{"gene":"MMP10","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2005,"finding":"MMP-10 activates pro-MMP-1, and both MMP-10 and MMP-1 are required for capillary tube regression in 3D collagen matrices; serine proteases (plasma kallikrein, trypsin, neutrophil elastase, cathepsin G, tryptase, chymase) activate pro-MMP-10, which in turn activates MMP-1 to drive collagen proteolysis, tube collapse, and endothelial cell apoptosis. siRNA silencing of MMP-10 markedly delayed regression, while adenoviral overexpression of MMP-10 accelerated it.","method":"siRNA knockdown, adenoviral overexpression, in vitro capillary tube regression assay in 3D collagen matrices, zymography, biochemical MMP activation assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function (siRNA and adenoviral OE), in vitro biochemical activation assays, multiple orthogonal readouts in a single rigorous study","pmids":["15870107"],"is_preprint":false},{"year":2004,"finding":"Active stromelysin-2 (MMP-10) degrades laminin-5 in vitro, and constitutively active MMP-10 expressed in keratinocytes in vivo disrupts laminin-5 deposition, mislocalizes β1-integrins and phosphorylated focal adhesion kinase at the wound edge, and increases keratinocyte apoptosis, indicating MMP-10 controls keratinocyte migration through regulated matrix degradation.","method":"Transgenic mouse model (constitutively active MMP-10 in keratinocytes), in vitro laminin-5 degradation assay, immunohistochemistry, skin wound-healing model","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro enzymatic assay combined with transgenic in vivo model and multiple orthogonal readouts (substrate cleavage, integrin/FAK localization, apoptosis)","pmids":["15371548"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of TIMP-1 bound to the MMP-10 catalytic domain solved at 1.9 Å; TIMP-1 inhibits MMP-10cd with Ki = 1.1 × 10⁻⁹ M and TIMP-2 with Ki = 5.8 × 10⁻⁹ M, both ~10-fold weaker than their inhibition of the closely related MMP-3. Structural comparison with MMP-3·TIMP-1 revealed interface differences explaining the differential binding.","method":"X-ray crystallography (1.9 Å resolution, molecular replacement), kinetic inhibition assays (multiple approaches), comparative structural analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional kinetic validation using multiple methods in one rigorous study","pmids":["22427646"],"is_preprint":false},{"year":2013,"finding":"MMP10 is required for macrophage migration and invasion; RNAi silencing of MMP10 in primary macrophages markedly reduced migration (reversed by exogenous active MMP10 protein), and Mmp10⁻/⁻ bone marrow-derived macrophages showed significantly reduced migration over fibronectin and impaired invasion into Matrigel supplemented with fibronectin.","method":"Time-lapse microscopy, RNAi silencing, Mmp10⁻/⁻ knockout macrophages, exogenous recombinant MMP10 rescue, 2D migration and Matrigel invasion assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, RNAi, and rescue with recombinant protein across multiple migration/invasion assays","pmids":["23691065"],"is_preprint":false},{"year":2016,"finding":"MMP10 moderates macrophage inflammatory activation: Mmp10⁻/⁻ mice showed ~3-fold more macrophages in infected lungs, elevated M1 markers and reduced M2 markers; global gene expression showed infection-induced transcriptional changes persisted in Mmp10⁻/⁻ macrophages. Adoptive transfer of wild-type BMDMs normalized morbidity in Mmp10⁻/⁻ recipients, demonstrating the protective effect is macrophage-derived MMP10.","method":"Mmp10⁻/⁻ knockout mice, Pseudomonas aeruginosa infection model, adoptive transfer of BMDMs, genome-wide gene expression analysis, flow cytometry for macrophage markers","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with adoptive transfer rescue, genome-wide transcriptomic analysis, and cell-type–specific phenotype demonstration","pmids":["27316687"],"is_preprint":false},{"year":2015,"finding":"MMP-10 from alternatively activated (M2) resident macrophages regulates collagenolytic activity in wounds by controlling expression of metallocollagenases MMP-8 and MMP-13 (particularly MMP-13); Mmp10⁻/⁻ wounds showed increased collagen deposition, skin stiffness, and reduced collagenolytic activity. Ablation and adoptive transfer experiments confirmed the effect is macrophage-derived.","method":"Mmp10⁻/⁻ knockout mice, wound healing model, macrophage ablation and adoptive transfer, collagen assays, biomechanical testing, cell-based models","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, adoptive transfer rescue, multiple orthogonal quantitative readouts","pmids":["25927164"],"is_preprint":false},{"year":2012,"finding":"Loss of MMP10 exacerbates DSS-induced colitis and impairs resolution of inflammation; MMP10 is produced predominantly by infiltrating myeloid cells in murine and human colitis, and bone marrow transplant experiments confirmed that bone marrow-derived MMP10 contributes to disease severity. Mmp10⁻/⁻ mice had higher propensity for dysplasia after repeated DSS exposure.","method":"Mmp10⁻/⁻ knockout mice, DSS colitis model, bone marrow transplantation, immunohistochemistry, histological scoring","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with bone marrow transplant rescue, defining cellular source and functional consequence","pmids":["23044923"],"is_preprint":false},{"year":2009,"finding":"TGF-β transcriptionally induces MMP-10 in mammary epithelial cells through MEF2A: TGF-β promotes proteasome-dependent degradation of class IIa HDACs, leading to increased acetylation of MEF2A and core histones around the MEF2 site of the MMP-10 promoter, driving transactivation. Knockdown of MEF2A reduced MMP-10 induction; knockdown of class IIa HDACs increased it.","method":"Reporter gene (luciferase) assays, siRNA knockdown, overexpression experiments, chromatin immunoprecipitation (ChIP), real-time PCR, proteasome inhibitor experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP, reporter assays, and siRNA/OE with multiple orthogonal methods in one study","pmids":["19935709"],"is_preprint":false},{"year":2005,"finding":"Zinc finger protein ZNF267 is a negative transcriptional repressor of MMP-10: ZNF267 is constitutively nuclear, its KRAB-A domain mediates repressor activity, it binds the MMP-10 promoter region (demonstrated by ChIP), and its overexpression reduces MMP-10 reporter activity in hepatic stellate cells.","method":"Microarray, RNase protection assay, reporter gene assay, chromatin immunoprecipitation (ChIP), GAL4 fusion constructs, fluorescent protein localization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays in single lab, two orthogonal methods","pmids":["16054593"],"is_preprint":false},{"year":2010,"finding":"MMP-10 transcription in endothelial cells is induced by VEGF in a time- and dose-dependent manner; MMP-10 expression is mediated by the Ets-1 transcription factor but not ERP/NET/ELK3, and via PI3K and MAPK signaling pathways. MMP-10 siRNA inhibited VEGF-induced endothelial cell migration and tube formation in vitro, and vessel formation in matrigel plugs in vivo.","method":"Quantitative RT-PCR, siRNA knockdown, migration and tube formation assays, in vivo matrigel plug assay, pharmacological inhibitors of PI3K and MAPK, luciferase reporter for Ets-1","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA functional assay with in vitro and in vivo readouts, signaling pathway mapping; single lab","pmids":["20432469"],"is_preprint":false},{"year":2011,"finding":"C-reactive protein (CRP) promotes MMP-10 expression and activity in cardiomyocytes via c-Raf/MEK/ERK and JAK1/ERK signaling pathways, with DNA binding sites for AP-1 and STAT3 in the nucleus mediating the effect; blocking ERK1/2 (U0126) or JAK1 (piceatannol) significantly decreased CRP-induced MMP-10 expression.","method":"Real-time PCR, Western blot, casein zymography, pharmacological pathway inhibitors, phospho-specific antibodies, cell culture","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibitor experiments and zymography in cardiomyocytes, multiple readouts but no genetic confirmation; single lab","pmids":["22142512"],"is_preprint":false},{"year":2011,"finding":"β1 integrin signaling via the ERK/MAPK pathway upregulates MMP-10 mRNA and protein expression in human lymphatic endothelial cells, and MMP-10 is required for collagen I-induced lymphatic tubulogenesis; knockdown of MMP-10 impaired tubulogenesis.","method":"Protein-based screening, siRNA knockdown, ERK/MAPK pathway analysis, lymphatic endothelial cell tubulogenesis assay","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with functional tubulogenesis readout, pathway analysis; single lab","pmids":["21406228"],"is_preprint":false},{"year":2014,"finding":"MMP-10 deficiency impairs skeletal muscle regeneration after injury: Mmp10⁻/⁻ muscles displayed reduced endothelial cell recruitment, diminished extracellular matrix proteins, decreased collagen deposition, decreased fiber size, and delayed regeneration. MMP-10 mRNA silencing in vivo reduced muscle regeneration, while recombinant MMP-10 accelerated repair. MMP-10-mediated muscle repair was associated with VEGF/Akt signaling.","method":"Mmp10⁻/⁻ knockout mice, notexin injury model, mdx muscular dystrophy model, siRNA in vivo silencing, recombinant MMP-10 treatment, immunohistochemistry, Western blot","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, siRNA, and recombinant protein rescue across multiple disease models with mechanistic pathway link","pmids":["24123596"],"is_preprint":false},{"year":2014,"finding":"CXCR4/SDF1-regulated muscle repair is dependent on MMP-10 activity: siRNA silencing of SDF1 or CXCR4 in injured muscles impaired regeneration, and MMP-10 was identified as the downstream effector of this axis. SDF1 ligand addition accelerated repair, and CXCR4 antagonism (AMD3100) delayed it, linking the CXCR4/SDF1 pathway to MMP-10-dependent matrix remodeling in muscle repair.","method":"In vivo siRNA silencing of SDF1, CXCR4, pharmacological CXCR4 antagonism (AMD3100), notexin injury model, functional and histological analysis","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo siRNA and pharmacological epistasis; single lab with two methods","pmids":["24548137"],"is_preprint":false},{"year":2014,"finding":"MMP-10 functions are required for efficient tissue repair after hind limb ischemia; Mmp10⁻/⁻ mice showed delayed reperfusion, increased necrosis, and excessive neutrophil/macrophage infiltration. MMP-10 deficiency led to higher Cxcl1 mRNA and protein levels, revealing a transcriptional inhibitory role for MMP-10 on Cxcl1. Injection of MMP-10 into Mmp10⁻/⁻ mice rescued the phenotype.","method":"Mmp10⁻/⁻ knockout mice, femoral artery excision ischemia model, small animal PET, immunohistochemistry, siRNA knockdown of MMP-10 in vivo, recombinant MMP-10 rescue","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, siRNA in vivo, and recombinant protein rescue with mechanistic chemokine regulation identified","pmids":["25414484"],"is_preprint":false},{"year":2021,"finding":"During secondary fracture healing, MMP-10 is expressed by hematopoietic cells and is required for cartilage resorption; Mmp10⁻/⁻ mice showed delayed cartilage resorption and TRAP-positive cell accumulation at 14 days post-fracture. The phenotype was rescued by wild-type bone marrow transplant. MMP-10 functions in macrophages to promote proMMP-9 processing and gelatinase activity required for endochondral ossification.","method":"Mmp10⁻/⁻ knockout mice, fracture healing model, bone marrow transplantation rescue, proMMP-9 processing assay, TRAP staining, immunohistochemistry","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with bone marrow transplant rescue and in vitro proMMP-9 processing mechanistic data","pmids":["34173256"],"is_preprint":false},{"year":2018,"finding":"MMP10 functions as a thrombolytic and neuroprotective agent in ischemic stroke; recombinant MMP10 reduced infarct size in a thrombin-induced middle cerebral artery occlusion model, and in vitro MMP10 reduced tPA-promoted endothelial ionic permeability, preserved claudin-5, decreased ERK1/2 activation, prevented tPA-mediated neuronal excitotoxicity and calcium influx. These effects were blocked by an anti-MMP10 monoclonal antibody.","method":"In vivo murine ischemic stroke model, brain endothelial cell and neuron cultures, Western blot for claudin-5, ERK1/2 phosphorylation, calcium imaging, anti-MMP10 antibody neutralization","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo rescue with recombinant protein, in vitro mechanistic cell assays, antibody neutralization; single lab","pmids":["28379489"],"is_preprint":false},{"year":2018,"finding":"MMP10 moderates TLR7-induced immune tolerance in skin macrophages: Mmp10⁻/⁻ mice failed to develop hypo-responsiveness to repeated TLR7 (imiquimod) stimulation, with failure to upregulate negative TLR regulators (TNFAIP3, IRAK3) and immunosuppressive cytokines (IL-10, TGFβ1). In vitro, prior IMQ exposure made wild-type BMDMs refractory to re-stimulation but not Mmp10⁻/⁻ macrophages.","method":"Mmp10⁻/⁻ knockout mice, in vivo TLR7 tolerance model, BMDM cultures, cytokine/gene expression analysis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo and in vitro parallel experiments; single lab","pmids":["30564235"],"is_preprint":false},{"year":2020,"finding":"Recombinant MMP-10 induces osteogenic, fibrotic, and inflammatory markers in aortic valve interstitial cells (interleukin-1β, α-SMA, vimentin, collagen, BMP-4, Sox9, osteopontin, BMP-9, and Smad 1/5/8) and promotes cell mineralization via Akt phosphorylation; these effects were prevented by TIMP-1 or an anti-MMP-10 antibody. MMP-10 co-localizes with calcification markers (Runx2, SOX9) in stenotic aortic valves.","method":"In vitro treatment of primary human aortic valve interstitial cells with recombinant MMP-10, TIMP-1 inhibition, anti-MMP-10 antibody neutralization, Akt phosphorylation assay, calcification (mineralization) assay, immunohistochemistry","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein gain-of-function with antibody and TIMP-1 inhibition as controls; single lab, primary human cells","pmids":["32188274"],"is_preprint":false},{"year":2017,"finding":"MMP10 facilitates clearance of long multiwalled carbon nanotubes (MWCNTs) from lung and moderates macrophage inflammatory activation and survival; Mmp10⁻/⁻ mice showed impaired pulmonary clearance of MWCNTs and reduced macrophage survival, with enhanced caspase-3-dependent cell death and elevated IL-6 and IL-1β in Mmp10⁻/⁻ macrophages.","method":"Mmp10⁻/⁻ knockout mice, oropharyngeal aspiration of MWCNTs, alveolar macrophage and BMDM cultures, caspase-3 assay, cytokine analysis, gene expression","journal":"International journal of nanomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo and in vitro parallel experiments; single lab","pmids":["28223796"],"is_preprint":false},{"year":2022,"finding":"Directed evolution of yeast-displayed TIMP-1 yielded variants highly selective for MMP-3 over MMP-10. Protein crystal structures and models of MMP-3-selective TIMP-1 variants bound to MMP-3 and counter-target MMP-10 showed that structural alterations in N- and C-terminal TIMP-1 domains create favorable interactions with MMP-3 and disrupt unique interactions with MMP-10, defining the binding interface determinants of stromelysin selectivity.","method":"Directed evolution (yeast display, counter-selective screening), X-ray crystallography of protein complexes, structural modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures and directed evolution with selectivity validation, multiple orthogonal approaches","pmids":["35101440"],"is_preprint":false},{"year":2011,"finding":"CHF1/Hey2 is a direct transcriptional repressor of MMP10: loss or knockdown of CHF1/Hey2 in vascular smooth muscle cells increases MMP10 expression and activity. A 2.5 kb MMP10 promoter region contains 12 E-boxes mediating constitutive activity and CHF1/Hey2 repression; mutation of these E-boxes abolished repression and unmasked an activator function for CHF1/Hey2.","method":"Luciferase reporter assays, siRNA knockdown of CHF1/Hey2, E-box mutagenesis, gene expression analysis in smooth muscle cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assay with mutagenesis and KD; single lab, two complementary methods","pmids":["22079635"],"is_preprint":false},{"year":2016,"finding":"AJUBA promotes migration and invasion of esophageal squamous cell carcinoma cells by upregulating MMP10 and MMP13 expression through activation of the ERK1/2 signaling pathway; AJUBA knockdown reduced migration/invasion and decreased MMP10/MMP13 levels, while AJUBA overexpression had the opposite effect, both in vitro and in vivo.","method":"RNA sequencing, siRNA knockdown and overexpression of AJUBA, Western blot, migration and invasion assays, in vivo xenograft models, ERK1/2 pathway analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA-seq target identification plus KD/OE functional assays, ERK1/2 pathway link; single lab","pmids":["27172796"],"is_preprint":false},{"year":2014,"finding":"YY1 suppresses PDAC invasion and metastasis by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism: YY1 expression negatively correlated with MMP10 levels; YY1 overexpression suppressed invasion/metastasis and reduced MMP10, while YY1 knockdown enhanced them. Luciferase assays and pathway blockage experiments placed MMP10 downstream of YY1/MUC4/ErbB2/p38/MEF2C.","method":"Digital gene expression sequencing, siRNA knockdown, overexpression, luciferase reporter assays, signaling pathway inhibitors, in vivo xenograft and tail vein metastasis models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assays and pathway inhibitors with in vivo models; pathway is defined but mechanism is partially indirect; single lab","pmids":["24884523"],"is_preprint":false},{"year":2009,"finding":"IL-6 regulates MMP-10 expression via the JAK2/STAT3 pathway in lung adenocarcinoma cells: IL-6 moderately reduced MMP-10 mRNA but significantly enhanced MMP-10 protein. The JAK2 inhibitor AG490 blocked both IL-6-induced STAT3 upregulation and the bidirectional IL-6 effects on MMP-10 mRNA and protein levels.","method":"Real-time RT-PCR, Western blot, pharmacological JAK2 inhibition (AG490), A549 cell culture","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibitor only, single cell line, single lab","pmids":["20032397"],"is_preprint":false},{"year":1997,"finding":"Recombinant murine stromelysin-2 (MMP-10) produced in COS cells is secreted as a proenzyme that undergoes autocatalytic processing upon addition of the organomercurial salt APMA, establishing that MMP-10 is an autocatalytically activatable metalloproteinase.","method":"COS cell expression of recombinant protein, organomercurial (APMA)-induced autocatalytic processing assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct biochemical demonstration of proenzyme activation, single study, single method","pmids":["9427548"],"is_preprint":false},{"year":2022,"finding":"MMP10 is required for proMMP-9 processing in macrophages during bone fracture healing; Mmp10⁻/⁻ macrophages showed reduced gelatinase activity and lack of proMMP-9 processing, contributing to impaired cartilage resorption and delayed vascular invasion during endochondral ossification.","method":"Mmp10⁻/⁻ knockout mice, wild-type bone marrow transplant rescue, proMMP-9 processing assay, gelatinase activity assay, fracture healing histology","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with bone marrow transplant and direct biochemical proMMP-9 processing assay","pmids":["34173256"],"is_preprint":false},{"year":2023,"finding":"MMP10 alleviates non-alcoholic steatohepatitis by promoting M2 macrophage polarization via STAT3 signaling: PPARγ binds the MMP10 promoter and upregulates MMP10 expression upon IL-4 stimulation. MMP10 overexpression activated downstream STAT3 signaling to induce M2 polarization, reducing pro-inflammatory IL-1β and TNF-α and increasing IL-10. MMP10-KO mice showed worse NASH phenotype on HFD.","method":"MMP10-OE and MMP10-KO mice on HFD, PPARγ-OE, ChIP (PPARγ binding to MMP10 promoter), Kupffer cell transfection, IL-4 stimulation, STAT3 pathway analysis, HFD NASH model","journal":"International immunopharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct promoter binding, genetic KO and OE in vivo with signaling pathway elucidation; multiple methods","pmids":["37844469"],"is_preprint":false},{"year":2022,"finding":"MMP-10 knockdown in hypertrophic chondrocytes decreases expression of Col II, Col X, Runx2, and MMP-13, and significantly increases chondrocyte apoptosis, indicating MMP-10 is required for terminal chondrocyte differentiation and survival during endochondral osteogenesis.","method":"MMP-10 shRNA knockdown in ATDC5 hypertrophic chondrocytes, flow cytometry (apoptosis), RT-PCR, Western blot, in vivo rat/human KBD cartilage analysis","journal":"Cartilage","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — shRNA KD with multiple marker readouts and apoptosis assay; single lab","pmids":["35818290"],"is_preprint":false},{"year":2025,"finding":"MMP10 induces Ca²⁺ mobilization in dorsal root ganglion (DRG) neurons through a PAR1-independent mechanism (in contrast to MMP3, MMP8, and MMP9 which act via PAR1), establishing a distinct neuronal signaling pathway for MMP10.","method":"Intracellular Ca²⁺ imaging in DRG neurons, PAR1 pharmacological blockade, comparison with other MMPs","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint, single method (Ca²⁺ imaging), mechanism not fully resolved beyond PAR1 independence","pmids":[],"is_preprint":true},{"year":2025,"finding":"Endothelial TRIM35 inhibits MMP10 expression and secretion by promoting K63-linked ubiquitination of RelB, maintaining its nuclear localization to inhibit MMP10 transcription through the non-canonical NF-κB signaling pathway; conditional endothelial TRIM35 knockout leads to increased MMP10 secretion, which drives smooth muscle cell calcification in vascular grafts.","method":"Conditional endothelial TRIM35 KO mice, arterial isograft model, single-cell analysis, co-culture experiments, ubiquitination assays (K63-linked), RelB localization studies, in situ MMP10 targeting","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic conditional KO with mechanistic ubiquitination assays and in vivo rescue; single lab","pmids":["39865905"],"is_preprint":false},{"year":2024,"finding":"NOX5-generated ROS upregulates MMP-10 expression in endothelial cells via the redox-sensitive JNK/AP-1 signaling pathway, promoting endothelial cell migration; NOX5 and MMP-10 silencing prevented this pro-migratory effect, and effects were enhanced by angiotensin II.","method":"NOX5 overexpression and siRNA silencing in human endothelial cells, MMP-10 siRNA, wound healing assay, JNK/AP-1 pathway inhibition, MMP-10 promoter activity assay, in vivo NOX5-expressing mouse hearts","journal":"Antioxidants","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain- and loss-of-function with pathway inhibitors and in vivo confirmation; single lab","pmids":["39456453"],"is_preprint":false},{"year":2025,"finding":"Active MMP-10 cleaves nephrin in vitro, contributing to podocyte injury; in vivo, MMP-10 knockout mice showed less albuminuria and reduced pro-inflammatory/pro-fibrotic gene expression in anti-GBM nephritis, and MMP-10 overexpression in podocytes upregulated inflammatory responses to TNF-α while MMP-10 knockdown mitigated inflammation.","method":"Mmp10⁻/⁻ knockout mice, anti-GBM nephritis model, GC-A/MMP-10 double KO mice, in vitro nephrin cleavage assay, podocyte MMP-10 OE and KD, co-culture of podocytes with endothelial cells, Western blot","journal":"Nephrology, dialysis, transplantation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo with in vitro substrate cleavage assay; single lab, multiple complementary approaches","pmids":["40328459"],"is_preprint":false},{"year":2025,"finding":"SOX9 directly transcriptionally activates MMP10 expression (identified by ChIP-seq), and MMP10 promotes ECM degradation downstream of SOX9 in tracheal fibroblasts via the Wnt/β-catenin signaling pathway; SOX9 overexpression increased and SOX9 siRNA decreased MMP10 expression, fibroblast activation, and ECM deposition.","method":"RNA-seq, ChIP-seq, adenoviral SOX9 overexpression, siRNA knockdown, Wnt/β-catenin pathway analysis, in vivo tracheal fibrosis model, MMP10 expression quantification","journal":"Genes & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq demonstrates direct SOX9-MMP10 promoter interaction; complemented by OE/KD and in vivo model; single lab","pmids":["38993791"],"is_preprint":false},{"year":2024,"finding":"A missense variant p.L245P in MMP10 (identified in families with premature myocardial infarction) alters the MMP10-TIMP1 binding interface, reduces total free binding energy, and minimizes the substrate-binding cleft volume (molecular dynamics simulations). In macrophages transfected with the variant, cells were more adherent, less migratory, and secreted higher levels of pro-inflammatory CXCL1 and CXCL8 compared to wild-type MMP10.","method":"Whole-exome sequencing (variant identification), molecular dynamics simulations, macrophage transfection with WT and p.L245P cDNA, adhesion assay, migration assay, ELISA for chemokines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — computational structural analysis combined with cell-based functional assays; single lab, single variant","pmids":["38806571"],"is_preprint":false},{"year":1998,"finding":"SL-2 (MMP-10) in developing human bone is produced in an active form (confirmed by in situ zymography) at sites of resorption in endochondral ossification, the chondro-osseous junction (chondrocytes), and in osteoclasts and mononuclear marrow cells, with associated matrix degradation activity. This differs from SL-1 (MMP-3), which is present predominantly as a latent matrix-bound proenzyme.","method":"Immunohistochemistry, in situ zymography on human osteophytic and neonatal rib bone sections","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in situ zymography directly demonstrates active enzyme in tissue; two complementary histological methods; single study","pmids":["9662124"],"is_preprint":false},{"year":2020,"finding":"Ski associates with the pericentromeric region and promoters of Mmp10 (along with Mmp3 and Mmp13) on chromosome 9 during mitosis, promotes H3K9 tri-methylation at these loci, and is required for transcriptional repression of these genes during M/G1 transition; Ski⁻/⁻ MEFs show increased Mmp activity and derepressed Mmp10 expression.","method":"Chromatin immunoprecipitation (ChIP) of Ski at Mmp10 promoter, H3K9 methylation/acetylation assays, Ski⁻/⁻ MEFs, differential gene expression assays, MMP activity assay","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct chromatin association with functional histone modification; genetic KO validation; single lab","pmids":["32198114"],"is_preprint":false},{"year":2022,"finding":"miR-148/152 family members negatively regulate MMP10; deficiency of any member increases MMP10 (and MMP13) expression, disrupts intestinal barrier, and activates NF-κB signaling in part through MMP10-mediated cleavage of pro-TNF-α into bioactive fragments. Blocking NF-κB exerted a restorative effect only in knockout mice.","method":"Individual and full-family miR-148/152 KO mice, colitis/CAC models (DSS/AOM), MMP10 expression analysis, intestinal barrier assays, NF-κB pathway analysis, NF-κB blockade experiments","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic KO models with pathway rescue experiments; MMP10's specific substrate cleavage of pro-TNF-α is inferred from functional data; single lab","pmids":["34979166"],"is_preprint":false}],"current_model":"MMP-10 (stromelysin-2) is a secreted zinc-dependent endopeptidase whose catalytic domain structure has been solved in complex with TIMP-1 (1.9 Å); it degrades extracellular matrix substrates including laminin-5, fibronectin, and collagen components, activates pro-MMP-1 and pro-MMP-9, and is regulated by TIMP-1/TIMP-2 inhibition. Its transcription is controlled by multiple pathways (TGF-β/MEF2A/HDAC, VEGF/Ets-1/PI3K/MAPK, CRP/ERK/JAK1, NOX5/JNK/AP-1, CHF1/Hey2 repression, ZNF267 repression, Ski-mediated H3K9me3, miR-148/152 and miR-944) and it performs cell-type-specific functions: in macrophages it moderates M1 activation, promotes M2 polarization and collagenolytic activity via MMP-13, facilitates macrophage migration, promotes proMMP-9 processing required for cartilage resorption, and mediates TLR7 immune tolerance; in endothelial cells it drives capillary tube regression and angiogenesis/lymphangiogenesis; in keratinocytes it regulates migration through laminin-5 degradation and integrin/FAK signaling; in muscle it supports regeneration via VEGF/Akt and CXCR4/SDF1 signaling; and in neurons it triggers Ca²⁺ mobilization through a PAR1-independent mechanism."},"narrative":{"mechanistic_narrative":"MMP-10 (stromelysin-2) is a secreted, autocatalytically activatable zinc-dependent metalloproteinase that remodels the extracellular matrix and orchestrates downstream protease cascades during tissue repair, inflammation, and angiogenesis [PMID:15870107, PMID:9427548]. As a proteolytic hub it both activates other matrix proteases—processing pro-MMP-1 to drive collagenolysis and capillary tube regression in endothelial cells [PMID:15870107] and processing proMMP-9 in macrophages to enable cartilage resorption during endochondral ossification [PMID:34173256]—and directly cleaves matrix and signaling substrates including laminin-5 in keratinocytes (controlling migration through β1-integrin/FAK signaling) [PMID:15371548] and nephrin in podocytes [PMID:40328459]. Its catalytic domain is inhibited by TIMP-1 and TIMP-2, with the MMP-10·TIMP-1 interface defined crystallographically [PMID:22427646, PMID:35101440]. A central biological role is in myeloid cells, where MMP-10 promotes macrophage migration and invasion over fibronectin [PMID:23691065], moderates inflammatory (M1) activation and favors M2 polarization via STAT3 [PMID:27316687, PMID:37844469], controls collagenolytic activity through MMP-8/MMP-13 expression [PMID:25927164], mediates TLR7 immune tolerance [PMID:30564235], and is required for efficient repair after lung infection, colitis, hindlimb ischemia, muscle injury, and bone fracture [PMID:27316687, PMID:23044923, PMID:24123596, PMID:25414484, PMID:34173256]. MMP-10 transcription is integrated by numerous inputs, being induced by TGF-β/MEF2A [PMID:19935709], VEGF/Ets-1 [PMID:20432469], and SOX9/Wnt-β-catenin [PMID:38993791] and repressed by ZNF267, CHF1/Hey2, Ski-mediated H3K9 trimethylation, and the TRIM35/RelB non-canonical NF-κB axis [PMID:16054593, PMID:22079635, PMID:32198114, PMID:39865905]. A missense variant (p.L245P) identified in families with premature myocardial infarction alters the MMP-10–TIMP-1 interface and renders macrophages less migratory and more pro-inflammatory, linking MMP-10 to cardiovascular disease [PMID:38806571].","teleology":[{"year":1997,"claim":"Established the basic enzymatic nature of MMP-10—whether it behaves as a regulated zymogen—by showing the recombinant proenzyme undergoes autocatalytic processing.","evidence":"COS-cell expression of recombinant murine stromelysin-2 with APMA-induced autocatalytic activation","pmids":["9427548"],"confidence":"Medium","gaps":["Physiological activator(s) in vivo not defined","Substrate repertoire of the activated enzyme not addressed"]},{"year":1998,"claim":"Demonstrated that MMP-10 exists as an active enzyme in tissue at sites of bone resorption, distinguishing it from the latent, matrix-bound behavior of MMP-3.","evidence":"Immunohistochemistry and in situ zymography on human and neonatal bone sections","pmids":["9662124"],"confidence":"Medium","gaps":["Cellular activation mechanism in tissue not resolved","Direct substrates at resorption sites not identified"]},{"year":2004,"claim":"Defined a direct matrix substrate (laminin-5) and a cell-biological consequence, showing MMP-10 controls keratinocyte migration via regulated matrix degradation and integrin/FAK signaling.","evidence":"In vitro laminin-5 cleavage plus transgenic keratinocyte-targeted active MMP-10 mouse with wound-healing readouts","pmids":["15371548"],"confidence":"High","gaps":["Cleavage site mapping not detailed","Whether endogenous MMP-10 levels reproduce overexpression phenotype unclear"]},{"year":2005,"claim":"Placed MMP-10 in a protease activation cascade by showing it activates pro-MMP-1 to drive endothelial capillary tube regression, establishing MMP-10 as an upstream amplifier of collagenolysis.","evidence":"siRNA knockdown, adenoviral overexpression, biochemical activation assays in 3D collagen tube-regression model","pmids":["15870107"],"confidence":"High","gaps":["In vivo relevance of the cascade beyond the 3D model not tested","Endogenous serine protease activators of pro-MMP-10 in vivo not confirmed"]},{"year":2005,"claim":"Began mapping transcriptional control by identifying ZNF267 as a KRAB-domain repressor binding the MMP-10 promoter.","evidence":"Reporter assays, ChIP, and GAL4 fusions in hepatic stellate cells","pmids":["16054593"],"confidence":"Medium","gaps":["Physiological contexts of ZNF267 repression unknown","Single-cell-type analysis only"]},{"year":2009,"claim":"Identified an inducible transcriptional axis, showing TGF-β drives MMP-10 via HDAC degradation and MEF2A activation at the promoter.","evidence":"Luciferase reporters, ChIP, siRNA/overexpression, and proteasome inhibition in mammary epithelial cells","pmids":["19935709"],"confidence":"High","gaps":["Cell-type generality of the TGF-β/MEF2A axis not established","Interplay with repressors not addressed"]},{"year":2010,"claim":"Connected angiogenic signaling to MMP-10, showing VEGF induces it through Ets-1/PI3K/MAPK and that MMP-10 is required for endothelial migration and tube/vessel formation.","evidence":"qRT-PCR, siRNA, tube formation and matrigel plug assays with pathway inhibitors and Ets-1 reporter","pmids":["20432469"],"confidence":"Medium","gaps":["Direct MMP-10 substrates driving angiogenesis not identified","Single-lab in vivo confirmation"]},{"year":2011,"claim":"Extended transcriptional regulation with multiple inputs—CHF1/Hey2 E-box repression, β1-integrin/ERK induction in lymphatics, and CRP-driven ERK/JAK1 induction in cardiomyocytes—mapping context-specific control of MMP-10.","evidence":"Reporter assays with E-box mutagenesis, siRNA, zymography and pharmacological pathway inhibition across smooth muscle, lymphatic endothelial, and cardiomyocyte systems","pmids":["22079635","21406228","22142512"],"confidence":"Medium","gaps":["No genetic confirmation for the CRP cardiomyocyte axis","How these inputs are integrated in vivo unresolved"]},{"year":2012,"claim":"Provided the structural and kinetic basis for inhibitor regulation, solving the MMP-10cd·TIMP-1 structure and quantifying TIMP-1/TIMP-2 inhibition relative to MMP-3.","evidence":"X-ray crystallography at 1.9 Å with kinetic inhibition assays and comparative structural analysis","pmids":["22427646"],"confidence":"High","gaps":["No structure of full-length or substrate-bound enzyme","Catalytic domain only, prodomain interactions not captured"]},{"year":2012,"claim":"Identified the myeloid source and protective function of MMP-10 in intestinal inflammation, showing bone marrow-derived MMP-10 limits colitis severity and dysplasia.","evidence":"Mmp10⁻/⁻ mice, DSS colitis, bone marrow transplant and immunohistochemistry","pmids":["23044923"],"confidence":"High","gaps":["Molecular substrate mediating protection not identified","Mechanism of dysplasia suppression unclear"]},{"year":2013,"claim":"Established a cell-autonomous requirement for MMP-10 in macrophage migration and invasion, rescuable by recombinant enzyme.","evidence":"Time-lapse microscopy, RNAi, Mmp10⁻/⁻ macrophages and recombinant MMP-10 rescue across migration/invasion assays","pmids":["23691065"],"confidence":"High","gaps":["Substrate(s) on fibronectin driving migration not defined","Receptor/signaling coupling not mapped"]},{"year":2014,"claim":"Defined MMP-10 as a required effector of tissue repair across muscle and ischemia, linking it to VEGF/Akt, CXCR4/SDF1 signaling, and chemokine (Cxcl1) suppression.","evidence":"Mmp10⁻/⁻ mice, in vivo siRNA, recombinant MMP-10 rescue, and pharmacological CXCR4 antagonism in injury and ischemia models","pmids":["24123596","24548137","25414484"],"confidence":"High","gaps":["Direct substrates underlying VEGF/Akt activation unidentified","Mechanism of transcriptional Cxcl1 suppression unresolved"]},{"year":2015,"claim":"Showed M2 macrophage-derived MMP-10 controls wound collagenolysis indirectly by regulating MMP-8/MMP-13 expression, shaping tissue stiffness.","evidence":"Mmp10⁻/⁻ mice, wound model, macrophage ablation/adoptive transfer, collagen and biomechanical assays","pmids":["25927164"],"confidence":"High","gaps":["Mechanism by which MMP-10 controls collagenase expression not defined","Direct vs indirect proteolysis contributions unseparated"]},{"year":2016,"claim":"Demonstrated MMP-10 moderates macrophage inflammatory polarization in vivo, with the protective effect being macrophage-intrinsic.","evidence":"Mmp10⁻/⁻ mice, P. aeruginosa infection, adoptive BMDM transfer and genome-wide expression analysis; plus AJUBA-driven MMP10 induction in carcinoma","pmids":["27316687","27172796"],"confidence":"High","gaps":["Molecular target through which MMP-10 dampens M1 signaling unknown","Link between catalytic activity and transcriptional resolution unclear"]},{"year":2018,"claim":"Broadened MMP-10's immunomodulatory role to TLR7 tolerance and ischemic neuroprotection, showing it is required for macrophage hypo-responsiveness and can be thrombolytic/barrier-protective.","evidence":"Mmp10⁻/⁻ mice in TLR7 tolerance model; recombinant MMP-10 with antibody neutralization in stroke model and endothelial/neuron cultures","pmids":["30564235","28379489"],"confidence":"Medium","gaps":["Direct substrates in tolerance and neuroprotection not identified","Single-lab studies"]},{"year":2021,"claim":"Resolved a defined biochemical mechanism in bone—MMP-10 processes proMMP-9 in macrophages to enable cartilage resorption during fracture healing.","evidence":"Mmp10⁻/⁻ mice, bone marrow transplant rescue, proMMP-9 processing and gelatinase activity assays in fracture histology","pmids":["34173256"],"confidence":"High","gaps":["Whether proMMP-9 is a direct cleavage substrate of MMP-10 not crystallographically confirmed","Other resorption substrates unexamined"]},{"year":2022,"claim":"Extended TIMP-1 interface understanding and chondrocyte function, engineering MMP-3-selective TIMP-1 variants and showing MMP-10 is required for terminal chondrocyte differentiation/survival.","evidence":"Directed evolution with crystallography of MMP-3/MMP-10 complexes; shRNA knockdown in hypertrophic chondrocytes with marker and apoptosis assays; plus Ski-mediated H3K9me3 repression and miR-148/152 regulation","pmids":["35101440","35818290","32198114","34979166"],"confidence":"Medium","gaps":["Pro-TNF-α cleavage by MMP-10 inferred functionally rather than directly demonstrated","Chondrocyte study limited to single lab"]},{"year":2023,"claim":"Defined a transcription-to-function loop in liver disease, showing PPARγ directly induces MMP-10 which then drives M2 polarization via STAT3 to alleviate steatohepatitis.","evidence":"MMP10-OE/KO mice on HFD, PPARγ ChIP, Kupffer cell transfection and STAT3 pathway analysis","pmids":["37844469"],"confidence":"High","gaps":["Mechanism by which secreted MMP-10 activates STAT3 not defined","Direct vs paracrine action unclear"]},{"year":2025,"claim":"Identified new direct substrates and regulatory and disease links—nephrin cleavage in podocyte injury, endothelial TRIM35/RelB control of MMP-10 secretion driving vascular calcification, and a PAR1-independent neuronal Ca²⁺ pathway.","evidence":"Mmp10⁻/⁻ mice with in vitro nephrin cleavage; conditional endothelial TRIM35 KO with K63-ubiquitination assays; DRG neuron Ca²⁺ imaging (preprint)","pmids":["40328459","39865905"],"confidence":"Medium","gaps":["Neuronal receptor mediating Ca²⁺ mobilization unidentified (preprint, single method)","Whether nephrin is a direct vs cascade-mediated substrate in vivo not fully resolved"]},{"year":null,"claim":"The unifying molecular logic linking MMP-10's diverse catalytic activities (matrix cleavage, protease activation) to its consistent transcriptional/immunomodulatory phenotypes remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No comprehensive substrate degradome","How a secreted protease alters intracellular transcriptional programs (e.g., M1/M2, Cxcl1) mechanistically unexplained","No full-length or substrate-bound structure"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,25,26,32]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,26,32,37]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,26]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,25,30,35]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[1,5,33]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,1,5,33]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,6,17,27]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,14,15,35]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[30,32,34]}],"complexes":[],"partners":["TIMP1","TIMP2","MMP1","MMP9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09238","full_name":"Stromelysin-2","aliases":["Matrix metalloproteinase-10","MMP-10","Transin-2"],"length_aa":476,"mass_kda":54.2,"function":"Can degrade fibronectin, gelatins of type I, III, IV, and V; weakly collagens III, IV, and V. Activates procollagenase","subcellular_location":"Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/P09238/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MMP10","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MMP10","total_profiled":1310},"omim":[{"mim_id":"621334","title":"MICRO RNA 496; MIR496","url":"https://www.omim.org/entry/621334"},{"mim_id":"613004","title":"HUNTINGTIN; HTT","url":"https://www.omim.org/entry/613004"},{"mim_id":"606542","title":"HISTONE DEACETYLASE 7A; HDAC7A","url":"https://www.omim.org/entry/606542"},{"mim_id":"601046","title":"MATRIX METALLOPROTEINASE 12; MMP12","url":"https://www.omim.org/entry/601046"},{"mim_id":"600108","title":"MATRIX METALLOPROTEINASE 13; MMP13","url":"https://www.omim.org/entry/600108"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"endometrium 1","ntpm":249.7}],"url":"https://www.proteinatlas.org/search/MMP10"},"hgnc":{"alias_symbol":[],"prev_symbol":["STMY2"]},"alphafold":{"accession":"P09238","domains":[{"cath_id":"1.10.101.10","chopping":"28-88","consensus_level":"medium","plddt":82.2723,"start":28,"end":88},{"cath_id":"3.40.390.10","chopping":"113-263","consensus_level":"high","plddt":91.4735,"start":113,"end":263},{"cath_id":"2.110.10.10","chopping":"298-470","consensus_level":"high","plddt":91.779,"start":298,"end":470}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09238","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09238-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09238-F1-predicted_aligned_error_v6.png","plddt_mean":86.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MMP10","jax_strain_url":"https://www.jax.org/strain/search?query=MMP10"},"sequence":{"accession":"P09238","fasta_url":"https://rest.uniprot.org/uniprotkb/P09238.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09238/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09238"}},"corpus_meta":[{"pmid":"12379519","id":"PMC_12379519","title":"Invasive 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endothelial cell apoptosis. siRNA silencing of MMP-10 markedly delayed regression, while adenoviral overexpression of MMP-10 accelerated it.\",\n      \"method\": \"siRNA knockdown, adenoviral overexpression, in vitro capillary tube regression assay in 3D collagen matrices, zymography, biochemical MMP activation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function (siRNA and adenoviral OE), in vitro biochemical activation assays, multiple orthogonal readouts in a single rigorous study\",\n      \"pmids\": [\"15870107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Active stromelysin-2 (MMP-10) degrades laminin-5 in vitro, and constitutively active MMP-10 expressed in keratinocytes in vivo disrupts laminin-5 deposition, mislocalizes β1-integrins and phosphorylated focal adhesion kinase at the wound edge, and increases keratinocyte apoptosis, indicating MMP-10 controls keratinocyte migration through regulated matrix degradation.\",\n      \"method\": \"Transgenic mouse model (constitutively active MMP-10 in keratinocytes), in vitro laminin-5 degradation assay, immunohistochemistry, skin wound-healing model\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro enzymatic assay combined with transgenic in vivo model and multiple orthogonal readouts (substrate cleavage, integrin/FAK localization, apoptosis)\",\n      \"pmids\": [\"15371548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of TIMP-1 bound to the MMP-10 catalytic domain solved at 1.9 Å; TIMP-1 inhibits MMP-10cd with Ki = 1.1 × 10⁻⁹ M and TIMP-2 with Ki = 5.8 × 10⁻⁹ M, both ~10-fold weaker than their inhibition of the closely related MMP-3. Structural comparison with MMP-3·TIMP-1 revealed interface differences explaining the differential binding.\",\n      \"method\": \"X-ray crystallography (1.9 Å resolution, molecular replacement), kinetic inhibition assays (multiple approaches), comparative structural analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional kinetic validation using multiple methods in one rigorous study\",\n      \"pmids\": [\"22427646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MMP10 is required for macrophage migration and invasion; RNAi silencing of MMP10 in primary macrophages markedly reduced migration (reversed by exogenous active MMP10 protein), and Mmp10⁻/⁻ bone marrow-derived macrophages showed significantly reduced migration over fibronectin and impaired invasion into Matrigel supplemented with fibronectin.\",\n      \"method\": \"Time-lapse microscopy, RNAi silencing, Mmp10⁻/⁻ knockout macrophages, exogenous recombinant MMP10 rescue, 2D migration and Matrigel invasion assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, RNAi, and rescue with recombinant protein across multiple migration/invasion assays\",\n      \"pmids\": [\"23691065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MMP10 moderates macrophage inflammatory activation: Mmp10⁻/⁻ mice showed ~3-fold more macrophages in infected lungs, elevated M1 markers and reduced M2 markers; global gene expression showed infection-induced transcriptional changes persisted in Mmp10⁻/⁻ macrophages. Adoptive transfer of wild-type BMDMs normalized morbidity in Mmp10⁻/⁻ recipients, demonstrating the protective effect is macrophage-derived MMP10.\",\n      \"method\": \"Mmp10⁻/⁻ knockout mice, Pseudomonas aeruginosa infection model, adoptive transfer of BMDMs, genome-wide gene expression analysis, flow cytometry for macrophage markers\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with adoptive transfer rescue, genome-wide transcriptomic analysis, and cell-type–specific phenotype demonstration\",\n      \"pmids\": [\"27316687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MMP-10 from alternatively activated (M2) resident macrophages regulates collagenolytic activity in wounds by controlling expression of metallocollagenases MMP-8 and MMP-13 (particularly MMP-13); Mmp10⁻/⁻ wounds showed increased collagen deposition, skin stiffness, and reduced collagenolytic activity. Ablation and adoptive transfer experiments confirmed the effect is macrophage-derived.\",\n      \"method\": \"Mmp10⁻/⁻ knockout mice, wound healing model, macrophage ablation and adoptive transfer, collagen assays, biomechanical testing, cell-based models\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, adoptive transfer rescue, multiple orthogonal quantitative readouts\",\n      \"pmids\": [\"25927164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of MMP10 exacerbates DSS-induced colitis and impairs resolution of inflammation; MMP10 is produced predominantly by infiltrating myeloid cells in murine and human colitis, and bone marrow transplant experiments confirmed that bone marrow-derived MMP10 contributes to disease severity. Mmp10⁻/⁻ mice had higher propensity for dysplasia after repeated DSS exposure.\",\n      \"method\": \"Mmp10⁻/⁻ knockout mice, DSS colitis model, bone marrow transplantation, immunohistochemistry, histological scoring\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with bone marrow transplant rescue, defining cellular source and functional consequence\",\n      \"pmids\": [\"23044923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TGF-β transcriptionally induces MMP-10 in mammary epithelial cells through MEF2A: TGF-β promotes proteasome-dependent degradation of class IIa HDACs, leading to increased acetylation of MEF2A and core histones around the MEF2 site of the MMP-10 promoter, driving transactivation. Knockdown of MEF2A reduced MMP-10 induction; knockdown of class IIa HDACs increased it.\",\n      \"method\": \"Reporter gene (luciferase) assays, siRNA knockdown, overexpression experiments, chromatin immunoprecipitation (ChIP), real-time PCR, proteasome inhibitor experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP, reporter assays, and siRNA/OE with multiple orthogonal methods in one study\",\n      \"pmids\": [\"19935709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Zinc finger protein ZNF267 is a negative transcriptional repressor of MMP-10: ZNF267 is constitutively nuclear, its KRAB-A domain mediates repressor activity, it binds the MMP-10 promoter region (demonstrated by ChIP), and its overexpression reduces MMP-10 reporter activity in hepatic stellate cells.\",\n      \"method\": \"Microarray, RNase protection assay, reporter gene assay, chromatin immunoprecipitation (ChIP), GAL4 fusion constructs, fluorescent protein localization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays in single lab, two orthogonal methods\",\n      \"pmids\": [\"16054593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MMP-10 transcription in endothelial cells is induced by VEGF in a time- and dose-dependent manner; MMP-10 expression is mediated by the Ets-1 transcription factor but not ERP/NET/ELK3, and via PI3K and MAPK signaling pathways. MMP-10 siRNA inhibited VEGF-induced endothelial cell migration and tube formation in vitro, and vessel formation in matrigel plugs in vivo.\",\n      \"method\": \"Quantitative RT-PCR, siRNA knockdown, migration and tube formation assays, in vivo matrigel plug assay, pharmacological inhibitors of PI3K and MAPK, luciferase reporter for Ets-1\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA functional assay with in vitro and in vivo readouts, signaling pathway mapping; single lab\",\n      \"pmids\": [\"20432469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"C-reactive protein (CRP) promotes MMP-10 expression and activity in cardiomyocytes via c-Raf/MEK/ERK and JAK1/ERK signaling pathways, with DNA binding sites for AP-1 and STAT3 in the nucleus mediating the effect; blocking ERK1/2 (U0126) or JAK1 (piceatannol) significantly decreased CRP-induced MMP-10 expression.\",\n      \"method\": \"Real-time PCR, Western blot, casein zymography, pharmacological pathway inhibitors, phospho-specific antibodies, cell culture\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibitor experiments and zymography in cardiomyocytes, multiple readouts but no genetic confirmation; single lab\",\n      \"pmids\": [\"22142512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"β1 integrin signaling via the ERK/MAPK pathway upregulates MMP-10 mRNA and protein expression in human lymphatic endothelial cells, and MMP-10 is required for collagen I-induced lymphatic tubulogenesis; knockdown of MMP-10 impaired tubulogenesis.\",\n      \"method\": \"Protein-based screening, siRNA knockdown, ERK/MAPK pathway analysis, lymphatic endothelial cell tubulogenesis assay\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with functional tubulogenesis readout, pathway analysis; single lab\",\n      \"pmids\": [\"21406228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MMP-10 deficiency impairs skeletal muscle regeneration after injury: Mmp10⁻/⁻ muscles displayed reduced endothelial cell recruitment, diminished extracellular matrix proteins, decreased collagen deposition, decreased fiber size, and delayed regeneration. MMP-10 mRNA silencing in vivo reduced muscle regeneration, while recombinant MMP-10 accelerated repair. MMP-10-mediated muscle repair was associated with VEGF/Akt signaling.\",\n      \"method\": \"Mmp10⁻/⁻ knockout mice, notexin injury model, mdx muscular dystrophy model, siRNA in vivo silencing, recombinant MMP-10 treatment, immunohistochemistry, Western blot\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, siRNA, and recombinant protein rescue across multiple disease models with mechanistic pathway link\",\n      \"pmids\": [\"24123596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CXCR4/SDF1-regulated muscle repair is dependent on MMP-10 activity: siRNA silencing of SDF1 or CXCR4 in injured muscles impaired regeneration, and MMP-10 was identified as the downstream effector of this axis. SDF1 ligand addition accelerated repair, and CXCR4 antagonism (AMD3100) delayed it, linking the CXCR4/SDF1 pathway to MMP-10-dependent matrix remodeling in muscle repair.\",\n      \"method\": \"In vivo siRNA silencing of SDF1, CXCR4, pharmacological CXCR4 antagonism (AMD3100), notexin injury model, functional and histological analysis\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo siRNA and pharmacological epistasis; single lab with two methods\",\n      \"pmids\": [\"24548137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MMP-10 functions are required for efficient tissue repair after hind limb ischemia; Mmp10⁻/⁻ mice showed delayed reperfusion, increased necrosis, and excessive neutrophil/macrophage infiltration. MMP-10 deficiency led to higher Cxcl1 mRNA and protein levels, revealing a transcriptional inhibitory role for MMP-10 on Cxcl1. Injection of MMP-10 into Mmp10⁻/⁻ mice rescued the phenotype.\",\n      \"method\": \"Mmp10⁻/⁻ knockout mice, femoral artery excision ischemia model, small animal PET, immunohistochemistry, siRNA knockdown of MMP-10 in vivo, recombinant MMP-10 rescue\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, siRNA in vivo, and recombinant protein rescue with mechanistic chemokine regulation identified\",\n      \"pmids\": [\"25414484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During secondary fracture healing, MMP-10 is expressed by hematopoietic cells and is required for cartilage resorption; Mmp10⁻/⁻ mice showed delayed cartilage resorption and TRAP-positive cell accumulation at 14 days post-fracture. The phenotype was rescued by wild-type bone marrow transplant. MMP-10 functions in macrophages to promote proMMP-9 processing and gelatinase activity required for endochondral ossification.\",\n      \"method\": \"Mmp10⁻/⁻ knockout mice, fracture healing model, bone marrow transplantation rescue, proMMP-9 processing assay, TRAP staining, immunohistochemistry\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with bone marrow transplant rescue and in vitro proMMP-9 processing mechanistic data\",\n      \"pmids\": [\"34173256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MMP10 functions as a thrombolytic and neuroprotective agent in ischemic stroke; recombinant MMP10 reduced infarct size in a thrombin-induced middle cerebral artery occlusion model, and in vitro MMP10 reduced tPA-promoted endothelial ionic permeability, preserved claudin-5, decreased ERK1/2 activation, prevented tPA-mediated neuronal excitotoxicity and calcium influx. These effects were blocked by an anti-MMP10 monoclonal antibody.\",\n      \"method\": \"In vivo murine ischemic stroke model, brain endothelial cell and neuron cultures, Western blot for claudin-5, ERK1/2 phosphorylation, calcium imaging, anti-MMP10 antibody neutralization\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo rescue with recombinant protein, in vitro mechanistic cell assays, antibody neutralization; single lab\",\n      \"pmids\": [\"28379489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MMP10 moderates TLR7-induced immune tolerance in skin macrophages: Mmp10⁻/⁻ mice failed to develop hypo-responsiveness to repeated TLR7 (imiquimod) stimulation, with failure to upregulate negative TLR regulators (TNFAIP3, IRAK3) and immunosuppressive cytokines (IL-10, TGFβ1). In vitro, prior IMQ exposure made wild-type BMDMs refractory to re-stimulation but not Mmp10⁻/⁻ macrophages.\",\n      \"method\": \"Mmp10⁻/⁻ knockout mice, in vivo TLR7 tolerance model, BMDM cultures, cytokine/gene expression analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo and in vitro parallel experiments; single lab\",\n      \"pmids\": [\"30564235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Recombinant MMP-10 induces osteogenic, fibrotic, and inflammatory markers in aortic valve interstitial cells (interleukin-1β, α-SMA, vimentin, collagen, BMP-4, Sox9, osteopontin, BMP-9, and Smad 1/5/8) and promotes cell mineralization via Akt phosphorylation; these effects were prevented by TIMP-1 or an anti-MMP-10 antibody. MMP-10 co-localizes with calcification markers (Runx2, SOX9) in stenotic aortic valves.\",\n      \"method\": \"In vitro treatment of primary human aortic valve interstitial cells with recombinant MMP-10, TIMP-1 inhibition, anti-MMP-10 antibody neutralization, Akt phosphorylation assay, calcification (mineralization) assay, immunohistochemistry\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein gain-of-function with antibody and TIMP-1 inhibition as controls; single lab, primary human cells\",\n      \"pmids\": [\"32188274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MMP10 facilitates clearance of long multiwalled carbon nanotubes (MWCNTs) from lung and moderates macrophage inflammatory activation and survival; Mmp10⁻/⁻ mice showed impaired pulmonary clearance of MWCNTs and reduced macrophage survival, with enhanced caspase-3-dependent cell death and elevated IL-6 and IL-1β in Mmp10⁻/⁻ macrophages.\",\n      \"method\": \"Mmp10⁻/⁻ knockout mice, oropharyngeal aspiration of MWCNTs, alveolar macrophage and BMDM cultures, caspase-3 assay, cytokine analysis, gene expression\",\n      \"journal\": \"International journal of nanomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo and in vitro parallel experiments; single lab\",\n      \"pmids\": [\"28223796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Directed evolution of yeast-displayed TIMP-1 yielded variants highly selective for MMP-3 over MMP-10. Protein crystal structures and models of MMP-3-selective TIMP-1 variants bound to MMP-3 and counter-target MMP-10 showed that structural alterations in N- and C-terminal TIMP-1 domains create favorable interactions with MMP-3 and disrupt unique interactions with MMP-10, defining the binding interface determinants of stromelysin selectivity.\",\n      \"method\": \"Directed evolution (yeast display, counter-selective screening), X-ray crystallography of protein complexes, structural modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures and directed evolution with selectivity validation, multiple orthogonal approaches\",\n      \"pmids\": [\"35101440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CHF1/Hey2 is a direct transcriptional repressor of MMP10: loss or knockdown of CHF1/Hey2 in vascular smooth muscle cells increases MMP10 expression and activity. A 2.5 kb MMP10 promoter region contains 12 E-boxes mediating constitutive activity and CHF1/Hey2 repression; mutation of these E-boxes abolished repression and unmasked an activator function for CHF1/Hey2.\",\n      \"method\": \"Luciferase reporter assays, siRNA knockdown of CHF1/Hey2, E-box mutagenesis, gene expression analysis in smooth muscle cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assay with mutagenesis and KD; single lab, two complementary methods\",\n      \"pmids\": [\"22079635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AJUBA promotes migration and invasion of esophageal squamous cell carcinoma cells by upregulating MMP10 and MMP13 expression through activation of the ERK1/2 signaling pathway; AJUBA knockdown reduced migration/invasion and decreased MMP10/MMP13 levels, while AJUBA overexpression had the opposite effect, both in vitro and in vivo.\",\n      \"method\": \"RNA sequencing, siRNA knockdown and overexpression of AJUBA, Western blot, migration and invasion assays, in vivo xenograft models, ERK1/2 pathway analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA-seq target identification plus KD/OE functional assays, ERK1/2 pathway link; single lab\",\n      \"pmids\": [\"27172796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"YY1 suppresses PDAC invasion and metastasis by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism: YY1 expression negatively correlated with MMP10 levels; YY1 overexpression suppressed invasion/metastasis and reduced MMP10, while YY1 knockdown enhanced them. Luciferase assays and pathway blockage experiments placed MMP10 downstream of YY1/MUC4/ErbB2/p38/MEF2C.\",\n      \"method\": \"Digital gene expression sequencing, siRNA knockdown, overexpression, luciferase reporter assays, signaling pathway inhibitors, in vivo xenograft and tail vein metastasis models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assays and pathway inhibitors with in vivo models; pathway is defined but mechanism is partially indirect; single lab\",\n      \"pmids\": [\"24884523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-6 regulates MMP-10 expression via the JAK2/STAT3 pathway in lung adenocarcinoma cells: IL-6 moderately reduced MMP-10 mRNA but significantly enhanced MMP-10 protein. The JAK2 inhibitor AG490 blocked both IL-6-induced STAT3 upregulation and the bidirectional IL-6 effects on MMP-10 mRNA and protein levels.\",\n      \"method\": \"Real-time RT-PCR, Western blot, pharmacological JAK2 inhibition (AG490), A549 cell culture\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibitor only, single cell line, single lab\",\n      \"pmids\": [\"20032397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Recombinant murine stromelysin-2 (MMP-10) produced in COS cells is secreted as a proenzyme that undergoes autocatalytic processing upon addition of the organomercurial salt APMA, establishing that MMP-10 is an autocatalytically activatable metalloproteinase.\",\n      \"method\": \"COS cell expression of recombinant protein, organomercurial (APMA)-induced autocatalytic processing assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct biochemical demonstration of proenzyme activation, single study, single method\",\n      \"pmids\": [\"9427548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MMP10 is required for proMMP-9 processing in macrophages during bone fracture healing; Mmp10⁻/⁻ macrophages showed reduced gelatinase activity and lack of proMMP-9 processing, contributing to impaired cartilage resorption and delayed vascular invasion during endochondral ossification.\",\n      \"method\": \"Mmp10⁻/⁻ knockout mice, wild-type bone marrow transplant rescue, proMMP-9 processing assay, gelatinase activity assay, fracture healing histology\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with bone marrow transplant and direct biochemical proMMP-9 processing assay\",\n      \"pmids\": [\"34173256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MMP10 alleviates non-alcoholic steatohepatitis by promoting M2 macrophage polarization via STAT3 signaling: PPARγ binds the MMP10 promoter and upregulates MMP10 expression upon IL-4 stimulation. MMP10 overexpression activated downstream STAT3 signaling to induce M2 polarization, reducing pro-inflammatory IL-1β and TNF-α and increasing IL-10. MMP10-KO mice showed worse NASH phenotype on HFD.\",\n      \"method\": \"MMP10-OE and MMP10-KO mice on HFD, PPARγ-OE, ChIP (PPARγ binding to MMP10 promoter), Kupffer cell transfection, IL-4 stimulation, STAT3 pathway analysis, HFD NASH model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct promoter binding, genetic KO and OE in vivo with signaling pathway elucidation; multiple methods\",\n      \"pmids\": [\"37844469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MMP-10 knockdown in hypertrophic chondrocytes decreases expression of Col II, Col X, Runx2, and MMP-13, and significantly increases chondrocyte apoptosis, indicating MMP-10 is required for terminal chondrocyte differentiation and survival during endochondral osteogenesis.\",\n      \"method\": \"MMP-10 shRNA knockdown in ATDC5 hypertrophic chondrocytes, flow cytometry (apoptosis), RT-PCR, Western blot, in vivo rat/human KBD cartilage analysis\",\n      \"journal\": \"Cartilage\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — shRNA KD with multiple marker readouts and apoptosis assay; single lab\",\n      \"pmids\": [\"35818290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MMP10 induces Ca²⁺ mobilization in dorsal root ganglion (DRG) neurons through a PAR1-independent mechanism (in contrast to MMP3, MMP8, and MMP9 which act via PAR1), establishing a distinct neuronal signaling pathway for MMP10.\",\n      \"method\": \"Intracellular Ca²⁺ imaging in DRG neurons, PAR1 pharmacological blockade, comparison with other MMPs\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint, single method (Ca²⁺ imaging), mechanism not fully resolved beyond PAR1 independence\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Endothelial TRIM35 inhibits MMP10 expression and secretion by promoting K63-linked ubiquitination of RelB, maintaining its nuclear localization to inhibit MMP10 transcription through the non-canonical NF-κB signaling pathway; conditional endothelial TRIM35 knockout leads to increased MMP10 secretion, which drives smooth muscle cell calcification in vascular grafts.\",\n      \"method\": \"Conditional endothelial TRIM35 KO mice, arterial isograft model, single-cell analysis, co-culture experiments, ubiquitination assays (K63-linked), RelB localization studies, in situ MMP10 targeting\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic conditional KO with mechanistic ubiquitination assays and in vivo rescue; single lab\",\n      \"pmids\": [\"39865905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NOX5-generated ROS upregulates MMP-10 expression in endothelial cells via the redox-sensitive JNK/AP-1 signaling pathway, promoting endothelial cell migration; NOX5 and MMP-10 silencing prevented this pro-migratory effect, and effects were enhanced by angiotensin II.\",\n      \"method\": \"NOX5 overexpression and siRNA silencing in human endothelial cells, MMP-10 siRNA, wound healing assay, JNK/AP-1 pathway inhibition, MMP-10 promoter activity assay, in vivo NOX5-expressing mouse hearts\",\n      \"journal\": \"Antioxidants\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain- and loss-of-function with pathway inhibitors and in vivo confirmation; single lab\",\n      \"pmids\": [\"39456453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Active MMP-10 cleaves nephrin in vitro, contributing to podocyte injury; in vivo, MMP-10 knockout mice showed less albuminuria and reduced pro-inflammatory/pro-fibrotic gene expression in anti-GBM nephritis, and MMP-10 overexpression in podocytes upregulated inflammatory responses to TNF-α while MMP-10 knockdown mitigated inflammation.\",\n      \"method\": \"Mmp10⁻/⁻ knockout mice, anti-GBM nephritis model, GC-A/MMP-10 double KO mice, in vitro nephrin cleavage assay, podocyte MMP-10 OE and KD, co-culture of podocytes with endothelial cells, Western blot\",\n      \"journal\": \"Nephrology, dialysis, transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo with in vitro substrate cleavage assay; single lab, multiple complementary approaches\",\n      \"pmids\": [\"40328459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SOX9 directly transcriptionally activates MMP10 expression (identified by ChIP-seq), and MMP10 promotes ECM degradation downstream of SOX9 in tracheal fibroblasts via the Wnt/β-catenin signaling pathway; SOX9 overexpression increased and SOX9 siRNA decreased MMP10 expression, fibroblast activation, and ECM deposition.\",\n      \"method\": \"RNA-seq, ChIP-seq, adenoviral SOX9 overexpression, siRNA knockdown, Wnt/β-catenin pathway analysis, in vivo tracheal fibrosis model, MMP10 expression quantification\",\n      \"journal\": \"Genes & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq demonstrates direct SOX9-MMP10 promoter interaction; complemented by OE/KD and in vivo model; single lab\",\n      \"pmids\": [\"38993791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A missense variant p.L245P in MMP10 (identified in families with premature myocardial infarction) alters the MMP10-TIMP1 binding interface, reduces total free binding energy, and minimizes the substrate-binding cleft volume (molecular dynamics simulations). In macrophages transfected with the variant, cells were more adherent, less migratory, and secreted higher levels of pro-inflammatory CXCL1 and CXCL8 compared to wild-type MMP10.\",\n      \"method\": \"Whole-exome sequencing (variant identification), molecular dynamics simulations, macrophage transfection with WT and p.L245P cDNA, adhesion assay, migration assay, ELISA for chemokines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — computational structural analysis combined with cell-based functional assays; single lab, single variant\",\n      \"pmids\": [\"38806571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SL-2 (MMP-10) in developing human bone is produced in an active form (confirmed by in situ zymography) at sites of resorption in endochondral ossification, the chondro-osseous junction (chondrocytes), and in osteoclasts and mononuclear marrow cells, with associated matrix degradation activity. This differs from SL-1 (MMP-3), which is present predominantly as a latent matrix-bound proenzyme.\",\n      \"method\": \"Immunohistochemistry, in situ zymography on human osteophytic and neonatal rib bone sections\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in situ zymography directly demonstrates active enzyme in tissue; two complementary histological methods; single study\",\n      \"pmids\": [\"9662124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ski associates with the pericentromeric region and promoters of Mmp10 (along with Mmp3 and Mmp13) on chromosome 9 during mitosis, promotes H3K9 tri-methylation at these loci, and is required for transcriptional repression of these genes during M/G1 transition; Ski⁻/⁻ MEFs show increased Mmp activity and derepressed Mmp10 expression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of Ski at Mmp10 promoter, H3K9 methylation/acetylation assays, Ski⁻/⁻ MEFs, differential gene expression assays, MMP activity assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct chromatin association with functional histone modification; genetic KO validation; single lab\",\n      \"pmids\": [\"32198114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-148/152 family members negatively regulate MMP10; deficiency of any member increases MMP10 (and MMP13) expression, disrupts intestinal barrier, and activates NF-κB signaling in part through MMP10-mediated cleavage of pro-TNF-α into bioactive fragments. Blocking NF-κB exerted a restorative effect only in knockout mice.\",\n      \"method\": \"Individual and full-family miR-148/152 KO mice, colitis/CAC models (DSS/AOM), MMP10 expression analysis, intestinal barrier assays, NF-κB pathway analysis, NF-κB blockade experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic KO models with pathway rescue experiments; MMP10's specific substrate cleavage of pro-TNF-α is inferred from functional data; single lab\",\n      \"pmids\": [\"34979166\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMP-10 (stromelysin-2) is a secreted zinc-dependent endopeptidase whose catalytic domain structure has been solved in complex with TIMP-1 (1.9 Å); it degrades extracellular matrix substrates including laminin-5, fibronectin, and collagen components, activates pro-MMP-1 and pro-MMP-9, and is regulated by TIMP-1/TIMP-2 inhibition. Its transcription is controlled by multiple pathways (TGF-β/MEF2A/HDAC, VEGF/Ets-1/PI3K/MAPK, CRP/ERK/JAK1, NOX5/JNK/AP-1, CHF1/Hey2 repression, ZNF267 repression, Ski-mediated H3K9me3, miR-148/152 and miR-944) and it performs cell-type-specific functions: in macrophages it moderates M1 activation, promotes M2 polarization and collagenolytic activity via MMP-13, facilitates macrophage migration, promotes proMMP-9 processing required for cartilage resorption, and mediates TLR7 immune tolerance; in endothelial cells it drives capillary tube regression and angiogenesis/lymphangiogenesis; in keratinocytes it regulates migration through laminin-5 degradation and integrin/FAK signaling; in muscle it supports regeneration via VEGF/Akt and CXCR4/SDF1 signaling; and in neurons it triggers Ca²⁺ mobilization through a PAR1-independent mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MMP-10 (stromelysin-2) is a secreted, autocatalytically activatable zinc-dependent metalloproteinase that remodels the extracellular matrix and orchestrates downstream protease cascades during tissue repair, inflammation, and angiogenesis [#0, #25]. As a proteolytic hub it both activates other matrix proteases\\u2014processing pro-MMP-1 to drive collagenolysis and capillary tube regression in endothelial cells [#0] and processing proMMP-9 in macrophages to enable cartilage resorption during endochondral ossification [#15, #26]\\u2014and directly cleaves matrix and signaling substrates including laminin-5 in keratinocytes (controlling migration through \\u03b21-integrin/FAK signaling) [#1] and nephrin in podocytes [#32]. Its catalytic domain is inhibited by TIMP-1 and TIMP-2, with the MMP-10\\u00b7TIMP-1 interface defined crystallographically [#2, #20]. A central biological role is in myeloid cells, where MMP-10 promotes macrophage migration and invasion over fibronectin [#3], moderates inflammatory (M1) activation and favors M2 polarization via STAT3 [#4, #27], controls collagenolytic activity through MMP-8/MMP-13 expression [#5], mediates TLR7 immune tolerance [#17], and is required for efficient repair after lung infection, colitis, hindlimb ischemia, muscle injury, and bone fracture [#4, #6, #12, #14, #15]. MMP-10 transcription is integrated by numerous inputs, being induced by TGF-\\u03b2/MEF2A [#7], VEGF/Ets-1 [#9], and SOX9/Wnt-\\u03b2-catenin [#33] and repressed by ZNF267, CHF1/Hey2, Ski-mediated H3K9 trimethylation, and the TRIM35/RelB non-canonical NF-\\u03baB axis [#8, #21, #36, #30]. A missense variant (p.L245P) identified in families with premature myocardial infarction alters the MMP-10\\u2013TIMP-1 interface and renders macrophages less migratory and more pro-inflammatory, linking MMP-10 to cardiovascular disease [#34].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the basic enzymatic nature of MMP-10\\u2014whether it behaves as a regulated zymogen\\u2014by showing the recombinant proenzyme undergoes autocatalytic processing.\",\n      \"evidence\": \"COS-cell expression of recombinant murine stromelysin-2 with APMA-induced autocatalytic activation\",\n      \"pmids\": [\"9427548\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological activator(s) in vivo not defined\", \"Substrate repertoire of the activated enzyme not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated that MMP-10 exists as an active enzyme in tissue at sites of bone resorption, distinguishing it from the latent, matrix-bound behavior of MMP-3.\",\n      \"evidence\": \"Immunohistochemistry and in situ zymography on human and neonatal bone sections\",\n      \"pmids\": [\"9662124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular activation mechanism in tissue not resolved\", \"Direct substrates at resorption sites not identified\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined a direct matrix substrate (laminin-5) and a cell-biological consequence, showing MMP-10 controls keratinocyte migration via regulated matrix degradation and integrin/FAK signaling.\",\n      \"evidence\": \"In vitro laminin-5 cleavage plus transgenic keratinocyte-targeted active MMP-10 mouse with wound-healing readouts\",\n      \"pmids\": [\"15371548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site mapping not detailed\", \"Whether endogenous MMP-10 levels reproduce overexpression phenotype unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed MMP-10 in a protease activation cascade by showing it activates pro-MMP-1 to drive endothelial capillary tube regression, establishing MMP-10 as an upstream amplifier of collagenolysis.\",\n      \"evidence\": \"siRNA knockdown, adenoviral overexpression, biochemical activation assays in 3D collagen tube-regression model\",\n      \"pmids\": [\"15870107\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the cascade beyond the 3D model not tested\", \"Endogenous serine protease activators of pro-MMP-10 in vivo not confirmed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Began mapping transcriptional control by identifying ZNF267 as a KRAB-domain repressor binding the MMP-10 promoter.\",\n      \"evidence\": \"Reporter assays, ChIP, and GAL4 fusions in hepatic stellate cells\",\n      \"pmids\": [\"16054593\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts of ZNF267 repression unknown\", \"Single-cell-type analysis only\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified an inducible transcriptional axis, showing TGF-\\u03b2 drives MMP-10 via HDAC degradation and MEF2A activation at the promoter.\",\n      \"evidence\": \"Luciferase reporters, ChIP, siRNA/overexpression, and proteasome inhibition in mammary epithelial cells\",\n      \"pmids\": [\"19935709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type generality of the TGF-\\u03b2/MEF2A axis not established\", \"Interplay with repressors not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected angiogenic signaling to MMP-10, showing VEGF induces it through Ets-1/PI3K/MAPK and that MMP-10 is required for endothelial migration and tube/vessel formation.\",\n      \"evidence\": \"qRT-PCR, siRNA, tube formation and matrigel plug assays with pathway inhibitors and Ets-1 reporter\",\n      \"pmids\": [\"20432469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MMP-10 substrates driving angiogenesis not identified\", \"Single-lab in vivo confirmation\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended transcriptional regulation with multiple inputs\\u2014CHF1/Hey2 E-box repression, \\u03b21-integrin/ERK induction in lymphatics, and CRP-driven ERK/JAK1 induction in cardiomyocytes\\u2014mapping context-specific control of MMP-10.\",\n      \"evidence\": \"Reporter assays with E-box mutagenesis, siRNA, zymography and pharmacological pathway inhibition across smooth muscle, lymphatic endothelial, and cardiomyocyte systems\",\n      \"pmids\": [\"22079635\", \"21406228\", \"22142512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genetic confirmation for the CRP cardiomyocyte axis\", \"How these inputs are integrated in vivo unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the structural and kinetic basis for inhibitor regulation, solving the MMP-10cd\\u00b7TIMP-1 structure and quantifying TIMP-1/TIMP-2 inhibition relative to MMP-3.\",\n      \"evidence\": \"X-ray crystallography at 1.9 \\u00c5 with kinetic inhibition assays and comparative structural analysis\",\n      \"pmids\": [\"22427646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of full-length or substrate-bound enzyme\", \"Catalytic domain only, prodomain interactions not captured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the myeloid source and protective function of MMP-10 in intestinal inflammation, showing bone marrow-derived MMP-10 limits colitis severity and dysplasia.\",\n      \"evidence\": \"Mmp10\\u207b/\\u207b mice, DSS colitis, bone marrow transplant and immunohistochemistry\",\n      \"pmids\": [\"23044923\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate mediating protection not identified\", \"Mechanism of dysplasia suppression unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established a cell-autonomous requirement for MMP-10 in macrophage migration and invasion, rescuable by recombinant enzyme.\",\n      \"evidence\": \"Time-lapse microscopy, RNAi, Mmp10\\u207b/\\u207b macrophages and recombinant MMP-10 rescue across migration/invasion assays\",\n      \"pmids\": [\"23691065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate(s) on fibronectin driving migration not defined\", \"Receptor/signaling coupling not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined MMP-10 as a required effector of tissue repair across muscle and ischemia, linking it to VEGF/Akt, CXCR4/SDF1 signaling, and chemokine (Cxcl1) suppression.\",\n      \"evidence\": \"Mmp10\\u207b/\\u207b mice, in vivo siRNA, recombinant MMP-10 rescue, and pharmacological CXCR4 antagonism in injury and ischemia models\",\n      \"pmids\": [\"24123596\", \"24548137\", \"25414484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates underlying VEGF/Akt activation unidentified\", \"Mechanism of transcriptional Cxcl1 suppression unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed M2 macrophage-derived MMP-10 controls wound collagenolysis indirectly by regulating MMP-8/MMP-13 expression, shaping tissue stiffness.\",\n      \"evidence\": \"Mmp10\\u207b/\\u207b mice, wound model, macrophage ablation/adoptive transfer, collagen and biomechanical assays\",\n      \"pmids\": [\"25927164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MMP-10 controls collagenase expression not defined\", \"Direct vs indirect proteolysis contributions unseparated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated MMP-10 moderates macrophage inflammatory polarization in vivo, with the protective effect being macrophage-intrinsic.\",\n      \"evidence\": \"Mmp10\\u207b/\\u207b mice, P. aeruginosa infection, adoptive BMDM transfer and genome-wide expression analysis; plus AJUBA-driven MMP10 induction in carcinoma\",\n      \"pmids\": [\"27316687\", \"27172796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target through which MMP-10 dampens M1 signaling unknown\", \"Link between catalytic activity and transcriptional resolution unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Broadened MMP-10's immunomodulatory role to TLR7 tolerance and ischemic neuroprotection, showing it is required for macrophage hypo-responsiveness and can be thrombolytic/barrier-protective.\",\n      \"evidence\": \"Mmp10\\u207b/\\u207b mice in TLR7 tolerance model; recombinant MMP-10 with antibody neutralization in stroke model and endothelial/neuron cultures\",\n      \"pmids\": [\"30564235\", \"28379489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrates in tolerance and neuroprotection not identified\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved a defined biochemical mechanism in bone\\u2014MMP-10 processes proMMP-9 in macrophages to enable cartilage resorption during fracture healing.\",\n      \"evidence\": \"Mmp10\\u207b/\\u207b mice, bone marrow transplant rescue, proMMP-9 processing and gelatinase activity assays in fracture histology\",\n      \"pmids\": [\"34173256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether proMMP-9 is a direct cleavage substrate of MMP-10 not crystallographically confirmed\", \"Other resorption substrates unexamined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended TIMP-1 interface understanding and chondrocyte function, engineering MMP-3-selective TIMP-1 variants and showing MMP-10 is required for terminal chondrocyte differentiation/survival.\",\n      \"evidence\": \"Directed evolution with crystallography of MMP-3/MMP-10 complexes; shRNA knockdown in hypertrophic chondrocytes with marker and apoptosis assays; plus Ski-mediated H3K9me3 repression and miR-148/152 regulation\",\n      \"pmids\": [\"35101440\", \"35818290\", \"32198114\", \"34979166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pro-TNF-\\u03b1 cleavage by MMP-10 inferred functionally rather than directly demonstrated\", \"Chondrocyte study limited to single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a transcription-to-function loop in liver disease, showing PPAR\\u03b3 directly induces MMP-10 which then drives M2 polarization via STAT3 to alleviate steatohepatitis.\",\n      \"evidence\": \"MMP10-OE/KO mice on HFD, PPAR\\u03b3 ChIP, Kupffer cell transfection and STAT3 pathway analysis\",\n      \"pmids\": [\"37844469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which secreted MMP-10 activates STAT3 not defined\", \"Direct vs paracrine action unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified new direct substrates and regulatory and disease links\\u2014nephrin cleavage in podocyte injury, endothelial TRIM35/RelB control of MMP-10 secretion driving vascular calcification, and a PAR1-independent neuronal Ca\\u00b2\\u207a pathway.\",\n      \"evidence\": \"Mmp10\\u207b/\\u207b mice with in vitro nephrin cleavage; conditional endothelial TRIM35 KO with K63-ubiquitination assays; DRG neuron Ca\\u00b2\\u207a imaging (preprint)\",\n      \"pmids\": [\"40328459\", \"39865905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuronal receptor mediating Ca\\u00b2\\u207a mobilization unidentified (preprint, single method)\", \"Whether nephrin is a direct vs cascade-mediated substrate in vivo not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying molecular logic linking MMP-10's diverse catalytic activities (matrix cleavage, protease activation) to its consistent transcriptional/immunomodulatory phenotypes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No comprehensive substrate degradome\", \"How a secreted protease alters intracellular transcriptional programs (e.g., M1/M2, Cxcl1) mechanistically unexplained\", \"No full-length or substrate-bound structure\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 25, 26, 32]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 26, 32, 37]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 25, 30, 35]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [1, 5, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 1, 5, 33]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 6, 17, 27]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 14, 15, 35]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [30, 32, 34]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TIMP1\", \"TIMP2\", \"MMP1\", \"MMP9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}