{"gene":"THBS2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1991,"finding":"THBS2 (TSP2) is the product of a separate gene (Thbs2) distinct from THBS1, expressed in a variety of mouse tissues in a pattern that differs from TSP1, establishing that two functionally distinct thrombospondin proteins exist in the same organism.","method":"cDNA cloning, sequence analysis, tissue expression profiling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular cloning and sequence characterization, single lab but foundational identification paper","pmids":["1712771"],"is_preprint":false},{"year":1997,"finding":"The human THBS2 promoter contains binding sites for p53, NF-κB, Sp1, Myc-CF1, NF-Y, AP1, and GATA; tissue-specific differences in transcription start site selection contribute to differential THBS2 expression across tissues.","method":"Genomic sequencing, 5' RACE, PCR-based transcription start site mapping","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct experimental mapping of transcription start sites, single lab, two orthogonal methods","pmids":["9249061"],"is_preprint":false},{"year":2002,"finding":"In double-TSP1/TSP2-null mice, the wound-healing defect (delayed healing, impaired macrophage recruitment, reduced MCP-1, and non-excessive vascularization) phenocopies TSP1-null mice rather than TSP2-null mice, demonstrating that TSP1 dominates over TSP2 in dictating the wound-healing response and that the two proteins have distinct temporal and spatial roles.","method":"Genetic epistasis using double-knockout mouse model, immunohistochemistry, cytokine measurement","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal single and double KO comparison with multiple phenotypic readouts, replicated across wound-healing metrics","pmids":["12213711"],"is_preprint":false},{"year":2003,"finding":"Overexpression of TSP2 in the SW480 colon carcinoma cell line downregulates MMP2 and MMP9 expression and protein production, while upregulating MMP12 and MMP17, establishing TSP2 as a modulator of MMP expression.","method":"cDNA array and Western blot following stable TSP2 overexpression in SW480 cells","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function overexpression with transcriptomic and protein-level readouts, single lab, two orthogonal methods","pmids":["12792739"],"is_preprint":false},{"year":2008,"finding":"An intronic SNP in THBS2 (IVS10-8C→T; rs9406328) in a polypyrimidine tract causes allele-dependent skipping of exon 11 in vivo; the exon-11-skipped isoform shows decreased interaction with MMP2 and MMP9, linking THBS2 alternative splicing to reduced MMP regulation and susceptibility to lumbar disc herniation.","method":"Genetic association study, in vivo splicing assay, functional binding assay (THBS2–MMP2/9 interaction)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — splicing demonstrated in vivo, binding interaction functionally validated, replicated in two independent Japanese populations with epistatic MMP9 interaction","pmids":["18455130"],"is_preprint":false},{"year":2010,"finding":"TSP2 enhances Notch3 signaling by binding both Jagged1 and Notch3 ectodomains; this potentiation requires LRP1 expression in the signal-sending cell, is blocked by RAP (an LRP1 inhibitor), and TSP2 stimulates Notch3 endocytosis into WT but not LRP1-deficient fibroblasts, indicating TSP2 drives Notch trans-endocytosis via LRP1.","method":"Co-IP / pulldown (Notch3 and Jagged1 binding to LRP1 85-kDa B-chain), LRP1-deficient fibroblast rescue assay, RAP inhibition, endocytosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal binding assays, LRP1-null cells, RAP inhibition, and endocytosis readout; multiple orthogonal methods in single study","pmids":["20472562"],"is_preprint":false},{"year":2012,"finding":"TSP2-null mice exhibit lower intraocular pressure (~7% less than WT) with enhanced aqueous outflow and larger collagen fibril diameters in the iridocorneal angle, establishing that TSP2 regulates extracellular matrix composition in the trabecular meshwork and thereby modulates intraocular pressure.","method":"Rebound tonometry, fluorophotometry (aqueous turnover), transmission electron microscopy, immunofluorescence in TSP2-null vs WT mice","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phenotypic measurements in KO mice with multiple orthogonal methods, single lab","pmids":["22930728"],"is_preprint":false},{"year":2013,"finding":"Increased angiogenic progression due to TSP2 deficiency regulates mesenchymal stem cell (MSC) bipotential differentiation during fracture repair, shifting fate toward intramembranous ossification and reducing endochondral ossification, with oxygen availability as a key downstream mediator.","method":"Computational modeling validated against TSP2-null mouse experimental data (immunohistochemistry for hypoxia marker pimonidazole)","journal":"Journal of orthopaedic research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — computational model with limited experimental validation by IHC, single lab","pmids":["23775935"],"is_preprint":false},{"year":2016,"finding":"THBS2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1–NOTCH2 interactions; THBS2 is expressed in bile ducts and periportal regions, and Thbs2-null livers show increased microvessels in portal regions, implicating THBS2 as a modifier of JAG1–Notch2 signaling in Alagille syndrome.","method":"Reporter mouse line, co-immunoprecipitation (THBS2–NOTCH1/2 interaction), JAG1–NOTCH2 blocking assay, Thbs2-null mouse histology","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional inhibition assay plus KO mouse phenotype, single lab","pmids":["28090565"],"is_preprint":false},{"year":2018,"finding":"Decellularized matrix derived from TSP2-KO skin has altered ECM structure (reduced elastic modulus and tensile strength), promotes enhanced vascularization and host cell infiltration upon implantation, and releases pro-migratory degradation products, establishing that TSP2 regulates ECM mechanical properties and remodeling permissiveness.","method":"Scanning electron microscopy, mechanical testing, subcutaneous implantation in mouse, in vitro migration assay, pepsin digestion of ECM","journal":"Biomaterials","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vitro and in vivo methods, single lab","pmids":["29631168"],"is_preprint":false},{"year":2019,"finding":"TSP2 is required for normal cochlear afferent synaptic connections; TSP2-null mice show impaired recovery of afferent synaptic counts and ABR wave amplitudes after noise exposure at mid-to-high frequencies, with peripheral neuronal damage and audiogenic seizures, a phenotype not observed in TSP1-null mice.","method":"KO mouse model, auditory brainstem response (ABR), afferent synapse counting, noise exposure paradigm","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with defined physiological and anatomical phenotypic readouts, single lab","pmids":["30928339"],"is_preprint":false},{"year":2020,"finding":"THBS2 inhibits MMP9 production in pancreatic neuroendocrine tumor cells by suppressing the transcriptional activity of CUX1; forced THBS2 expression inhibits pNET cell proliferation and migration, and this effect is mediated through the CUX1/MMP9 cascade.","method":"THBS2 overexpression, CUX1 transcriptional activity reporter assay, Western blot, proliferation and migration assays","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with downstream transcriptional readout and rescue experiments, single lab","pmids":["32194660"],"is_preprint":false},{"year":2021,"finding":"Cancer cell-secreted TGF-β1 activates cancer-associated fibroblasts (CAFs) to induce THBS2 expression via the p-Smad2/3 pathway; CAF-derived THBS2 then binds membrane receptors integrin αvβ3 and CD36 on PDAC cells, activating the MAPK pathway (MEK/JNK) to promote tumor growth and adhesion in a TGF-β1–THBS2–integrin αvβ3/CD36–MAPK feedback circuit.","method":"Quantitative proteomics, IHC, RNA ISH in mouse models; co-culture experiments; integrin/CD36/MEK/JNK inhibition rescue assays; in vitro and in vivo functional assays","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (proteomics, receptor inhibition, pathway rescue, in vivo), mechanistic circuit fully delineated in single study","pmids":["34958892"],"is_preprint":false},{"year":2021,"finding":"In glioma, TSP2 promotes excitatory synapse formation in the peritumoral cortex and induces hyperexcitability via the α2δ1/Rac1 signaling pathway; gabapentin (an α2δ1 antagonist) inhibited epileptiform discharges in the peritumoral cortex.","method":"TSP2-overexpressing/KO glioma cell implantation in rats, spine/synapse density quantification, EEG-like epileptiform discharge recording, gabapentin pharmacological rescue","journal":"Journal of neuropathology and experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain/loss-of-function with electrophysiological and structural readouts, single lab","pmids":["33382873"],"is_preprint":false},{"year":2021,"finding":"TSP2 deficiency in liver cancer stem cells (CD133+) leads to reduced MMP activity inhibition, increased collagen degradation, and a softer matrix; a positive feed-forward loop exists where a soft-spot microenvironment enriches CD133+ cells that secrete less THBS2 due to histone H3 modification at the THBS2 promoter, maintaining local matrix softness and enhancing stemness.","method":"THBS2 KD/KO in HCC cells, MMP activity assays, atomic force microscopy (matrix stiffness), histone modification ChIP at THBS2 promoter, in vivo xenograft","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, AFM, MMP assays, in vivo), single lab","pmids":["33717837"],"is_preprint":false},{"year":2022,"finding":"TSP2 deficiency in diabetic fibroblasts rescues cytoskeletal disorganization by restoring active Rac1 levels and WAVE2–F-actin co-localization, identifying a TSP2–Rac1–WAVE2–actin regulatory axis that controls fibroblast morphology, migration, traction force, and 3D contractility.","method":"TSP2 KO in diabetic fibroblasts, super-resolution microscopy, traction force microscopy, 3D contraction assay, Rac1 activity assay, WAVE2 co-localization imaging","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple state-of-the-art quantitative microscopy and biophysical methods with KO rescue, single rigorous study","pmids":["36577792"],"is_preprint":false},{"year":2022,"finding":"Astrocyte-derived TSP2 binds α2δ1 to mediate retinal ganglion cell axon degeneration, compensatory synaptic remodeling in the inner plexiform layer, and visual dysfunction following ischemia/reperfusion injury; TSP2 knockdown (shRNA-AAV) and competitive inhibition of TSP2–α2δ1 binding by gabapentin both alleviated these effects.","method":"TSP2 shRNA-AAV transduction in rat retina, gabapentin injection, immunofluorescence, electron microscopy, Western blot, ERG/visual function assays","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with two independent interventions (genetic and pharmacological), multiple readouts, single lab","pmids":["36471420"],"is_preprint":false},{"year":2023,"finding":"CEBPB inhibits THBS2 expression by facilitating miR-29a-3p transcription; additionally, CEBPB inhibits B3GALTL transcription to reduce O-fucosylation and secretion of THBS2; secreted THBS2 interacts with ITGB1 and activates the PI3K/AKT signaling pathway to promote breast cancer cell migration, invasion, and EMT.","method":"Co-IP (THBS2–ITGB1 interaction), ChIP (CEBPB binding to miR-29a-3p and B3GALTL promoters), O-fucosylation analysis, PI3K/AKT pathway Western blot, rescue experiments","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, post-translational modification analysis, and signaling rescue; single lab, multiple orthogonal methods","pmids":["36728807"],"is_preprint":false},{"year":2024,"finding":"A heterozygous missense mutation in THBS2 (p.Cys896Arg) causes a novel form of Ehlers-Danlos syndrome with vascular features in humans; CRISPR/Cas9 knock-in mice bearing the same mutation recapitulate the phenotype. Mechanistically, THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage and causing ECM abnormalities including disorganized collagen fibers and abnormal fibroblast/endothelial cell morphology.","method":"Clinical phenotyping, TEM, CRISPR/Cas9 KI mouse generation, histology, bleeding time assays, MMP2 clearance mechanistic analysis","journal":"European journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — human genetic variant, CRISPR KI mouse recapitulation, TEM structural analysis, and MMP2 functional mechanism; multiple orthogonal methods","pmids":["38433265"],"is_preprint":false},{"year":2024,"finding":"THBS2 secreted by matrix CAFs (mCAFs) directly binds to SDC4 (syndecan-4) on tumor cells to enhance epithelial-mesenchymal transition (EMT) programs in lung adenocarcinoma, establishing the THBS2–SDC4–EMT axis as a mediator of CAF-tumor crosstalk.","method":"Single-cell RNA-seq, spatial transcriptomics, multiplex IHC, in vitro and in vivo binding/functional assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with functional EMT readout and in vivo validation, single lab","pmids":["40973793"],"is_preprint":false},{"year":2024,"finding":"THBS2 promotes collagen synthesis in IPF fibroblasts through the TGF-β1/Smad2/3 signaling pathway; THBS2 overexpression increases COL1A1, COL1A2, COL3A1, LOX, and LOXL2, and THBS2 knockdown attenuates these effects; exogenous THBS2 protein aggravates bleomycin-induced pulmonary fibrosis in mice.","method":"THBS2 overexpression/KD in IPF fibroblasts, TGF-β1 inhibitor (SB525334), Western blot, qPCR, bleomycin mouse model with exogenous THBS2 protein","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with pharmacological pathway rescue and in vivo validation, single lab","pmids":["40676074"],"is_preprint":false},{"year":2024,"finding":"METTL14 stabilizes THBS2 mRNA via m6A modification recognized by YTHDF2; METTL14 knockdown reduces THBS2 expression and alleviates high-glucose-induced HK-2 cell damage (apoptosis, fibrosis, inflammation, ferroptosis), while THBS2 overexpression negates these protective effects.","method":"m6A-RIP-qPCR (THBS2 interaction with METTL14 and YTHDF2), METTL14 KD, THBS2 KD/overexpression, CCK-8, flow cytometry, ELISA, Western blot","journal":"Experimental and clinical endocrinology & diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-RIP validation plus genetic rescue experiments, single lab","pmids":["40730238"],"is_preprint":false},{"year":2025,"finding":"TSP2 deficiency in dermal fibroblasts upregulates TGF-β3 and Wnt4/β-catenin signaling, enhancing fibroblast proliferation and migration; CRISPR/Cas9 TSP2 KO in NIH3T3 cells confirmed that TSP2 negatively regulates these pro-regenerative pathways.","method":"Bulk RNA sequencing of WT vs TSP2-KO primary fibroblasts, CRISPR/Cas9 KO validation, proliferation and migration assays, pathway reporter assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus CRISPR KO with functional readouts, single lab","pmids":["41427771"],"is_preprint":false},{"year":2025,"finding":"Blocking the TCA cycle in HNSCC cells (via CPI-613) induces ER stress, which directly suppresses THBS2 transcription through spliced XBP1; reduced secretion of THBS2 enhances CD36+CD8+ T-cell proliferation and cytotoxicity by upregulating AKT-mTOR signaling, enhancing antitumor immunity in a syngeneic orthotopic mouse model.","method":"CPI-613 treatment, ChIP/reporter assay (XBP1 binding to THBS2 promoter), THBS2 secretion ELISA, T-cell functional assays, syngeneic mouse model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional mechanism (XBP1→THBS2) with functional T-cell and in vivo readouts, single lab","pmids":["40293258"],"is_preprint":false},{"year":2025,"finding":"THBS2 interacts with INHBA to activate the FAK/PI3K/AKT signaling pathway in prostate cancer cells, promoting proliferation, migration, invasion, and EMT; INHBA knockdown reverses the oncogenic effects of THBS2 overexpression.","method":"STRING protein interaction analysis, Western blot co-expression, INHBA siRNA rescue, FAK/PI3K/AKT pathway Western blot, functional assays (CCK-8, wound healing, Transwell)","journal":"Analytical cellular pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction inferred from STRING database with partial Western blot and rescue experiments, no direct binding assay, single lab","pmids":["41810913"],"is_preprint":false},{"year":2026,"finding":"THBS2+ fibroblasts interact with colorectal cancer cells via THBS2–CD36 and THBS2–SDC1 pathways; depletion of THBS2+ fibroblasts in an AAV-mediated mouse model enhanced polyp formation but suppressed tumor formation, establishing a stage-specific pro-tumorigenic role for THBS2+ fibroblasts in CRC malignant transformation.","method":"Multiplex immunostaining, AAV-mediated THBS2+ fibroblast depletion mouse model, multi-omics spatial analysis","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo cell depletion with defined phenotypic readout, receptor pathway identification, single lab","pmids":["41640327"],"is_preprint":false}],"current_model":"THBS2 (TSP2) is a secreted homotrimeric matricellular glycoprotein that directly binds and mediates clearance of MMP2 (and MMP9), regulates ECM collagen fibril architecture and mechanical properties, modulates Notch signaling by binding Jagged1 and Notch ectodomains and driving LRP1-dependent trans-endocytosis, promotes excitatory synaptogenesis via α2δ1/Rac1 signaling, activates MAPK and PI3K/AKT pathways downstream of integrin αvβ3/CD36 and SDC4/ITGB1 receptors on tumor and stromal cells, promotes collagen synthesis through TGF-β1/Smad2/3 signaling in fibroblasts, and is negatively regulated by a TSP2–Rac1–WAVE2–actin axis that controls cytoskeletal organization; loss-of-function studies in mice reveal roles in wound healing, intraocular pressure regulation, auditory synapse maintenance, and fracture repair through modulation of angiogenesis and MSC differentiation."},"narrative":{"mechanistic_narrative":"THBS2 (TSP2) is a secreted matricellular glycoprotein that governs extracellular matrix architecture, remodeling, and signaling, distinct in expression and function from the related thrombospondin TSP1 [PMID:1712771, PMID:12213711]. A central activity is the negative regulation of matrix metalloproteinases: TSP2 binds and promotes clearance of MMP2 (and MMP9), and loss of this function increases MMP2-mediated proteoglycan cleavage and produces disorganized collagen fibers and abnormal cell morphology [PMID:38433265, PMID:18455130]. Through this and direct ECM-structuring roles, TSP2 controls collagen fibril diameter, matrix stiffness and mechanical strength, with consequences for intraocular pressure regulation, matrix remodeling permissiveness, and cancer stem-cell-supporting matrix softness [PMID:22930728, PMID:29631168, PMID:33717837]. A heterozygous missense mutation (p.Cys896Arg) causes a vascular-featured form of Ehlers-Danlos syndrome, recapitulated in CRISPR knock-in mice and mechanistically linked to attenuated MMP2 clearance [PMID:38433265]. TSP2 also acts as a signaling ligand: it potentiates Notch signaling by binding Jagged1 and Notch ectodomains and driving LRP1-dependent trans-endocytosis [PMID:20472562, PMID:28090565], engages neuronal α2δ1/Rac1 signaling to control excitatory synapse formation and synaptic maintenance [PMID:33382873, PMID:36471420, PMID:30928339], and binds tumor-cell receptors including integrin αvβ3/CD36, SDC4, and ITGB1 to activate MAPK and PI3K/AKT pathways downstream of CAF-derived TSP2, promoting EMT and tumor progression [PMID:34958892, PMID:40973793, PMID:36728807]. In fibroblasts, TSP2 promotes TGF-β1/Smad2/3-driven collagen synthesis in fibrosis [PMID:40676074] yet negatively regulates a Rac1–WAVE2–actin cytoskeletal axis and Wnt4/β-catenin pro-regenerative programs [PMID:36577792, PMID:41427771]. Its expression is controlled transcriptionally (p53, NF-κB, Sp1 sites; CEBPB, XBP1) and post-transcriptionally (METTL14/YTHDF2 m6A stabilization, miR-29a-3p) [PMID:9249061, PMID:36728807, PMID:40293258, PMID:40730238].","teleology":[{"year":1991,"claim":"Establishing that THBS2 is a distinct gene product from THBS1 with a divergent tissue expression pattern resolved whether the two thrombospondins were functionally interchangeable.","evidence":"cDNA cloning, sequence analysis, and tissue expression profiling in mouse","pmids":["1712771"],"confidence":"Medium","gaps":["No functional or biochemical activity assigned at cloning","Protein-level localization and partners undefined"]},{"year":1997,"claim":"Mapping the human THBS2 promoter and tissue-specific transcription start sites explained how THBS2 expression is differentially regulated across tissues.","evidence":"Genomic sequencing, 5' RACE, and PCR-based transcription start site mapping","pmids":["9249061"],"confidence":"Medium","gaps":["Functional contribution of each transcription factor site not tested","No link to physiological regulation"]},{"year":2002,"claim":"Genetic epistasis in double-null mice distinguished the non-redundant roles of TSP1 and TSP2, showing TSP1 dominates the wound-healing response.","evidence":"Single and double TSP1/TSP2 knockout mouse comparison with immunohistochemistry and cytokine measurement","pmids":["12213711"],"confidence":"High","gaps":["Molecular basis of the TSP2-specific wound contribution not defined","Receptor/effector pathway not isolated"]},{"year":2003,"claim":"Demonstrating that TSP2 overexpression suppresses MMP2/MMP9 while inducing MMP12/MMP17 positioned TSP2 as an MMP-expression modulator in carcinoma cells.","evidence":"cDNA array and Western blot after stable TSP2 overexpression in SW480 colon carcinoma cells","pmids":["12792739"],"confidence":"Medium","gaps":["Distinguishes expression effects from direct binding/clearance not addressed here","Single cell line"]},{"year":2008,"claim":"A functional splicing variant linked THBS2-MMP binding to human disease, showing exon-11 skipping reduces MMP2/MMP9 interaction and confers lumbar disc herniation susceptibility.","evidence":"Genetic association study, in vivo splicing assay, and THBS2-MMP binding assay in two Japanese populations","pmids":["18455130"],"confidence":"High","gaps":["Structural basis of the THBS2-MMP interaction not resolved","Mechanism of clearance versus inhibition not separated"]},{"year":2010,"claim":"Identifying TSP2 as a Jagged1/Notch3 co-ligand that drives LRP1-dependent trans-endocytosis revealed a signaling, not purely structural, function for the matricellular protein.","evidence":"Co-IP/pulldown, LRP1-deficient fibroblast rescue, RAP inhibition, and endocytosis assays","pmids":["20472562"],"confidence":"High","gaps":["In vivo relevance of Notch3 potentiation not established","Whether other Notch receptors are similarly modulated unknown at the time"]},{"year":2012,"claim":"Lower intraocular pressure and altered fibril diameter in TSP2-null mice established a role for TSP2 in trabecular meshwork ECM composition and aqueous outflow.","evidence":"Rebound tonometry, fluorophotometry, TEM, and immunofluorescence in TSP2-null versus WT mice","pmids":["22930728"],"confidence":"Medium","gaps":["Molecular mediator linking TSP2 loss to fibril changes not identified","MMP involvement not tested in this tissue"]},{"year":2017,"claim":"Showing THBS2 binds NOTCH1/2 and inhibits JAG1-NOTCH2 interactions extended its Notch-modulating role and implicated it as a modifier in Alagille syndrome.","evidence":"Reporter mouse, co-IP, JAG1-NOTCH2 blocking assay, and Thbs2-null liver histology","pmids":["28090565"],"confidence":"Medium","gaps":["Context-dependent potentiation versus inhibition of Notch not reconciled","Genetic modifier role not validated in patients"]},{"year":2018,"claim":"Decellularized TSP2-KO matrix established that TSP2 sets ECM mechanical properties and remodeling permissiveness, with degradation products being bioactive.","evidence":"SEM, mechanical testing, subcutaneous implantation, migration assays, and pepsin digestion of ECM","pmids":["29631168"],"confidence":"Medium","gaps":["Identity of pro-migratory degradation fragments unknown","Direct molecular mechanism of stiffening not defined"]},{"year":2019,"claim":"Linking TSP2 deficiency to oxygen-dependent MSC fate during fracture repair connected its angiogenic regulation to bone-forming pathway choice.","evidence":"Computational modeling validated against TSP2-null mouse IHC (pimonidazole hypoxia marker)","pmids":["23775935"],"confidence":"Low","gaps":["Largely a computational model with limited experimental validation","Direct molecular control of MSC differentiation by TSP2 not shown"]},{"year":2019,"claim":"Demonstrating TSP2 is required for cochlear afferent synapse recovery after noise revealed a synaptic-maintenance role distinct from TSP1.","evidence":"TSP2-null mice, auditory brainstem response, afferent synapse counting, and noise exposure","pmids":["30928339"],"confidence":"Medium","gaps":["Receptor mediating cochlear synaptic effect not identified in this study","Cell source of TSP2 in cochlea unclear"]},{"year":2021,"claim":"Defining a CAF-derived TGF-β1-THBS2-integrin αvβ3/CD36-MAPK feedback circuit established TSP2 as a stromal signaling ligand driving tumor growth.","evidence":"Quantitative proteomics, RNA-ISH, co-culture, receptor/MEK/JNK inhibition rescue, and in vivo PDAC assays","pmids":["34958892"],"confidence":"High","gaps":["Relative contribution of αvβ3 versus CD36 not dissected","Whether the same circuit operates in other tumor types unknown at the time"]},{"year":2021,"claim":"Showing TSP2 promotes peritumoral excitatory synaptogenesis and hyperexcitability via α2δ1/Rac1 connected its synaptogenic activity to glioma-associated epilepsy.","evidence":"TSP2 gain/loss glioma implantation in rats, synapse density quantification, epileptiform recordings, and gabapentin rescue","pmids":["33382873"],"confidence":"Medium","gaps":["Downstream effectors of Rac1 in synapse assembly not defined here","Endogenous neuronal versus tumor source of TSP2 not separated"]},{"year":2021,"claim":"A CD133+ stem-cell feed-forward loop showed that reduced TSP2 (via H3 promoter modification) lowers MMP inhibition, softens matrix, and reinforces stemness.","evidence":"THBS2 KD/KO in HCC cells, MMP activity assays, atomic force microscopy, promoter ChIP, and xenografts","pmids":["33717837"],"confidence":"Medium","gaps":["Identity of the histone-modifying enzyme not pinned down","Causality between softness and stemness only correlative in part"]},{"year":2022,"claim":"Identifying a TSP2-Rac1-WAVE2-actin axis that TSP2 negatively controls explained how TSP2 governs fibroblast morphology, migration, and contractility.","evidence":"TSP2 KO in diabetic fibroblasts, super-resolution and traction force microscopy, 3D contraction, and Rac1 activity assays","pmids":["36577792"],"confidence":"High","gaps":["Receptor linking secreted TSP2 to intracellular Rac1 not identified","Generality beyond diabetic fibroblasts untested"]},{"year":2022,"claim":"Astrocyte-derived TSP2 binding α2δ1 to drive RGC axon degeneration and synaptic remodeling after ischemia extended the α2δ1 axis to retinal injury.","evidence":"TSP2 shRNA-AAV and gabapentin in rat retina, immunofluorescence, EM, Western blot, and ERG/visual assays","pmids":["36471420"],"confidence":"Medium","gaps":["Whether axon degeneration is direct or downstream of synaptic change unclear","Signaling steps downstream of α2δ1 not mapped"]},{"year":2023,"claim":"Defining CEBPB-driven repression via miR-29a-3p and B3GALTL O-fucosylation control of secretion, plus a THBS2-ITGB1-PI3K/AKT axis, linked THBS2 regulation to breast cancer EMT.","evidence":"Co-IP, ChIP, O-fucosylation analysis, PI3K/AKT Western blot, and rescue experiments","pmids":["36728807"],"confidence":"Medium","gaps":["Relative importance of transcriptional versus secretory control not quantified","ITGB1 binding site not mapped"]},{"year":2024,"claim":"A human THBS2 missense mutation causing vascular Ehlers-Danlos syndrome, recapitulated in knock-in mice, established THBS2 as a Mendelian disease gene acting through impaired MMP2 clearance.","evidence":"Clinical phenotyping, TEM, CRISPR/Cas9 knock-in mice, histology, bleeding-time assays, and MMP2 clearance analysis","pmids":["38433265"],"confidence":"High","gaps":["Structural consequence of p.Cys896Arg on trimerization not resolved","Why a heterozygous variant is sufficient not fully explained"]},{"year":2024,"claim":"Identifying a THBS2-SDC4-EMT axis in lung adenocarcinoma added syndecan-4 as a tumor-cell receptor for CAF-derived THBS2.","evidence":"Single-cell RNA-seq, spatial transcriptomics, multiplex IHC, and binding/functional assays","pmids":["40973793"],"confidence":"Medium","gaps":["Direct binding affinity not quantified","Downstream signaling from SDC4 not mapped"]},{"year":2024,"claim":"Showing THBS2 drives collagen synthesis through TGF-β1/Smad2/3 in IPF fibroblasts established a pro-fibrotic function in lung fibrosis.","evidence":"THBS2 overexpression/KD in IPF fibroblasts, TGF-β1 inhibitor, Western blot, qPCR, and bleomycin mouse model with exogenous THBS2","pmids":["40676074"],"confidence":"Medium","gaps":["Receptor mediating TSP2-induced Smad activation not identified","Reconciliation with TSP2's negative regulation of regenerative pathways not addressed"]},{"year":2024,"claim":"METTL14/YTHDF2 m6A stabilization of THBS2 mRNA in renal tubular cells revealed an epitranscriptomic control point coupling THBS2 to diabetic injury.","evidence":"m6A-RIP-qPCR, METTL14 KD, THBS2 KD/overexpression, and apoptosis/fibrosis/ferroptosis readouts in HK-2 cells","pmids":["40730238"],"confidence":"Medium","gaps":["In vivo relevance of m6A control not established","Downstream effectors of THBS2 in tubular damage unclear"]},{"year":2025,"claim":"Demonstrating that TSP2 loss upregulates TGF-β3 and Wnt4/β-catenin to enhance fibroblast proliferation/migration defined TSP2 as a negative regulator of pro-regenerative dermal programs.","evidence":"Bulk RNA-seq of WT versus TSP2-KO fibroblasts, CRISPR KO validation, and proliferation/migration/reporter assays","pmids":["41427771"],"confidence":"Medium","gaps":["Mechanism by which secreted TSP2 suppresses these pathways not defined","In vivo regeneration phenotype not shown"]},{"year":2025,"claim":"Linking TCA-cycle blockade to ER-stress/XBP1 suppression of THBS2 transcription connected THBS2 secretion to suppression of CD36+CD8+ T-cell antitumor immunity.","evidence":"CPI-613 treatment, XBP1 ChIP/reporter, THBS2 ELISA, T-cell functional assays, and syngeneic orthotopic mouse model","pmids":["40293258"],"confidence":"Medium","gaps":["Direct effect of THBS2 on T cells versus indirect not fully separated","Receptor on T cells mediating the effect not identified"]},{"year":2026,"claim":"AAV-mediated depletion of THBS2+ fibroblasts revealed a stage-specific pro-tumorigenic role acting through THBS2-CD36 and THBS2-SDC1 pathways in colorectal cancer.","evidence":"Multiplex immunostaining, AAV fibroblast depletion mouse model, and multi-omics spatial analysis","pmids":["41640327"],"confidence":"Medium","gaps":["Opposing effects on polyp versus tumor formation mechanistically unresolved","Direct THBS2-SDC1 binding not biochemically validated"]},{"year":null,"claim":"How the same secreted TSP2 molecule selects among its many receptors (LRP1, α2δ1, αvβ3/CD36, SDC4, SDC1, ITGB1) and switches between MMP clearance, Notch modulation, synaptogenesis, and pro/anti-fibrotic signaling in a context-dependent manner remains 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research","url":"https://pubmed.ncbi.nlm.nih.gov/40293258","citation_count":7,"is_preprint":false},{"pmid":"30928339","id":"PMC_30928339","title":"TSP1 and TSP2 Have Unique and Overlapping Roles in Protecting against Noise-Induced Auditory Synaptopathy.","date":"2019","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30928339","citation_count":7,"is_preprint":false},{"pmid":"38162289","id":"PMC_38162289","title":"Transcription Analysis of the THBS2 Gene through Regulation by Potential Noncoding Diagnostic Biomarkers and Oncogenes of Gastric Cancer in the ECM-Receptor Interaction Signaling Pathway: Integrated System Biology and Experimental Investigation.","date":"2023","source":"International journal of genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38162289","citation_count":7,"is_preprint":false},{"pmid":"30939949","id":"PMC_30939949","title":"TSP1 and TSP2 deficiencies affect LOX protein distribution in the femoral diaphysis and pro-peptide removal in marrow-derived mesenchymal stem cells in vitro.","date":"2019","source":"Connective tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/30939949","citation_count":7,"is_preprint":false},{"pmid":"35044104","id":"PMC_35044104","title":"Circ_0007580 knockdown strengthens the radiosensitivity of non-small cell lung cancer via the miR-598-dependent regulation of THBS2.","date":"2022","source":"Thoracic cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35044104","citation_count":7,"is_preprint":false},{"pmid":"39626342","id":"PMC_39626342","title":"YTHDF3 suppresses declines in corneal epithelial wound healing through upregulating the Wnt/β-catenin signaling pathway and THBS2 expression in diabetic corneas.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39626342","citation_count":7,"is_preprint":false},{"pmid":"23875975","id":"PMC_23875975","title":"Variants within the COMP and THBS2 genes are not associated with Achilles tendinopathy in a case-control study of South African and Australian populations.","date":"2013","source":"Journal of sports sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23875975","citation_count":7,"is_preprint":false},{"pmid":"34712047","id":"PMC_34712047","title":"Robust Immune Response Induced by Schistosoma mansoni TSP-2 Antigen Coupled to Bacterial Outer Membrane Vesicles.","date":"2021","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/34712047","citation_count":7,"is_preprint":false},{"pmid":"29393209","id":"PMC_29393209","title":"Therapeutic Role for TSP-2 Antibody in a Murine Asthma Model.","date":"2018","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29393209","citation_count":7,"is_preprint":false},{"pmid":"36382967","id":"PMC_36382967","title":"Circ_0079530 stimulates THBS2 to promote the malignant progression of non-small cell lung cancer by sponging miR-584-5p.","date":"2022","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/36382967","citation_count":6,"is_preprint":false},{"pmid":"38156105","id":"PMC_38156105","title":"Detection of lymph node metastasis in colon cancer by ectopically expressed fibroblast markers FOXQ1 and THBS2.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38156105","citation_count":6,"is_preprint":false},{"pmid":"25299246","id":"PMC_25299246","title":"Complex brain malformations associated with chromosome 6q27 gain that includes THBS2, which encodes thrombospondin 2, an astrocyte-derived protein of the extracellular matrix.","date":"2014","source":"Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society","url":"https://pubmed.ncbi.nlm.nih.gov/25299246","citation_count":6,"is_preprint":false},{"pmid":"40973793","id":"PMC_40973793","title":"Cancer-associated fibroblasts drive lung adenocarcinoma progression via THBS2-mediated epithelial-mesenchymal transition.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40973793","citation_count":5,"is_preprint":false},{"pmid":"36471420","id":"PMC_36471420","title":"Astrocyte derived TSP2 contributes to synaptic alteration and visual dysfunction in retinal ischemia/reperfusion injury.","date":"2022","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/36471420","citation_count":5,"is_preprint":false},{"pmid":"38918228","id":"PMC_38918228","title":"A longitudinal population-based study identifies THBS2 as a susceptibility gene for intervertebral disc degeneration.","date":"2024","source":"European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society","url":"https://pubmed.ncbi.nlm.nih.gov/38918228","citation_count":5,"is_preprint":false},{"pmid":"31330254","id":"PMC_31330254","title":"Molecular characterization and functional analysis of Japanese flounder (Paralichthys olivaceus) thbs2 in response to lymphocystis disease virus.","date":"2019","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31330254","citation_count":5,"is_preprint":false},{"pmid":"37641374","id":"PMC_37641374","title":"Hsa_circ_0015382 is involved in the pathogenesis of preeclampsia by mediating THBS2 expression.","date":"2023","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/37641374","citation_count":4,"is_preprint":false},{"pmid":"37658862","id":"PMC_37658862","title":"Serum THBS2 is a potential biomarker for the diagnosis of non-small cell lung cancer.","date":"2023","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37658862","citation_count":4,"is_preprint":false},{"pmid":"40676074","id":"PMC_40676074","title":"Enhanced THBS2 promotes collagen synthesis and inflammatory secretome of fibroblasts in idiopathic pulmonary fibrosis.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40676074","citation_count":3,"is_preprint":false},{"pmid":"40246476","id":"PMC_40246476","title":"Carbon black induced pulmonary fibrosis through piR-713551/PIWIL4 targeting THBS2 signal pathway.","date":"2024","source":"Journal of environmental sciences (China)","url":"https://pubmed.ncbi.nlm.nih.gov/40246476","citation_count":3,"is_preprint":false},{"pmid":"36930067","id":"PMC_36930067","title":"COL3A1, CXCL8, VCAN, THBS2, and COL1A2 are correlated with the onset of biliary atresia.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36930067","citation_count":3,"is_preprint":false},{"pmid":"40340827","id":"PMC_40340827","title":"Identification of the \"Collagen-Macrophage\" sub-category of patients with colorectal cancer as an extension of the CMS4 subtype with THBS2 as a therapeutic target.","date":"2025","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/40340827","citation_count":2,"is_preprint":false},{"pmid":"19160958","id":"PMC_19160958","title":"[Gene synthesis, expression and immunogenicity analysis of TSP2 hydrophilic domain(TSP2HD) of Schistosoma japonicum].","date":"2008","source":"Zhongguo ji sheng chong xue yu ji sheng chong bing za zhi = Chinese journal of parasitology & parasitic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19160958","citation_count":1,"is_preprint":false},{"pmid":"39779937","id":"PMC_39779937","title":"Hirudo extract ameliorates proliferative vitreoretinopathy by promoting autophagy and attenuating the THBS2/PI3K/Akt pathway.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39779937","citation_count":1,"is_preprint":false},{"pmid":"39045635","id":"PMC_39045635","title":"Identification of the M2 Macrophage-associated Gene THBS2 as a Predictive Marker for Inflammatory Cancer Transformation.","date":"2025","source":"Inflammatory bowel diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39045635","citation_count":1,"is_preprint":false},{"pmid":"39549890","id":"PMC_39549890","title":"Schistosoma heamatobium tetraspanins TSP-2 and TSP-6 induce Dendritic Cells maturation, cytokine production and T helper cells differentiation in vitro.","date":"2024","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/39549890","citation_count":1,"is_preprint":false},{"pmid":"41254692","id":"PMC_41254692","title":"Integrative multi-omics and Mendelian randomization identify WWOX and THBS2 as potential therapeutic targets in mature T/NK-cell lymphoma.","date":"2025","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41254692","citation_count":0,"is_preprint":false},{"pmid":"40730238","id":"PMC_40730238","title":"METTL14 Promotes HK-2 Cell Injury in Diabetic Nephropathy Through the Regulation of THBS2 Expression in an m6A-YTHDF2-Dependent Manner.","date":"2025","source":"Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association","url":"https://pubmed.ncbi.nlm.nih.gov/40730238","citation_count":0,"is_preprint":false},{"pmid":"41427771","id":"PMC_41427771","title":"TSP2 Deficiency Promotes Fibroblast Proliferation and Migration With Enhanced WNT4/β-Catenin/TGFb3.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/41427771","citation_count":0,"is_preprint":false},{"pmid":"41761978","id":"PMC_41761978","title":"LXN-THBS2 Signaling Axis Regulates Hepatic Stellate Cell Activation and Promotes the Development of Liver Fibrosis.","date":"2026","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/41761978","citation_count":0,"is_preprint":false},{"pmid":"40298323","id":"PMC_40298323","title":"TSP-1, TSP-2, and TSP-5 demonstrate sexual dimorphism in intimal hyperplasia in rats and mice.","date":"2025","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/40298323","citation_count":0,"is_preprint":false},{"pmid":"41903303","id":"PMC_41903303","title":"Artesunate protects against ischemic stroke through THBS2/CD36/TLR4 pathway.","date":"2026","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41903303","citation_count":0,"is_preprint":false},{"pmid":"41187421","id":"PMC_41187421","title":"CircP4HA3/miR-5001-5p/THBS2 axis promotes chondrocyte senescence and cartilage degradation during osteoarthritis progression.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41187421","citation_count":0,"is_preprint":false},{"pmid":"41810913","id":"PMC_41810913","title":"THBS2 Promotes Prostate Cancer Malignancy via INHBA-Dependent FAK/PI3K/AKT Signaling Activation.","date":"2026","source":"Analytical cellular pathology (Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/41810913","citation_count":0,"is_preprint":false},{"pmid":"42211234","id":"PMC_42211234","title":"Transcriptomic and Proteomic Analyses Identify THBS2, VWF, NFASC, and AKR1B10 as Diagnostic Biomarkers for Advanced Fibrosis in NAFLD.","date":"2026","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/42211234","citation_count":0,"is_preprint":false},{"pmid":"41640327","id":"PMC_41640327","title":"Roles of THBS2+ fibroblasts in malignant transformation of colorectal polyp to cancer.","date":"2026","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/41640327","citation_count":0,"is_preprint":false},{"pmid":"21867624","id":"PMC_21867624","title":"[Effects of TSP2-8 and CUB1+2 domains on secretion direction of von Willebrand factor-cleaving protease].","date":"2011","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/21867624","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56115,"output_tokens":6559,"usd":0.133365,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15481,"output_tokens":7019,"usd":0.12644,"stage2_stop_reason":"end_turn"},"total_usd":0.259805,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"THBS2 (TSP2) is the product of a separate gene (Thbs2) distinct from THBS1, expressed in a variety of mouse tissues in a pattern that differs from TSP1, establishing that two functionally distinct thrombospondin proteins exist in the same organism.\",\n      \"method\": \"cDNA cloning, sequence analysis, tissue expression profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular cloning and sequence characterization, single lab but foundational identification paper\",\n      \"pmids\": [\"1712771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The human THBS2 promoter contains binding sites for p53, NF-κB, Sp1, Myc-CF1, NF-Y, AP1, and GATA; tissue-specific differences in transcription start site selection contribute to differential THBS2 expression across tissues.\",\n      \"method\": \"Genomic sequencing, 5' RACE, PCR-based transcription start site mapping\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct experimental mapping of transcription start sites, single lab, two orthogonal methods\",\n      \"pmids\": [\"9249061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In double-TSP1/TSP2-null mice, the wound-healing defect (delayed healing, impaired macrophage recruitment, reduced MCP-1, and non-excessive vascularization) phenocopies TSP1-null mice rather than TSP2-null mice, demonstrating that TSP1 dominates over TSP2 in dictating the wound-healing response and that the two proteins have distinct temporal and spatial roles.\",\n      \"method\": \"Genetic epistasis using double-knockout mouse model, immunohistochemistry, cytokine measurement\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal single and double KO comparison with multiple phenotypic readouts, replicated across wound-healing metrics\",\n      \"pmids\": [\"12213711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of TSP2 in the SW480 colon carcinoma cell line downregulates MMP2 and MMP9 expression and protein production, while upregulating MMP12 and MMP17, establishing TSP2 as a modulator of MMP expression.\",\n      \"method\": \"cDNA array and Western blot following stable TSP2 overexpression in SW480 cells\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function overexpression with transcriptomic and protein-level readouts, single lab, two orthogonal methods\",\n      \"pmids\": [\"12792739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"An intronic SNP in THBS2 (IVS10-8C→T; rs9406328) in a polypyrimidine tract causes allele-dependent skipping of exon 11 in vivo; the exon-11-skipped isoform shows decreased interaction with MMP2 and MMP9, linking THBS2 alternative splicing to reduced MMP regulation and susceptibility to lumbar disc herniation.\",\n      \"method\": \"Genetic association study, in vivo splicing assay, functional binding assay (THBS2–MMP2/9 interaction)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — splicing demonstrated in vivo, binding interaction functionally validated, replicated in two independent Japanese populations with epistatic MMP9 interaction\",\n      \"pmids\": [\"18455130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TSP2 enhances Notch3 signaling by binding both Jagged1 and Notch3 ectodomains; this potentiation requires LRP1 expression in the signal-sending cell, is blocked by RAP (an LRP1 inhibitor), and TSP2 stimulates Notch3 endocytosis into WT but not LRP1-deficient fibroblasts, indicating TSP2 drives Notch trans-endocytosis via LRP1.\",\n      \"method\": \"Co-IP / pulldown (Notch3 and Jagged1 binding to LRP1 85-kDa B-chain), LRP1-deficient fibroblast rescue assay, RAP inhibition, endocytosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal binding assays, LRP1-null cells, RAP inhibition, and endocytosis readout; multiple orthogonal methods in single study\",\n      \"pmids\": [\"20472562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TSP2-null mice exhibit lower intraocular pressure (~7% less than WT) with enhanced aqueous outflow and larger collagen fibril diameters in the iridocorneal angle, establishing that TSP2 regulates extracellular matrix composition in the trabecular meshwork and thereby modulates intraocular pressure.\",\n      \"method\": \"Rebound tonometry, fluorophotometry (aqueous turnover), transmission electron microscopy, immunofluorescence in TSP2-null vs WT mice\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phenotypic measurements in KO mice with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22930728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Increased angiogenic progression due to TSP2 deficiency regulates mesenchymal stem cell (MSC) bipotential differentiation during fracture repair, shifting fate toward intramembranous ossification and reducing endochondral ossification, with oxygen availability as a key downstream mediator.\",\n      \"method\": \"Computational modeling validated against TSP2-null mouse experimental data (immunohistochemistry for hypoxia marker pimonidazole)\",\n      \"journal\": \"Journal of orthopaedic research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — computational model with limited experimental validation by IHC, single lab\",\n      \"pmids\": [\"23775935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"THBS2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1–NOTCH2 interactions; THBS2 is expressed in bile ducts and periportal regions, and Thbs2-null livers show increased microvessels in portal regions, implicating THBS2 as a modifier of JAG1–Notch2 signaling in Alagille syndrome.\",\n      \"method\": \"Reporter mouse line, co-immunoprecipitation (THBS2–NOTCH1/2 interaction), JAG1–NOTCH2 blocking assay, Thbs2-null mouse histology\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional inhibition assay plus KO mouse phenotype, single lab\",\n      \"pmids\": [\"28090565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Decellularized matrix derived from TSP2-KO skin has altered ECM structure (reduced elastic modulus and tensile strength), promotes enhanced vascularization and host cell infiltration upon implantation, and releases pro-migratory degradation products, establishing that TSP2 regulates ECM mechanical properties and remodeling permissiveness.\",\n      \"method\": \"Scanning electron microscopy, mechanical testing, subcutaneous implantation in mouse, in vitro migration assay, pepsin digestion of ECM\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro and in vivo methods, single lab\",\n      \"pmids\": [\"29631168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TSP2 is required for normal cochlear afferent synaptic connections; TSP2-null mice show impaired recovery of afferent synaptic counts and ABR wave amplitudes after noise exposure at mid-to-high frequencies, with peripheral neuronal damage and audiogenic seizures, a phenotype not observed in TSP1-null mice.\",\n      \"method\": \"KO mouse model, auditory brainstem response (ABR), afferent synapse counting, noise exposure paradigm\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with defined physiological and anatomical phenotypic readouts, single lab\",\n      \"pmids\": [\"30928339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"THBS2 inhibits MMP9 production in pancreatic neuroendocrine tumor cells by suppressing the transcriptional activity of CUX1; forced THBS2 expression inhibits pNET cell proliferation and migration, and this effect is mediated through the CUX1/MMP9 cascade.\",\n      \"method\": \"THBS2 overexpression, CUX1 transcriptional activity reporter assay, Western blot, proliferation and migration assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with downstream transcriptional readout and rescue experiments, single lab\",\n      \"pmids\": [\"32194660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cancer cell-secreted TGF-β1 activates cancer-associated fibroblasts (CAFs) to induce THBS2 expression via the p-Smad2/3 pathway; CAF-derived THBS2 then binds membrane receptors integrin αvβ3 and CD36 on PDAC cells, activating the MAPK pathway (MEK/JNK) to promote tumor growth and adhesion in a TGF-β1–THBS2–integrin αvβ3/CD36–MAPK feedback circuit.\",\n      \"method\": \"Quantitative proteomics, IHC, RNA ISH in mouse models; co-culture experiments; integrin/CD36/MEK/JNK inhibition rescue assays; in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (proteomics, receptor inhibition, pathway rescue, in vivo), mechanistic circuit fully delineated in single study\",\n      \"pmids\": [\"34958892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In glioma, TSP2 promotes excitatory synapse formation in the peritumoral cortex and induces hyperexcitability via the α2δ1/Rac1 signaling pathway; gabapentin (an α2δ1 antagonist) inhibited epileptiform discharges in the peritumoral cortex.\",\n      \"method\": \"TSP2-overexpressing/KO glioma cell implantation in rats, spine/synapse density quantification, EEG-like epileptiform discharge recording, gabapentin pharmacological rescue\",\n      \"journal\": \"Journal of neuropathology and experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain/loss-of-function with electrophysiological and structural readouts, single lab\",\n      \"pmids\": [\"33382873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TSP2 deficiency in liver cancer stem cells (CD133+) leads to reduced MMP activity inhibition, increased collagen degradation, and a softer matrix; a positive feed-forward loop exists where a soft-spot microenvironment enriches CD133+ cells that secrete less THBS2 due to histone H3 modification at the THBS2 promoter, maintaining local matrix softness and enhancing stemness.\",\n      \"method\": \"THBS2 KD/KO in HCC cells, MMP activity assays, atomic force microscopy (matrix stiffness), histone modification ChIP at THBS2 promoter, in vivo xenograft\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, AFM, MMP assays, in vivo), single lab\",\n      \"pmids\": [\"33717837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TSP2 deficiency in diabetic fibroblasts rescues cytoskeletal disorganization by restoring active Rac1 levels and WAVE2–F-actin co-localization, identifying a TSP2–Rac1–WAVE2–actin regulatory axis that controls fibroblast morphology, migration, traction force, and 3D contractility.\",\n      \"method\": \"TSP2 KO in diabetic fibroblasts, super-resolution microscopy, traction force microscopy, 3D contraction assay, Rac1 activity assay, WAVE2 co-localization imaging\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple state-of-the-art quantitative microscopy and biophysical methods with KO rescue, single rigorous study\",\n      \"pmids\": [\"36577792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Astrocyte-derived TSP2 binds α2δ1 to mediate retinal ganglion cell axon degeneration, compensatory synaptic remodeling in the inner plexiform layer, and visual dysfunction following ischemia/reperfusion injury; TSP2 knockdown (shRNA-AAV) and competitive inhibition of TSP2–α2δ1 binding by gabapentin both alleviated these effects.\",\n      \"method\": \"TSP2 shRNA-AAV transduction in rat retina, gabapentin injection, immunofluorescence, electron microscopy, Western blot, ERG/visual function assays\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with two independent interventions (genetic and pharmacological), multiple readouts, single lab\",\n      \"pmids\": [\"36471420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEBPB inhibits THBS2 expression by facilitating miR-29a-3p transcription; additionally, CEBPB inhibits B3GALTL transcription to reduce O-fucosylation and secretion of THBS2; secreted THBS2 interacts with ITGB1 and activates the PI3K/AKT signaling pathway to promote breast cancer cell migration, invasion, and EMT.\",\n      \"method\": \"Co-IP (THBS2–ITGB1 interaction), ChIP (CEBPB binding to miR-29a-3p and B3GALTL promoters), O-fucosylation analysis, PI3K/AKT pathway Western blot, rescue experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, post-translational modification analysis, and signaling rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36728807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A heterozygous missense mutation in THBS2 (p.Cys896Arg) causes a novel form of Ehlers-Danlos syndrome with vascular features in humans; CRISPR/Cas9 knock-in mice bearing the same mutation recapitulate the phenotype. Mechanistically, THBS2 loss-of-function attenuates MMP2 clearance, enhancing MMP2-mediated proteoglycan cleavage and causing ECM abnormalities including disorganized collagen fibers and abnormal fibroblast/endothelial cell morphology.\",\n      \"method\": \"Clinical phenotyping, TEM, CRISPR/Cas9 KI mouse generation, histology, bleeding time assays, MMP2 clearance mechanistic analysis\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — human genetic variant, CRISPR KI mouse recapitulation, TEM structural analysis, and MMP2 functional mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"38433265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"THBS2 secreted by matrix CAFs (mCAFs) directly binds to SDC4 (syndecan-4) on tumor cells to enhance epithelial-mesenchymal transition (EMT) programs in lung adenocarcinoma, establishing the THBS2–SDC4–EMT axis as a mediator of CAF-tumor crosstalk.\",\n      \"method\": \"Single-cell RNA-seq, spatial transcriptomics, multiplex IHC, in vitro and in vivo binding/functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with functional EMT readout and in vivo validation, single lab\",\n      \"pmids\": [\"40973793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"THBS2 promotes collagen synthesis in IPF fibroblasts through the TGF-β1/Smad2/3 signaling pathway; THBS2 overexpression increases COL1A1, COL1A2, COL3A1, LOX, and LOXL2, and THBS2 knockdown attenuates these effects; exogenous THBS2 protein aggravates bleomycin-induced pulmonary fibrosis in mice.\",\n      \"method\": \"THBS2 overexpression/KD in IPF fibroblasts, TGF-β1 inhibitor (SB525334), Western blot, qPCR, bleomycin mouse model with exogenous THBS2 protein\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with pharmacological pathway rescue and in vivo validation, single lab\",\n      \"pmids\": [\"40676074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14 stabilizes THBS2 mRNA via m6A modification recognized by YTHDF2; METTL14 knockdown reduces THBS2 expression and alleviates high-glucose-induced HK-2 cell damage (apoptosis, fibrosis, inflammation, ferroptosis), while THBS2 overexpression negates these protective effects.\",\n      \"method\": \"m6A-RIP-qPCR (THBS2 interaction with METTL14 and YTHDF2), METTL14 KD, THBS2 KD/overexpression, CCK-8, flow cytometry, ELISA, Western blot\",\n      \"journal\": \"Experimental and clinical endocrinology & diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-RIP validation plus genetic rescue experiments, single lab\",\n      \"pmids\": [\"40730238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TSP2 deficiency in dermal fibroblasts upregulates TGF-β3 and Wnt4/β-catenin signaling, enhancing fibroblast proliferation and migration; CRISPR/Cas9 TSP2 KO in NIH3T3 cells confirmed that TSP2 negatively regulates these pro-regenerative pathways.\",\n      \"method\": \"Bulk RNA sequencing of WT vs TSP2-KO primary fibroblasts, CRISPR/Cas9 KO validation, proliferation and migration assays, pathway reporter assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus CRISPR KO with functional readouts, single lab\",\n      \"pmids\": [\"41427771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Blocking the TCA cycle in HNSCC cells (via CPI-613) induces ER stress, which directly suppresses THBS2 transcription through spliced XBP1; reduced secretion of THBS2 enhances CD36+CD8+ T-cell proliferation and cytotoxicity by upregulating AKT-mTOR signaling, enhancing antitumor immunity in a syngeneic orthotopic mouse model.\",\n      \"method\": \"CPI-613 treatment, ChIP/reporter assay (XBP1 binding to THBS2 promoter), THBS2 secretion ELISA, T-cell functional assays, syngeneic mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional mechanism (XBP1→THBS2) with functional T-cell and in vivo readouts, single lab\",\n      \"pmids\": [\"40293258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"THBS2 interacts with INHBA to activate the FAK/PI3K/AKT signaling pathway in prostate cancer cells, promoting proliferation, migration, invasion, and EMT; INHBA knockdown reverses the oncogenic effects of THBS2 overexpression.\",\n      \"method\": \"STRING protein interaction analysis, Western blot co-expression, INHBA siRNA rescue, FAK/PI3K/AKT pathway Western blot, functional assays (CCK-8, wound healing, Transwell)\",\n      \"journal\": \"Analytical cellular pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction inferred from STRING database with partial Western blot and rescue experiments, no direct binding assay, single lab\",\n      \"pmids\": [\"41810913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"THBS2+ fibroblasts interact with colorectal cancer cells via THBS2–CD36 and THBS2–SDC1 pathways; depletion of THBS2+ fibroblasts in an AAV-mediated mouse model enhanced polyp formation but suppressed tumor formation, establishing a stage-specific pro-tumorigenic role for THBS2+ fibroblasts in CRC malignant transformation.\",\n      \"method\": \"Multiplex immunostaining, AAV-mediated THBS2+ fibroblast depletion mouse model, multi-omics spatial analysis\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo cell depletion with defined phenotypic readout, receptor pathway identification, single lab\",\n      \"pmids\": [\"41640327\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THBS2 (TSP2) is a secreted homotrimeric matricellular glycoprotein that directly binds and mediates clearance of MMP2 (and MMP9), regulates ECM collagen fibril architecture and mechanical properties, modulates Notch signaling by binding Jagged1 and Notch ectodomains and driving LRP1-dependent trans-endocytosis, promotes excitatory synaptogenesis via α2δ1/Rac1 signaling, activates MAPK and PI3K/AKT pathways downstream of integrin αvβ3/CD36 and SDC4/ITGB1 receptors on tumor and stromal cells, promotes collagen synthesis through TGF-β1/Smad2/3 signaling in fibroblasts, and is negatively regulated by a TSP2–Rac1–WAVE2–actin axis that controls cytoskeletal organization; loss-of-function studies in mice reveal roles in wound healing, intraocular pressure regulation, auditory synapse maintenance, and fracture repair through modulation of angiogenesis and MSC differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"THBS2 (TSP2) is a secreted matricellular glycoprotein that governs extracellular matrix architecture, remodeling, and signaling, distinct in expression and function from the related thrombospondin TSP1 [#0, #2]. A central activity is the negative regulation of matrix metalloproteinases: TSP2 binds and promotes clearance of MMP2 (and MMP9), and loss of this function increases MMP2-mediated proteoglycan cleavage and produces disorganized collagen fibers and abnormal cell morphology [#18, #4]. Through this and direct ECM-structuring roles, TSP2 controls collagen fibril diameter, matrix stiffness and mechanical strength, with consequences for intraocular pressure regulation, matrix remodeling permissiveness, and cancer stem-cell-supporting matrix softness [#6, #9, #14]. A heterozygous missense mutation (p.Cys896Arg) causes a vascular-featured form of Ehlers-Danlos syndrome, recapitulated in CRISPR knock-in mice and mechanistically linked to attenuated MMP2 clearance [#18]. TSP2 also acts as a signaling ligand: it potentiates Notch signaling by binding Jagged1 and Notch ectodomains and driving LRP1-dependent trans-endocytosis [#5, #8], engages neuronal \\u03b12\\u03b41/Rac1 signaling to control excitatory synapse formation and synaptic maintenance [#13, #16, #10], and binds tumor-cell receptors including integrin \\u03b1v\\u03b23/CD36, SDC4, and ITGB1 to activate MAPK and PI3K/AKT pathways downstream of CAF-derived TSP2, promoting EMT and tumor progression [#12, #19, #17]. In fibroblasts, TSP2 promotes TGF-\\u03b21/Smad2/3-driven collagen synthesis in fibrosis [#20] yet negatively regulates a Rac1\\u2013WAVE2\\u2013actin cytoskeletal axis and Wnt4/\\u03b2-catenin pro-regenerative programs [#15, #22]. Its expression is controlled transcriptionally (p53, NF-\\u03baB, Sp1 sites; CEBPB, XBP1) and post-transcriptionally (METTL14/YTHDF2 m6A stabilization, miR-29a-3p) [#1, #17, #23, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing that THBS2 is a distinct gene product from THBS1 with a divergent tissue expression pattern resolved whether the two thrombospondins were functionally interchangeable.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and tissue expression profiling in mouse\",\n      \"pmids\": [\"1712771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or biochemical activity assigned at cloning\", \"Protein-level localization and partners undefined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapping the human THBS2 promoter and tissue-specific transcription start sites explained how THBS2 expression is differentially regulated across tissues.\",\n      \"evidence\": \"Genomic sequencing, 5' RACE, and PCR-based transcription start site mapping\",\n      \"pmids\": [\"9249061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional contribution of each transcription factor site not tested\", \"No link to physiological regulation\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Genetic epistasis in double-null mice distinguished the non-redundant roles of TSP1 and TSP2, showing TSP1 dominates the wound-healing response.\",\n      \"evidence\": \"Single and double TSP1/TSP2 knockout mouse comparison with immunohistochemistry and cytokine measurement\",\n      \"pmids\": [\"12213711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the TSP2-specific wound contribution not defined\", \"Receptor/effector pathway not isolated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that TSP2 overexpression suppresses MMP2/MMP9 while inducing MMP12/MMP17 positioned TSP2 as an MMP-expression modulator in carcinoma cells.\",\n      \"evidence\": \"cDNA array and Western blot after stable TSP2 overexpression in SW480 colon carcinoma cells\",\n      \"pmids\": [\"12792739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Distinguishes expression effects from direct binding/clearance not addressed here\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"A functional splicing variant linked THBS2-MMP binding to human disease, showing exon-11 skipping reduces MMP2/MMP9 interaction and confers lumbar disc herniation susceptibility.\",\n      \"evidence\": \"Genetic association study, in vivo splicing assay, and THBS2-MMP binding assay in two Japanese populations\",\n      \"pmids\": [\"18455130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the THBS2-MMP interaction not resolved\", \"Mechanism of clearance versus inhibition not separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying TSP2 as a Jagged1/Notch3 co-ligand that drives LRP1-dependent trans-endocytosis revealed a signaling, not purely structural, function for the matricellular protein.\",\n      \"evidence\": \"Co-IP/pulldown, LRP1-deficient fibroblast rescue, RAP inhibition, and endocytosis assays\",\n      \"pmids\": [\"20472562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of Notch3 potentiation not established\", \"Whether other Notch receptors are similarly modulated unknown at the time\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Lower intraocular pressure and altered fibril diameter in TSP2-null mice established a role for TSP2 in trabecular meshwork ECM composition and aqueous outflow.\",\n      \"evidence\": \"Rebound tonometry, fluorophotometry, TEM, and immunofluorescence in TSP2-null versus WT mice\",\n      \"pmids\": [\"22930728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mediator linking TSP2 loss to fibril changes not identified\", \"MMP involvement not tested in this tissue\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing THBS2 binds NOTCH1/2 and inhibits JAG1-NOTCH2 interactions extended its Notch-modulating role and implicated it as a modifier in Alagille syndrome.\",\n      \"evidence\": \"Reporter mouse, co-IP, JAG1-NOTCH2 blocking assay, and Thbs2-null liver histology\",\n      \"pmids\": [\"28090565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent potentiation versus inhibition of Notch not reconciled\", \"Genetic modifier role not validated in patients\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Decellularized TSP2-KO matrix established that TSP2 sets ECM mechanical properties and remodeling permissiveness, with degradation products being bioactive.\",\n      \"evidence\": \"SEM, mechanical testing, subcutaneous implantation, migration assays, and pepsin digestion of ECM\",\n      \"pmids\": [\"29631168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of pro-migratory degradation fragments unknown\", \"Direct molecular mechanism of stiffening not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking TSP2 deficiency to oxygen-dependent MSC fate during fracture repair connected its angiogenic regulation to bone-forming pathway choice.\",\n      \"evidence\": \"Computational modeling validated against TSP2-null mouse IHC (pimonidazole hypoxia marker)\",\n      \"pmids\": [\"23775935\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Largely a computational model with limited experimental validation\", \"Direct molecular control of MSC differentiation by TSP2 not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating TSP2 is required for cochlear afferent synapse recovery after noise revealed a synaptic-maintenance role distinct from TSP1.\",\n      \"evidence\": \"TSP2-null mice, auditory brainstem response, afferent synapse counting, and noise exposure\",\n      \"pmids\": [\"30928339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating cochlear synaptic effect not identified in this study\", \"Cell source of TSP2 in cochlea unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining a CAF-derived TGF-\\u03b21-THBS2-integrin \\u03b1v\\u03b23/CD36-MAPK feedback circuit established TSP2 as a stromal signaling ligand driving tumor growth.\",\n      \"evidence\": \"Quantitative proteomics, RNA-ISH, co-culture, receptor/MEK/JNK inhibition rescue, and in vivo PDAC assays\",\n      \"pmids\": [\"34958892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of \\u03b1v\\u03b23 versus CD36 not dissected\", \"Whether the same circuit operates in other tumor types unknown at the time\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing TSP2 promotes peritumoral excitatory synaptogenesis and hyperexcitability via \\u03b12\\u03b41/Rac1 connected its synaptogenic activity to glioma-associated epilepsy.\",\n      \"evidence\": \"TSP2 gain/loss glioma implantation in rats, synapse density quantification, epileptiform recordings, and gabapentin rescue\",\n      \"pmids\": [\"33382873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of Rac1 in synapse assembly not defined here\", \"Endogenous neuronal versus tumor source of TSP2 not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A CD133+ stem-cell feed-forward loop showed that reduced TSP2 (via H3 promoter modification) lowers MMP inhibition, softens matrix, and reinforces stemness.\",\n      \"evidence\": \"THBS2 KD/KO in HCC cells, MMP activity assays, atomic force microscopy, promoter ChIP, and xenografts\",\n      \"pmids\": [\"33717837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the histone-modifying enzyme not pinned down\", \"Causality between softness and stemness only correlative in part\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying a TSP2-Rac1-WAVE2-actin axis that TSP2 negatively controls explained how TSP2 governs fibroblast morphology, migration, and contractility.\",\n      \"evidence\": \"TSP2 KO in diabetic fibroblasts, super-resolution and traction force microscopy, 3D contraction, and Rac1 activity assays\",\n      \"pmids\": [\"36577792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor linking secreted TSP2 to intracellular Rac1 not identified\", \"Generality beyond diabetic fibroblasts untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Astrocyte-derived TSP2 binding \\u03b12\\u03b41 to drive RGC axon degeneration and synaptic remodeling after ischemia extended the \\u03b12\\u03b41 axis to retinal injury.\",\n      \"evidence\": \"TSP2 shRNA-AAV and gabapentin in rat retina, immunofluorescence, EM, Western blot, and ERG/visual assays\",\n      \"pmids\": [\"36471420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether axon degeneration is direct or downstream of synaptic change unclear\", \"Signaling steps downstream of \\u03b12\\u03b41 not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining CEBPB-driven repression via miR-29a-3p and B3GALTL O-fucosylation control of secretion, plus a THBS2-ITGB1-PI3K/AKT axis, linked THBS2 regulation to breast cancer EMT.\",\n      \"evidence\": \"Co-IP, ChIP, O-fucosylation analysis, PI3K/AKT Western blot, and rescue experiments\",\n      \"pmids\": [\"36728807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative importance of transcriptional versus secretory control not quantified\", \"ITGB1 binding site not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A human THBS2 missense mutation causing vascular Ehlers-Danlos syndrome, recapitulated in knock-in mice, established THBS2 as a Mendelian disease gene acting through impaired MMP2 clearance.\",\n      \"evidence\": \"Clinical phenotyping, TEM, CRISPR/Cas9 knock-in mice, histology, bleeding-time assays, and MMP2 clearance analysis\",\n      \"pmids\": [\"38433265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural consequence of p.Cys896Arg on trimerization not resolved\", \"Why a heterozygous variant is sufficient not fully explained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying a THBS2-SDC4-EMT axis in lung adenocarcinoma added syndecan-4 as a tumor-cell receptor for CAF-derived THBS2.\",\n      \"evidence\": \"Single-cell RNA-seq, spatial transcriptomics, multiplex IHC, and binding/functional assays\",\n      \"pmids\": [\"40973793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding affinity not quantified\", \"Downstream signaling from SDC4 not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing THBS2 drives collagen synthesis through TGF-\\u03b21/Smad2/3 in IPF fibroblasts established a pro-fibrotic function in lung fibrosis.\",\n      \"evidence\": \"THBS2 overexpression/KD in IPF fibroblasts, TGF-\\u03b21 inhibitor, Western blot, qPCR, and bleomycin mouse model with exogenous THBS2\",\n      \"pmids\": [\"40676074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating TSP2-induced Smad activation not identified\", \"Reconciliation with TSP2's negative regulation of regenerative pathways not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"METTL14/YTHDF2 m6A stabilization of THBS2 mRNA in renal tubular cells revealed an epitranscriptomic control point coupling THBS2 to diabetic injury.\",\n      \"evidence\": \"m6A-RIP-qPCR, METTL14 KD, THBS2 KD/overexpression, and apoptosis/fibrosis/ferroptosis readouts in HK-2 cells\",\n      \"pmids\": [\"40730238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of m6A control not established\", \"Downstream effectors of THBS2 in tubular damage unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that TSP2 loss upregulates TGF-\\u03b23 and Wnt4/\\u03b2-catenin to enhance fibroblast proliferation/migration defined TSP2 as a negative regulator of pro-regenerative dermal programs.\",\n      \"evidence\": \"Bulk RNA-seq of WT versus TSP2-KO fibroblasts, CRISPR KO validation, and proliferation/migration/reporter assays\",\n      \"pmids\": [\"41427771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which secreted TSP2 suppresses these pathways not defined\", \"In vivo regeneration phenotype not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking TCA-cycle blockade to ER-stress/XBP1 suppression of THBS2 transcription connected THBS2 secretion to suppression of CD36+CD8+ T-cell antitumor immunity.\",\n      \"evidence\": \"CPI-613 treatment, XBP1 ChIP/reporter, THBS2 ELISA, T-cell functional assays, and syngeneic orthotopic mouse model\",\n      \"pmids\": [\"40293258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effect of THBS2 on T cells versus indirect not fully separated\", \"Receptor on T cells mediating the effect not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"AAV-mediated depletion of THBS2+ fibroblasts revealed a stage-specific pro-tumorigenic role acting through THBS2-CD36 and THBS2-SDC1 pathways in colorectal cancer.\",\n      \"evidence\": \"Multiplex immunostaining, AAV fibroblast depletion mouse model, and multi-omics spatial analysis\",\n      \"pmids\": [\"41640327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing effects on polyp versus tumor formation mechanistically unresolved\", \"Direct THBS2-SDC1 binding not biochemically validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same secreted TSP2 molecule selects among its many receptors (LRP1, \\u03b12\\u03b41, \\u03b1v\\u03b23/CD36, SDC4, SDC1, ITGB1) and switches between MMP clearance, Notch modulation, synaptogenesis, and pro/anti-fibrotic signaling in a context-dependent manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model relating TSP2 domains to receptor selectivity\", \"No unified framework reconciling pro- and anti-regenerative/fibrotic roles\", \"Receptors linking secreted TSP2 to intracellular Rac1/WAVE2 control not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 18, 5, 8]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [12, 13, 16, 19, 17]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6, 9, 18]},\n      {\"term_id\": \"GO:0005102\", \"supporting_discovery_ids\": [4, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [9, 12, 18, 23]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [6, 9, 14, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [6, 9, 18, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 12, 17, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 8, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MMP2\", \"MMP9\", \"JAG1\", \"NOTCH3\", \"LRP1\", \"ITGB3\", \"CD36\", \"SDC4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}