permeability. Intradermal melanoma injection in MMP-13 knockout mice, MRI measurement of vessel permeability, immunohistochemistry of vascularity The Journal of investigative dermatology High 19516266
2009 MMP13 amplification on chromosome 9A1 (syntenic with human 11q22) cooperates with p53 deficiency in osteosarcoma. High MMP13 expression enhances osteosarcoma cell survival; shRNA-mediated knockdown of MMP13 reduces tumor growth in immunodeficient mice. Array CGH, lentiviral shRNA knockdown, xenograft transplantation, microarray expression analysis Cancer research Medium 19276372
2010 p38γ isoform is activated by IL-1β and fibronectin fragments in chondrocytes but suppresses MMP-13 production; constitutively active p38γ decreases MMP-13 output while dominant-negative p38γ increases it. p38α (nuclear localized) promotes MMP-13 while p38γ (cytosolic) counteracts this. Constitutively active and dominant-negative p38γ transfection, isoform-selective inhibitors (SB203580, BIRB796), immunoblotting, ELISA, RT-PCR Osteoarthritis and cartilage High 20633667
2011 Interstitial flow induces MMP-13 expression and cell motility in vascular smooth muscle cells via heparan sulfate proteoglycan (HSPG)-mediated FAK phosphorylation at Tyr925 and subsequent ERK1/2 activation. Disruption of HSPGs (heparinase or NDST1 silencing) or FAK inhibition abolishes this response. Heparinase treatment, NDST1 siRNA silencing, FAK inhibition/knockdown, ERK1/2 phosphorylation assays in 3D collagen culture PloS one High 21246051
2012 MMP-13 directly promotes tumor angiogenesis by activating focal adhesion kinase (FAK) and ERK in endothelial cells, enhancing capillary tube formation in vitro and in vivo. MMP-13 also indirectly promotes angiogenesis by stimulating VEGF-A secretion from fibroblasts and endothelial cells. Conditioned medium assays, recombinant MMP-13 treatment, capillary tube formation assays in vitro and in vivo, FAK/ERK activation measurement The Journal of biological chemistry High 22992737
2012 Osterix physically interacts with Runx2 and cooperates with it to induce MMP13 expression during chondrocyte differentiation and endochondral ossification. Osterix-deficient mice arrest at the hypertrophic stage; introduction of MMP13 into Osterix-deficient limb bud cells restores matrix calcification. Global and conditional Osterix-KO mice, microarray analysis, Co-IP (Osterix-Runx2 interaction), adenoviral MMP13 rescue in deficient cells The Journal of biological chemistry High 22869368
2013 Chondrocyte-specific deletion of Mmp13 (Mmp13Col2ER mice) decelerates OA progression, maintains higher cartilage area/thickness and type II collagen/proteoglycan levels, and reduces chondrocyte apoptosis. Pharmacological inhibition of MMP13 with CL82198 (confirmed by ELISA to inhibit >85% activity) recapitulates these protective effects. Conditional chondrocyte-specific Mmp13 knockout (Col2CreER), meniscal-ligamentous injury OA model, ELISA-based MMP13 activity assay, histology/histomorphometry, TUNEL staining Arthritis research & therapy High 23298463
2013 Knee loading reduces MMP13 activity in OA mouse cartilage through Rac1 GTPase-mediated p38 MAPK and NF-κB signaling. Silencing Rac1 reduces MMP13 expression and p-p38; constitutively active Rac1 increases and dominant-negative Rac1 decreases MMP13 activity. Mouse knee loading model, FRET-based Rac1 activity imaging, siRNA knockdown, constitutively active/dominant-negative Rac1 transfection, MMP13 activity assay, immunoblotting BMC musculoskeletal disorders High 24180431
2014 MMP-13 shows substrate selectivity for collagen II over collagens I and III, binding specifically to two triple-helical peptides in Collagen Toolkit II (peptides II-44 and II-8). Binding requires the triple-helical conformation (MMP-13 cannot bind linear peptide). The hemopexin domain (not the free catalytic subunit) mediates this binding; the canonical cleavage site in collagen II is at Gly775-Leu776. Triple-helical peptide Collagen Toolkit libraries, solid-phase binding assays, proteolysis assays with recombinant proMMP-13, MMP-13, free hemopexin domain, and free catalytic subunit The Journal of biological chemistry High 25008319
2014 ANKRD1 acts as a transcriptional repressor of MMP13 via the AP-1 site on the MMP13 promoter, operating in association with nucleolin (identified by yeast two-hybrid and Co-IP). Ankrd1 deletion increases c-Jun binding to the MMP13 AP-1 site (shown by ChIP), elevates MMP13 mRNA and protein in skin and wounds. Yeast two-hybrid, Co-IP, ChIP, EMSA, MMP13 promoter activity assays, Ankrd1 KO mice, siRNA knockdown, Ankrd1 reconstitution Molecular and cellular biology High 24515436
2014 GDF5 reduces MMP13 expression in human chondrocytes via induction of the canonical Wnt inhibitor DKK1. Inhibition of DKK1 by a small molecule (WAY-262621) reverses GDF5-mediated suppression of MMP13, establishing DKK1 as the intermediate mediator. Pellet mass culture system, qPCR, ELISA, Wnt pathway agonists (Wnt3a, CHIR-99021), DKK1 small molecule inhibitor (WAY-262621), siRNA knockdown Osteoarthritis and cartilage High 24561281
2015 MMP13 promotes colorectal cancer metastasis to the liver: both stromal (host) and tumor-derived MMP13 contribute to tumor cell extravasation from hepatic vasculature. MMP13 deficiency in host mice or stable MMP13 knockdown in tumor cells reduces extravasation and metastatic burden in vivo. MMP13 upregulation in steatotic liver increases metastatic burden. Splenic injection liver metastasis model in Mmp13-deficient mice, stable shRNA knockdown cell lines, whole-organ confocal microscopy, MTT/migration/invasion assays Molecular cancer High 25880591
2015 SENP2 inhibits MMP13 expression in bladder cancer cells by de-SUMOylating TBL1/TBLR1, which prevents β-catenin nuclear translocation and thereby reduces MMP13 transcriptional activation by β-catenin at the MMP13 promoter. SENP2 overexpression/knockdown, TBL1/TBLR1 SUMOylation assays, β-catenin nuclear translocation assays, luciferase promoter assays Scientific reports Medium 26369384
2016 ATF3 directly binds the proximal AP-1 motif of the MMP13 promoter in stimulated human chondrocytes at time points after transient cFOS binding has ceased, acting as a direct transcriptional activator. cFOS plays an earlier, indirect role. ATF3 expression itself is AP-1 (cFOS/cJUN)-dependent, creating a regulatory cascade. ChIP assays for promoter occupancy, siRNA-mediated ATF3 silencing, mRNA transcriptome analysis, protein synthesis inhibition experiments The Journal of biological chemistry High 27956552
2016 ETV4 directly regulates MMP13 gene transcription, and MMP13 mediates ETV4-driven proliferation, migration, invasion, and anchorage-independent growth in mammary epithelial cells. MMP13 inhibition partially blocks ETV4-induced tumor formation in immunodeficient mice. MMP13 promoter reporter constructs, gain/loss-of-function for ETV4 and MMP13 in cell lines and xenografts Breast cancer research : BCR Medium 29996935
2016 FGF23 drives MMP13 expression in OA chondrocytes through FGFR1 in a Klotho-independent manner, predominantly via MEK/ERK cascade with lesser PI3K/AKT contribution. RNA silencing of FGFR1 (but not Klotho) blocks FGF23-induced MMP13 upregulation. siRNA silencing of FGFR1 and Klotho, phosphoprotein array, immunoblotting, selective MAPK inhibitors, fluorescent MMP13 activity assay, immunohistochemistry Osteoarthritis and cartilage High 27307356
2017 DNA methylation of specific CpG sites in the RUNX2 P1 promoter controls RUNX2 expression; reduced methylation increases RUNX2 availability which transactivates MMP13. RUNX2 overexpression enhanced MMP13 promoter activity independently of MMP13 promoter methylation status. qPCR correlation in human OA chondrocytes, RUNX2 overexpression, in vitro methylation treatment of RUNX2 promoter constructs, MMP13 promoter reporter assays Scientific reports Medium 28798419
2019 Osteocyte-derived MMP13 is required for perilacunar/canalicular remodeling (PLR) in subchondral bone. Osteocyte-specific Mmp13 ablation (DMP1-Cre) suppresses PLR, disorganizes bone extracellular matrix, and secondarily impairs cartilage homeostasis (reduced proteoglycan, altered collagen II, increased cartilage lesions), demonstrating a bone-cartilage crosstalk mediated by osteocytic MMP13. Osteocyte-specific Cre-mediated Mmp13 conditional KO (DMP1-Cre), histomorphometry, IHC, without surgical injury model Bone research High 31700695
2019 Bleomycin-induced lung fibrosis resolves more slowly and more severely in Mmp13-null mice, with decreased overall collagenolytic activity and persistent fibrotic foci. MMP13 is expressed mainly by macrophages during inflammation and fibrosis resolution phases, establishing an antifibrotic role for MMP13. Mmp13 knockout mice, bleomycin intratracheal instillation, bronchoalveolar lavage cytokine array, gelatinase activity assays, histology American journal of physiology. Lung cellular and molecular physiology High 30785343
2021 MMP13 cleaves and remodels type I collagen matrix to expose cryptic ligands that bind integrin α3 (ITGA3), activating FAK and RUNX2 in mesenchymal stem cells to drive osteogenic differentiation. RUNX2 in turn binds the MMP13 promoter to upregulate MMP13, forming a positive feedback loop (MMP13/ITGA3/RUNX2). MMP13 knockdown, recombinant MMP13 pre-treatment of collagen matrix, ITGA3 expression analysis, RUNX2 ChIP on MMP13 promoter, in vivo bone formation assays Acta biomaterialia High 33677160
2014 Hsp90β and p130(cas) are identified as regulatory proteins that bind the AGRE site of the MMP-13 promoter in L-OA chondrocytes (identified by mass spectrometry). Silencing Hsp90β or p130(cas) significantly increases MMP-13 expression and production; combined silencing has an additive effect. IL-1β decreases p130(cas) and Hsp90β expression, providing a mechanism for cytokine-driven MMP-13 upregulation. Mass spectrometry identification of promoter-binding proteins, siRNA knockdown of Hsp90β/p130(cas)/NMP4, ELISA, RT-PCR, Western blotting Annals of the rheumatic diseases Medium 18593760
2016 High molecular weight hyaluronic acid (HA) inhibits TNF-α-induced MMP13 expression in chondrocytes via CD44 interaction, which induces DUSP10/MKP5 (a negative regulator of p38 MAPK and JNK), thereby suppressing AP-1 transcriptional activity. CD44 blocking antibody abolishes HA-mediated MMP13 inhibition. CD44-blocking antibody, HA treatment, p38/JNK phosphorylation assays, AP-1 reporter assay, DUSP10/MKP5 expression analysis by RT-PCR, western blot, immunofluorescence Journal of orthopaedic research Medium 27101204
2008 Angiotensin II activates MMP8 and MMP13 in atherosclerotic plaques with vulnerable phenotype, leading to increased collagen type I degradation and intra-plaque hemorrhage. ATII treatment increased MMP13 levels 2-fold and collagen I degradation by MMP13 3-fold in vulnerable upstream lesions. Extravascular device carotid artery model in ApoE KO mice with ATII infusion, immunohistochemistry for MMP8/MMP13 activity, collagen content assessment, MRI Atherosclerosis Medium 19233360
2019 IL-17A induces MMP-13 expression and activation in human aortic smooth muscle cells via TRAF3IP2-dependent JNK, p38 MAPK, AP-1, and NF-κB activation. Recombinant MMP-13 stimulates SMC migration via ERK. RECK (membrane-anchored inhibitor) overexpression attenuates MMP-13 activity (without affecting mRNA/protein), blocking IL-17A- and MMP-13-induced SMC migration. TRAF3IP2 knockdown/overexpression, recombinant MMP-13 treatment, RECK gain-of-function, kinase activation assays, SMC migration assays Journal of cellular physiology Medium 31074012
2017 MMP-2 and MMP-13 have opposing roles in vasculogenic mimicry (VM) in large cell lung cancer. MMP-2 cleaves laminin-5 (Ln-5) to generate fragments that promote VM by activating EGFR/F-actin, while MMP-13 cleaves Ln-5 to generate different fragments that decrease EGFR/F-actin expression and disrupt VM formation. MMP-13 overexpression, recombinant MMP-13 treatment, 3D culture tube formation assays, xenograft tumor models, immunohistochemistry Journal of cellular and molecular medicine Medium 28766880
2014 VEGFc/VEGFr3 signaling induces MMP13 expression in keratocytes (via MMP13 promoter luciferase assay). Keratocyte-derived MMP13 directly degrades type I collagen, creating stromal spaces that enable corneal neovascularization. A selective MMP13 inhibitor attenuates alkali-burn-induced corneal neovascularization. qRT-PCR, Western blot, in situ hybridization, luciferase MMP13 promoter assay, hydroxyproline content assay, selective MMP13 inhibitor treatment, immunohistochemistry Investigative ophthalmology & visual science Medium 25190659

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis research & therapy 413 23298463
2016 Circular RNA Related to the Chondrocyte ECM Regulates MMP13 Expression by Functioning as a MiR-136 'Sponge' in Human Cartilage Degradation. Scientific reports 251 26931159
2004 Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage. Osteoarthritis and cartilage 243 15564063
2008 Joint diseases and matrix metalloproteinases: a role for MMP-13. Current pharmaceutical biotechnology 229 18289056
2022 The Role of Matrix Metalloproteinases (MMP-8, MMP-9, MMP-13) in Periodontal and Peri-Implant Pathological Processes. International journal of molecular sciences 221 35163727
1997 Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13). Genomics 169 9119388
2012 Osterix regulates calcification and degradation of chondrogenic matrices through matrix metalloproteinase 13 (MMP13) expression in association with transcription factor Runx2 during endochondral ossification. The Journal of biological chemistry 137 22869368
2012 Matrix metalloproteinase-13 (MMP-13) directly and indirectly promotes tumor angiogenesis. The Journal of biological chemistry 114 22992737
2000 Differential expression of MT1-MMP (MMP-14) and collagenase III (MMP-13) genes in normal and wounded rat corneas. Investigative ophthalmology & visual science 102 10967042
1999 Expression of collagenase-3 (MMP-13) in human abdominal aortic aneurysms and vascular smooth muscle cells in culture. Biochemical and biophysical research communications 99 10441523
2019 Osteocyte dysfunction promotes osteoarthritis through MMP13-dependent suppression of subchondral bone homeostasis. Bone research 93 31700695
2009 Stromal expression of MMP-13 is required for melanoma invasion and metastasis. The Journal of investigative dermatology 90 19516266
2009 MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), amplified on chromosome 9, collaborate with p53 deficiency in mouse osteosarcoma progression. Cancer research 84 19276372
2004 Mechanical strain induces collagenase-3 (MMP-13) expression in MC3T3-E1 osteoblastic cells. The Journal of biological chemistry 84 15044466
2003 Expression of MMP-8 and MMP-13 genes in the periodontal ligament during tooth movement in rats. Journal of dental research 81 12885852
2006 Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells. Oncogene 79 16407850
2014 GDF5 reduces MMP13 expression in human chondrocytes via DKK1 mediated canonical Wnt signaling inhibition. Osteoarthritis and cartilage 78 24561281
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2016 Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish. Proceedings of the National Academy of Sciences of the United States of America 65 27035978
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2002 Adenoviral delivery of p53 gene suppresses expression of collagenase-3 (MMP-13) in squamous carcinoma cells. Oncogene 60 11850838
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2014 The recognition of collagen and triple-helical toolkit peptides by MMP-13: sequence specificity for binding and cleavage. The Journal of biological chemistry 48 25008319
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2009 Activation of MMP8 and MMP13 by angiotensin II correlates to severe intra-plaque hemorrhages and collagen breakdown in atherosclerotic lesions with a vulnerable phenotype. Atherosclerosis 45 19233360
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