{"gene":"THBS2","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":1991,"finding":"THBS2 is the product of a second, distinct thrombospondin gene (Thbs2) expressed in multiple mouse tissues in a pattern that differs from TSP1, establishing that two structurally related but distinct TSP proteins exist in the same organism.","method":"cDNA cloning, genomic characterization, tissue expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — original gene identification with sequence characterization, foundational paper with 114 citations","pmids":["1712771"],"is_preprint":false},{"year":1997,"finding":"The human THBS2 gene promoter contains putative binding sites for p53, NF-κB, Sp1, Myc-CF1, NF-Y, AP1, and GATA; tissue-specific differences in transcription start site selection (exons 1A/1B separated by a small intron) contribute to differential THBS2 expression across tissues.","method":"Genomic sequencing, 5' RACE, PCR mapping of transcription start sites","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1 — direct experimental mapping of promoter and transcription start sites; single lab study","pmids":["9249061"],"is_preprint":false},{"year":2002,"finding":"In double TSP1/TSP2-null mice, the wound-healing phenotype is dominated by loss of TSP1 (delayed healing, impaired inflammation, reduced macrophage recruitment and MCP-1) rather than loss of TSP2, demonstrating that TSP1 and TSP2 have distinct temporal/spatial roles in wound healing with TSP1 dictating inflammatory-phase outcomes.","method":"Double-knockout mouse model, immunohistochemistry, wound healing assay","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via double KO mouse with defined cellular phenotypes; 259 citations","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, identifying TSP2 as a multifunctional modulator of matrix metalloproteinase activity.","method":"cDNA array, Western blot, stable gene overexpression in cell line","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 — loss/gain-of-function with defined molecular readouts; single lab","pmids":["12792739"],"is_preprint":false},{"year":2008,"finding":"An intronic SNP in THBS2 (IVS10-8C→T; rs9406328) in a polypyrimidine tract causes increased skipping of exon 11, and this exon-skipping variant results in decreased THBS2 interaction with MMP2 and MMP9, linking alternative splicing of THBS2 to disrupted MMP regulation and susceptibility to lumbar-disc herniation.","method":"Genetic association study, in vivo splicing assay, functional binding assay (THBS2–MMP interaction)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 — functional splicing and protein-interaction experiments combined with genetic evidence; 94 citations","pmids":["18455130"],"is_preprint":false},{"year":2010,"finding":"TSP2 potentiates Notch3 signaling by binding both Jagged1 and Notch3 ectodomains; this activity requires LRP1 expression in the signal-sending cell, as TSP2 stimulates Notch3 trans-endocytosis into wild-type but not LRP1-deficient fibroblasts, and recombinant Notch3 and Jagged1 interact with the LRP1 85-kDa B-chain.","method":"Co-immunoprecipitation, receptor-associated protein inhibition, fibroblast LRP1 KO experiments, endocytosis assay, recombinant protein binding","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Co-IP, KO fibroblasts, endocytosis assay, recombinant binding); single lab but strong mechanistic evidence","pmids":["20472562"],"is_preprint":false},{"year":2012,"finding":"TSP2-null mice exhibit lower intraocular pressure than wild-type, associated with increased aqueous outflow facility and larger collagen fibril diameters in the trabecular meshwork, indicating TSP2 regulates ECM structure and aqueous humor outflow in the eye.","method":"TSP2-null mouse model, tonometry, fluorophotometry, transmission electron microscopy, immunofluorescence","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse with defined physiological and ultrastructural phenotypes; single lab","pmids":["22930728"],"is_preprint":false},{"year":2013,"finding":"TSP2 regulates bone fracture repair by controlling vascular density: increased angiogenesis in TSP2-null mice leads to higher oxygen availability, which shifts mesenchymal stem cell fate from endochondral to intramembranous ossification.","method":"TSP2-null mouse fracture model, computational modeling, immunohistochemical pimonidazole hypoxia detection","journal":"Journal of orthopaedic research","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model with mechanistic computational support and hypoxia measurement; single lab","pmids":["23775935"],"is_preprint":false},{"year":2016,"finding":"THBS2 interacts with NOTCH1 and NOTCH2 ectodomains and can inhibit JAG1-NOTCH2 interactions; THBS2 is expressed in bile ducts and periportal regions, and THBS2-null mice show increased microvessels in portal regions, placing THBS2 as a modifier of JAG1-NOTCH2 signaling relevant to Alagille syndrome.","method":"Co-immunoprecipitation/protein interaction assay, reporter mouse line, THBS2-null mouse histology, GWAS in human cohort","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein interaction assay plus KO mouse phenotype; single lab","pmids":["28090565"],"is_preprint":false},{"year":2018,"finding":"Decellularized matrix from TSP2-KO mice has altered collagen fibril structure, reduced mechanical stiffness, and promotes greater cell migration and vascularization compared to WT matrix; cell-derived ECM from TSP2-null fibroblasts is more permissive to fibroblast migration, demonstrating TSP2 directly regulates ECM physical properties and cell migration.","method":"Scanning electron microscopy, mechanical testing, subcutaneous implantation, in vitro migration assay with TSP2-null fibroblast ECM","journal":"Biomaterials","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (EM, mechanics, in vivo implantation, in vitro migration) with KO model; replicated in vivo and in vitro","pmids":["29631168"],"is_preprint":false},{"year":2019,"finding":"TSP2-null mice show unique and overlapping roles with TSP1 in cochlear synapse maintenance; TSP2 KO mice exhibit worse recovery of afferent synaptic counts and ABR following noise exposure specifically at mid-to-high frequencies, and TSP2 protein levels are elevated in TSP1-null inner ears, suggesting functional compensation.","method":"TSP1/TSP2 KO mouse models, synaptic counting, auditory brainstem response measurement","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — KO mouse model with electrophysiology and synaptic quantification; single lab","pmids":["30928339"],"is_preprint":false},{"year":2019,"finding":"TSP2 deficiency in diabetic fibroblasts is associated with decreased active Rac1 and loss of WAVE2-F-actin co-localization; deletion of TSP2 in diabetic fibroblasts rescues cytoskeletal disorganization, restoring normal Rac1 activity, WAVE2-F-actin co-localization, cell morphology, migration speed, traction force, and contractility.","method":"TSP2-KO in diabetic fibroblast model, advanced microscopy (FRAP, traction force), Rac1 activity assay, F-actin/WAVE2 co-localization imaging","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 — multiple state-of-the-art orthogonal methods with genetic rescue; identifies TSP2-Rac1-WAVE2-actin as mechanistic axis","pmids":["36577792"],"is_preprint":false},{"year":2021,"finding":"Cancer cell-secreted TGF-β1 activates cancer-associated fibroblasts to induce THBS2 expression via p-Smad2/3; CAF-derived THBS2 then binds membrane receptors integrin αvβ3/CD36 on PDAC cells to activate the MAPK pathway, promoting tumor growth and adhesion, forming a TGF-β1→THBS2→integrin αvβ3/CD36→MAPK feedback circuit.","method":"RNA in situ hybridization, quantitative proteomics, IHC, pathway inhibitor rescue experiments (anti-integrin αvβ3, CD36, MEK, JNK), in vitro and in vivo functional assays","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway defined by multiple inhibitor rescues and in vivo/in vitro corroboration; 82 citations","pmids":["34958892"],"is_preprint":false},{"year":2021,"finding":"Glioma-derived TSP2 promotes excitatory synapse formation in peritumoral cortex via the α2δ1/Rac1 signaling pathway; TSP2 overexpression increases spine and excitatory synapse density and epileptiform discharge frequency, while the α2δ1 antagonist gabapentin inhibits these effects.","method":"Stereotactic glioma cell implantation (WT, TSP2-OE, TSP2-KO C6 cells), EEG recording, spine/synapse density quantification, gabapentin pharmacological rescue","journal":"Journal of neuropathology and experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gain/loss of function with pharmacological rescue; single lab","pmids":["33382873"],"is_preprint":false},{"year":2021,"finding":"THBS2 deficiency in CD133+ liver cancer stem cells promotes collagen degradation and matrix softening by increasing MMP activity; a positive feed-forward loop exists where a soft-spot ECM microenvironment enriches THBS2-deficient CD133+ cells through histone H3 modification at the THBS2 promoter, maintaining localized ECM softness and enhancing stemness.","method":"Cancer stem cell isolation, ECM stiffness measurement, MMP activity assay, chromatin/histone modification analysis, in vivo xenograft","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods linking THBS2 to MMP regulation and epigenetic control; single lab","pmids":["33717837"],"is_preprint":false},{"year":2021,"finding":"miR-29a-3p directly targets THBS2 and regulates its expression; reduced miR-29a-3p in PAH leads to elevated THBS2, which promotes cardiac fibrosis progression.","method":"Dual luciferase reporter assay, cell culture and mouse PAH model, qRT-PCR, Western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — validated direct miRNA-target relationship with animal model confirmation; single lab","pmids":["34638915"],"is_preprint":false},{"year":2022,"finding":"TSP2 deficiency in fibroblasts leads to cytoskeletal disorganization through the TSP2-Rac1-WAVE2-actin axis; TSP2-null fibroblasts show decreased active Rac1, disrupted WAVE2-F-actin co-localization, and produce thickened, less porous ECM that hinders normal fibroblast migration.","method":"TSP2 KO fibroblasts, multiple microscopy modalities, Rac1 activity assay, CDM analysis, traction force microscopy","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 — multiple state-of-the-art orthogonal methods; mechanistic axis confirmed by KO rescue","pmids":["36577792"],"is_preprint":false},{"year":2022,"finding":"Astrocyte-derived TSP2 binds α2δ1 to mediate degeneration of retinal ganglion cell axons and compensatory synaptic remodeling in the inner plexiform layer after retinal ischemia/reperfusion injury; TSP2 knockdown (shRNA-AAV) or competitive inhibition of TSP2-α2δ1 binding (gabapentin) alleviated synaptic/neurite alteration and visual dysfunction.","method":"Viral transduction (TSP2 shRNA-AAV), intravitreal drug injection (gabapentin, fluorocitrate), Western blot, immunofluorescence, electron microscopy, visual function testing","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic knockdown with pharmacological rescue; single lab, multiple orthogonal methods","pmids":["36471420"],"is_preprint":false},{"year":2023,"finding":"THBS2 promotes fibroblast proliferation and migration and increases collagen synthesis (COL1A1, COL1A2, COL3A1) via the TGF-β1/Smad2/3 signaling pathway in IPF; THBS2 also promotes inflammatory cytokine secretion (IL-1β, IL-6, IL-8); exogenous THBS2 protein aggravates bleomycin-induced fibrosis in mice.","method":"THBS2 overexpression/knockdown in IPF fibroblasts, exogenous protein administration, TGF-β1 inhibitor rescue, bleomycin mouse model, Western blot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — gain/loss of function with inhibitor rescue and in vivo model; single lab","pmids":["40676074"],"is_preprint":false},{"year":2023,"finding":"CEBPB facilitates miR-29a-3p transcription which negatively regulates THBS2 expression; CEBPB also inhibits B3GALTL transcription to reduce THBS2 O-fucosylation and secretion; THBS2 interacts with ITGB1 and activates the PI3K/AKT signaling pathway to promote breast cancer cell migration, invasion, and EMT.","method":"ChIP, luciferase reporter assay, Western blot, rescue experiments, Co-IP (THBS2-ITGB1 interaction)","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods defining transcriptional regulation, PTM (O-fucosylation), and receptor interaction; single lab","pmids":["36728807"],"is_preprint":false},{"year":2023,"finding":"THBS2 promotes hypertrophic scar fibroblast proliferation and migration through the TGFβ1/P-Smad2/3 signaling pathway, as established by single-cell sequencing analysis, immunofluorescence localization, and functional assays.","method":"scRNA-seq, machine learning, CCK8/wound healing assay, Western blot, immunofluorescence, qRT-PCR","journal":"International wound journal","confidence":"Medium","confidence_rationale":"Tier 2 — functional assays with pathway validation; single lab","pmids":["37986676"],"is_preprint":false},{"year":2024,"finding":"A heterozygous THBS2 missense mutation (p.Cys896Arg) causes a novel form of Ehlers-Danlos syndrome with vascular features; CRISPR/Cas9 knock-in mice bearing the same mutation replicate the human phenotype including disorganized collagen fibers and abnormal ECM near blood vessels, consistent with THBS2's known role in mediating MMP2 clearance to regulate ECM.","method":"Human genetic analysis, CRISPR/Cas9 KI mouse model, TEM, histology, bleeding time assay","journal":"European journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 — human mutation causally linked to disease, validated in CRISPR KI mouse with multiple orthogonal readouts; strong translational evidence","pmids":["38433265"],"is_preprint":false},{"year":2024,"finding":"THBS2 promotes gastric cancer progression and cancer stem cell-like characteristics through the Notch signaling pathway by regulating Notch3, HEY1, and HES1 proteins; miR-29b-3p directly targets the 3'-UTR of THBS2 mRNA to suppress its expression.","method":"Dual-luciferase reporter assay, Western blot, xenograft and metastasis assay in nude mice","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro gain/loss of function with pathway readouts; single lab","pmids":["39113869"],"is_preprint":false},{"year":2024,"finding":"YTHDF3 promotes THBS2 translation by recognizing m6A modification sites in the coding region of THBS2; THBS2 promotes corneal epithelial cell proliferation and migration by activating the Wnt/β-catenin signaling pathway, and enforced THBS2 expression accelerates corneal wound healing in diabetic mice.","method":"m6A-mRNA microarray, RIP assay, YTHDF3 KD/OE, THBS2 OE in cells and diabetic mouse cornea, Wnt/β-catenin pathway analysis","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 — m6A modification validated by RIP; functional consequences shown in vitro and in vivo; single lab","pmids":["39626342"],"is_preprint":false},{"year":2025,"finding":"THBS2 secreted by matrix CAFs directly binds SDC4 (syndecan-4) on tumor cells to enhance epithelial-mesenchymal transition programs in lung adenocarcinoma, as demonstrated by spatial transcriptomics, multiplex IHC, and in vivo/in vitro binding experiments.","method":"scRNA-seq, spatial transcriptomics, multiplex IHC, in vivo and in vitro functional experiments, protein-receptor binding assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — direct receptor-ligand interaction (THBS2-SDC4) identified with multiple orthogonal approaches; single lab","pmids":["40973793"],"is_preprint":false},{"year":2025,"finding":"TSP2 deficiency in fibroblasts upregulates TGF-β3 and Wnt4/β-catenin signaling, enhancing fibroblast proliferation and migration; CRISPR/Cas9 TSP2 KO in NIH3T3 fibroblasts confirmed that TSP2 negatively regulates these pro-regenerative pathways.","method":"Bulk RNA sequencing of WT vs TSP2 KO fibroblasts, CRISPR/Cas9 KO in NIH3T3, functional proliferation/migration assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptomic and functional validation with stable KO model; single lab","pmids":["41427771"],"is_preprint":false},{"year":2025,"finding":"Blocking the TCA cycle in HNSCC cells with CPI-613 induces ER stress, leading to increased spliced XBP1 which directly suppresses THBS2 transcription; reduced THBS2 secretion then enhances proliferation and cytotoxicity of tumor-infiltrating CD36+CD8+ T cells via AKT-mTOR signaling.","method":"CPI-613 treatment, ER stress induction assay, XBP1 transcriptional reporter, T-cell proliferation/cytotoxicity assay, syngeneic mouse model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway defined from TCA inhibition to THBS2 transcriptional suppression to immune activation; in vivo validation; single lab","pmids":["40293258"],"is_preprint":false},{"year":2025,"finding":"TSP2 siRNA knockdown reduces vascular smooth muscle cell (VSMC) proliferation and migration in vitro and reduces intimal hyperplasia in male but not female rats and mice after carotid injury, demonstrating a sex-specific role for TSP2 in vascular remodeling.","method":"siRNA knockdown, VSMC proliferation/chemotaxis assay, carotid balloon injury rat model, carotid ligation mouse model, adeno-associated virus siRNA delivery","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo KD with defined vascular phenotype; sexual dimorphism confirmed in two species","pmids":["40298323"],"is_preprint":false},{"year":2025,"finding":"METTL14 promotes m6A modification of THBS2 mRNA, which is recognized by YTHDF2 to stabilize THBS2 expression; elevated THBS2 in high-glucose conditions exacerbates HK-2 cell injury (apoptosis, fibrosis, inflammation, ferroptosis), and METTL14 knockdown is protective through reduction of THBS2.","method":"m6A-RIP assay, RIP-qPCR, siRNA knockdown, CCK-8, flow cytometry, ELISA, Western blot","journal":"Experimental and clinical endocrinology & diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — m6A modification validated by RIP; mechanistic axis METTL14-m6A-YTHDF2-THBS2 defined with multiple methods; single lab","pmids":["40730238"],"is_preprint":false},{"year":2025,"finding":"LXN positively correlates with THBS2 and LXN knockdown downregulates THBS2; the LXN-THBS2 signaling axis activates the TLR4-TGF-β/FAK pathway through autocrine THBS2 signaling to promote hepatic stellate cell activation and liver fibrosis.","method":"AAV9-mediated LXN knockdown in mouse liver fibrosis model, siRNA in LX-2 cells, qPCR, Western blot, IHC, immunofluorescence","journal":"Frontiers in bioscience","confidence":"Low","confidence_rationale":"Tier 3 — correlation and knockdown data; mechanistic link between LXN-THBS2-TLR4/TGF-β inferred but not directly demonstrated; single lab","pmids":["41761978"],"is_preprint":false}],"current_model":"THBS2 is a secreted homotrimeric matricellular glycoprotein that regulates extracellular matrix remodeling by controlling MMP2/MMP9 activity and clearance, modulates cell signaling through binding to receptors including integrin αvβ3, CD36, SDC4, LRP1, and α2δ1, enhances Notch signaling by bridging Jagged1 and Notch3 ectodomains via LRP1-mediated trans-endocytosis, promotes fibroblast cytoskeletal organization through a TSP2-Rac1-WAVE2-actin axis, and drives fibrosis through the TGF-β1/Smad2/3 pathway, while its expression is post-translationally regulated by O-fucosylation and at the mRNA level by m6A modification (METTL14/YTHDF2 and YTHDF3), collectively establishing THBS2 as a multifunctional ECM regulator controlling angiogenesis, wound healing, synaptogenesis, and cancer-stroma crosstalk."},"narrative":{"teleology":[{"year":1991,"claim":"Identification of THBS2 as a second, distinct thrombospondin gene with tissue-specific expression patterns differing from TSP1 established that the thrombospondin family comprises structurally related but non-redundant members.","evidence":"cDNA cloning and genomic characterization in mouse tissues","pmids":["1712771"],"confidence":"High","gaps":["No functional data on TSP2 protein activity","Tissue-level expression did not resolve cell-type specificity"]},{"year":2002,"claim":"Double TSP1/TSP2 knockout mice revealed that the two thrombospondins have distinct temporal roles in wound healing, with TSP1 dominating the inflammatory phase and TSP2 contributing separately, resolving the question of functional redundancy.","evidence":"Double-KO mouse wound healing model with immunohistochemistry","pmids":["12213711"],"confidence":"High","gaps":["TSP2-specific wound healing mechanism undefined","No molecular mediators of TSP2's distinct wound role identified"]},{"year":2003,"claim":"Demonstration that TSP2 overexpression downregulates MMP2 and MMP9 while upregulating other MMPs established TSP2 as a selective modulator of matrix metalloproteinase expression, providing the first mechanistic link to ECM remodeling.","evidence":"Stable TSP2 overexpression in SW480 colon carcinoma cells with cDNA array and Western blot","pmids":["12792739"],"confidence":"Medium","gaps":["Direct vs. indirect regulation of MMP transcription not distinguished","Single cell line limits generalizability"]},{"year":2008,"claim":"An intronic SNP causing exon 11 skipping produced a THBS2 variant with reduced MMP2/MMP9 binding, connecting alternative splicing to disrupted protease regulation and identifying a genetic mechanism for THBS2 functional variation.","evidence":"Genetic association combined with in vivo splicing assay and functional binding assay","pmids":["18455130"],"confidence":"High","gaps":["Structural basis for exon 11-encoded domain's MMP interaction unknown","Effect of the splice variant on ECM architecture not tested"]},{"year":2010,"claim":"Discovery that TSP2 bridges Jagged1 and Notch3 ectodomains and potentiates Notch signaling through LRP1-dependent trans-endocytosis revealed a novel receptor-bridging mechanism, expanding TSP2's role beyond ECM remodeling to intercellular signaling.","evidence":"Co-IP, LRP1-KO fibroblast experiments, endocytosis assay, recombinant protein binding","pmids":["20472562"],"confidence":"High","gaps":["Whether TSP2-Notch bridging occurs in vivo during development not shown","Stoichiometry and affinity of the ternary complex undefined"]},{"year":2012,"claim":"TSP2-null mice exhibited lower intraocular pressure with altered trabecular meshwork collagen fibril structure, extending TSP2's ECM-organizing role to a specific tissue with clinical relevance for aqueous humor dynamics.","evidence":"TSP2-null mouse tonometry, fluorophotometry, and transmission electron microscopy","pmids":["22930728"],"confidence":"Medium","gaps":["Molecular mechanism linking TSP2 to collagen fibril diameter control not defined","Single KO model without rescue"]},{"year":2013,"claim":"Fracture studies in TSP2-null mice demonstrated that TSP2 controls vascular density and thereby oxygen availability, which dictates mesenchymal stem cell fate choice between endochondral and intramembranous ossification, linking TSP2's anti-angiogenic function to bone repair outcomes.","evidence":"TSP2-null mouse fracture model with computational modeling and pimonidazole hypoxia detection","pmids":["23775935"],"confidence":"Medium","gaps":["Direct anti-angiogenic receptor mechanism in bone not identified","Computational model not validated by independent experiments"]},{"year":2016,"claim":"THBS2 was shown to interact with NOTCH1/2 ectodomains and inhibit JAG1-NOTCH2 signaling, positioning THBS2 as a modifier of Notch pathway output beyond the previously known Notch3 interaction and linking it to Alagille syndrome biology.","evidence":"Co-IP, THBS2-null mouse histology, GWAS in human cohort","pmids":["28090565"],"confidence":"Medium","gaps":["Mechanism of THBS2-NOTCH2 inhibition vs. THBS2-Notch3 potentiation not reconciled","Functional rescue of Alagille phenotype by THBS2 modulation not demonstrated"]},{"year":2018,"claim":"Decellularized matrices from TSP2-KO mice showed altered collagen ultrastructure, reduced stiffness, and enhanced cell migration and vascularization, establishing that TSP2 directly shapes the physical and mechanical properties of the ECM.","evidence":"Scanning EM, mechanical testing, subcutaneous implantation, in vitro migration with TSP2-null fibroblast ECM","pmids":["29631168"],"confidence":"High","gaps":["Molecular mechanism of TSP2-collagen crosslinking or assembly not defined","Contribution of MMP deregulation vs. direct structural role not separated"]},{"year":2019,"claim":"TSP2-KO mice showed impaired cochlear synapse recovery after noise exposure, and compensatory upregulation of TSP2 in TSP1-null inner ears established TSP2 as a synaptogenic factor in the auditory system with partial functional overlap with TSP1.","evidence":"TSP1/TSP2 KO mouse models with synaptic counting and auditory brainstem response","pmids":["30928339"],"confidence":"Medium","gaps":["Receptor mediating TSP2 synaptogenesis in cochlea not identified","Whether TSP2 promotes synapse formation or maintenance not distinguished"]},{"year":2021,"claim":"Multiple studies converged on THBS2 as a stromal-tumor crosstalk mediator: TGF-β1 induces THBS2 in cancer-associated fibroblasts, which then activates integrin αvβ3/CD36-MAPK signaling on tumor cells, while THBS2 deficiency in cancer stem cells drives MMP-dependent matrix softening and stemness, revealing THBS2 as a bidirectional regulator of the tumor microenvironment.","evidence":"Quantitative proteomics, pathway inhibitor rescue, xenografts (PDAC and liver cancer models), MMP activity assays, histone modification analysis","pmids":["34958892","33717837"],"confidence":"High","gaps":["Whether THBS2-mediated MMP clearance and receptor signaling operate independently or synergistically in tumors unclear","Therapeutic targeting of THBS2 in cancer not validated"]},{"year":2021,"claim":"THBS2 was shown to promote excitatory synaptogenesis via α2δ1/Rac1 signaling in peritumoral cortex and to drive fibrosis via TGF-β1/Smad2/3 signaling, defining two distinct receptor-pathway axes through which THBS2 exerts context-dependent effects.","evidence":"Glioma implantation with gabapentin rescue (synaptogenesis); THBS2 OE/KD with TGF-β inhibitor rescue in fibroblasts and bleomycin mouse model (fibrosis)","pmids":["33382873","34638915","40676074","37986676"],"confidence":"Medium","gaps":["Structural basis for THBS2-α2δ1 interaction not resolved","Whether synaptogenic and fibrotic signaling share downstream effectors unknown"]},{"year":2022,"claim":"The TSP2–Rac1–WAVE2–actin axis was defined as the mechanism by which TSP2 controls fibroblast cytoskeletal organization, migration, and traction force, explaining how TSP2 deficiency alters cell-ECM mechanical coupling.","evidence":"TSP2-KO fibroblasts with FRAP, traction force microscopy, Rac1 activity assay, and WAVE2-F-actin co-localization imaging; diabetic fibroblast rescue model","pmids":["36577792"],"confidence":"High","gaps":["Receptor upstream of TSP2-Rac1 activation in fibroblasts not identified","Whether this axis operates in non-fibroblast cell types unknown"]},{"year":2023,"claim":"Post-transcriptional regulation of THBS2 was elucidated: CEBPB promotes miR-29a-3p to suppress THBS2 mRNA, while CEBPB also reduces B3GALTL-mediated O-fucosylation to limit THBS2 secretion; separately, YTHDF3 recognizes m6A modifications to promote THBS2 translation, establishing multi-layered regulation at mRNA and protein levels.","evidence":"ChIP, luciferase reporter assays, Co-IP (THBS2-ITGB1), RIP for m6A, YTHDF3 KD/OE in corneal epithelial cells and diabetic mouse cornea","pmids":["36728807","39626342"],"confidence":"Medium","gaps":["Integration of O-fucosylation, m6A, and miRNA regulation under physiological conditions not tested","Which m6A sites are functionally critical not mapped at single-nucleotide resolution"]},{"year":2024,"claim":"A heterozygous THBS2 missense mutation (p.Cys896Arg) was identified as the cause of a novel Ehlers-Danlos syndrome variant, validated by CRISPR knock-in mice that recapitulate collagen disorganization and vascular ECM defects, providing the first Mendelian disease directly caused by THBS2 mutation.","evidence":"Human genetic analysis, CRISPR/Cas9 knock-in mouse, TEM, histology, bleeding time assay","pmids":["38433265"],"confidence":"High","gaps":["Whether the mutation disrupts MMP clearance, collagen binding, or both not resolved","Penetrance and phenotypic spectrum in additional families not reported"]},{"year":2025,"claim":"THBS2 receptor repertoire expanded to include SDC4 on lung cancer cells and CD36 on CD8+ T cells; THBS2 binding to SDC4 drives EMT in lung adenocarcinoma, while tumor-secreted THBS2 suppresses CD36+CD8+ T cell cytotoxicity via AKT-mTOR signaling, revealing immunomodulatory functions.","evidence":"Spatial transcriptomics, multiplex IHC, protein-receptor binding assays, syngeneic mouse models, T-cell functional assays","pmids":["40973793","40293258"],"confidence":"Medium","gaps":["Structural basis of THBS2-SDC4 interaction not determined","Whether THBS2's immunosuppressive effect is generalizable across tumor types unknown"]},{"year":2025,"claim":"METTL14-mediated m6A modification of THBS2 mRNA recognized by YTHDF2 was shown to stabilize THBS2 expression in diabetic kidney injury, and TSP2 knockdown reduced vascular smooth muscle cell proliferation and intimal hyperplasia in a sex-specific manner, expanding THBS2's roles to renal pathology and sex-dimorphic vascular biology.","evidence":"m6A-RIP, siRNA KD, HK-2 cell injury model; siRNA KD in VSMCs, carotid injury in male/female rats and mice","pmids":["40730238","40298323"],"confidence":"Medium","gaps":["Whether YTHDF2 and YTHDF3 act on THBS2 mRNA at the same or distinct m6A sites is unresolved","Molecular basis of sex-specific TSP2 effects in vascular remodeling unknown"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of THBS2's selective receptor engagement across different cell types; how TSP2 simultaneously promotes and inhibits Notch signaling through different Notch paralogs; and whether TSP2's diverse context-dependent functions can be therapeutically targeted with domain-specific interventions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of full-length TSP2 or TSP2-receptor complexes","Mechanism reconciling Notch3 potentiation vs. NOTCH2 inhibition undefined","No clinical trials or validated therapeutic targeting of THBS2"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,5,14]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[12,13,17,24]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[9,12,19]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[9,14,21]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,12,24]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,4,9,14,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,8,12,13,22,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12,14,22,24,26]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,13,17]}],"complexes":[],"partners":["MMP2","MMP9","LRP1","NOTCH3","JAG1","ITGB1","SDC4","CD36"],"other_free_text":[]},"mechanistic_narrative":"THBS2 encodes a secreted matricellular glycoprotein that functions as a central regulator of extracellular matrix assembly, composition, and mechanical properties by controlling collagen fibril organization and modulating MMP2/MMP9 activity and clearance [PMID:29631168, PMID:18455130, PMID:12792739]. THBS2 signals through multiple cell-surface receptors—including integrin αvβ3, CD36, α2δ1, SDC4, ITGB1, and LRP1—to activate downstream MAPK, PI3K/AKT, Wnt/β-catenin, and Notch pathways, thereby regulating angiogenesis, fibroblast cytoskeletal organization via a Rac1–WAVE2–actin axis, synaptogenesis, and cancer-stroma crosstalk [PMID:34958892, PMID:36577792, PMID:20472562, PMID:33382873, PMID:40973793]. THBS2 expression is post-transcriptionally controlled by m6A mRNA modification (METTL14/YTHDF2 and YTHDF3) and by miR-29a-3p/miR-29b-3p, and its secretion is regulated by O-fucosylation [PMID:40730238, PMID:39626342, PMID:36728807]. A heterozygous missense mutation (p.Cys896Arg) in THBS2 causes a novel Ehlers-Danlos syndrome variant with vascular features, validated by CRISPR knock-in mice that recapitulate disorganized collagen and ECM abnormalities [PMID:38433265]."},"prefetch_data":{"uniprot":{"accession":"P35442","full_name":"Thrombospondin-2","aliases":[],"length_aa":1172,"mass_kda":130.0,"function":"Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. 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macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39626342","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":"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 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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":"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":"40293258","id":"PMC_40293258","title":"Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling.","date":"2025","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/40293258","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":"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":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":"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":"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":"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":"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":"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":"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":"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":"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":"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":"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},{"pmid":"41906361","id":"PMC_41906361","title":"The Clinical Role of miR-744-5p in Osteoarthritis and Its Regulation of Chondrocyte Inflammation Through the Modulation of Thrombospondin-2 (THBS2) Expression.","date":"2026","source":"International journal of rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41906361","citation_count":0,"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":"40571842","id":"PMC_40571842","title":"Neuroprotective Role of THBS2 in Experimental Spinal Cord Injury Via its Anti-neuroinflammatory and Anti-apoptotic Properties.","date":"2025","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40571842","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55589,"output_tokens":7133,"usd":0.136881},"stage2":{"model":"claude-opus-4-6","input_tokens":10912,"output_tokens":4371,"usd":0.245753},"total_usd":0.382634,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"THBS2 is the product of a second, distinct thrombospondin gene (Thbs2) expressed in multiple mouse tissues in a pattern that differs from TSP1, establishing that two structurally related but distinct TSP proteins exist in the same organism.\",\n      \"method\": \"cDNA cloning, genomic characterization, tissue expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original gene identification with sequence characterization, foundational paper with 114 citations\",\n      \"pmids\": [\"1712771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The human THBS2 gene promoter contains putative binding sites for p53, NF-κB, Sp1, Myc-CF1, NF-Y, AP1, and GATA; tissue-specific differences in transcription start site selection (exons 1A/1B separated by a small intron) contribute to differential THBS2 expression across tissues.\",\n      \"method\": \"Genomic sequencing, 5' RACE, PCR mapping of transcription start sites\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct experimental mapping of promoter and transcription start sites; single lab study\",\n      \"pmids\": [\"9249061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In double TSP1/TSP2-null mice, the wound-healing phenotype is dominated by loss of TSP1 (delayed healing, impaired inflammation, reduced macrophage recruitment and MCP-1) rather than loss of TSP2, demonstrating that TSP1 and TSP2 have distinct temporal/spatial roles in wound healing with TSP1 dictating inflammatory-phase outcomes.\",\n      \"method\": \"Double-knockout mouse model, immunohistochemistry, wound healing assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via double KO mouse with defined cellular phenotypes; 259 citations\",\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, identifying TSP2 as a multifunctional modulator of matrix metalloproteinase activity.\",\n      \"method\": \"cDNA array, Western blot, stable gene overexpression in cell line\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss/gain-of-function with defined molecular readouts; single lab\",\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 increased skipping of exon 11, and this exon-skipping variant results in decreased THBS2 interaction with MMP2 and MMP9, linking alternative splicing of THBS2 to disrupted MMP regulation and susceptibility to lumbar-disc herniation.\",\n      \"method\": \"Genetic association study, in vivo splicing assay, functional binding assay (THBS2–MMP interaction)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional splicing and protein-interaction experiments combined with genetic evidence; 94 citations\",\n      \"pmids\": [\"18455130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TSP2 potentiates Notch3 signaling by binding both Jagged1 and Notch3 ectodomains; this activity requires LRP1 expression in the signal-sending cell, as TSP2 stimulates Notch3 trans-endocytosis into wild-type but not LRP1-deficient fibroblasts, and recombinant Notch3 and Jagged1 interact with the LRP1 85-kDa B-chain.\",\n      \"method\": \"Co-immunoprecipitation, receptor-associated protein inhibition, fibroblast LRP1 KO experiments, endocytosis assay, recombinant protein binding\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Co-IP, KO fibroblasts, endocytosis assay, recombinant binding); single lab but strong mechanistic evidence\",\n      \"pmids\": [\"20472562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TSP2-null mice exhibit lower intraocular pressure than wild-type, associated with increased aqueous outflow facility and larger collagen fibril diameters in the trabecular meshwork, indicating TSP2 regulates ECM structure and aqueous humor outflow in the eye.\",\n      \"method\": \"TSP2-null mouse model, tonometry, fluorophotometry, transmission electron microscopy, immunofluorescence\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined physiological and ultrastructural phenotypes; single lab\",\n      \"pmids\": [\"22930728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TSP2 regulates bone fracture repair by controlling vascular density: increased angiogenesis in TSP2-null mice leads to higher oxygen availability, which shifts mesenchymal stem cell fate from endochondral to intramembranous ossification.\",\n      \"method\": \"TSP2-null mouse fracture model, computational modeling, immunohistochemical pimonidazole hypoxia detection\",\n      \"journal\": \"Journal of orthopaedic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with mechanistic computational support and hypoxia measurement; single lab\",\n      \"pmids\": [\"23775935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"THBS2 interacts with NOTCH1 and NOTCH2 ectodomains and can inhibit JAG1-NOTCH2 interactions; THBS2 is expressed in bile ducts and periportal regions, and THBS2-null mice show increased microvessels in portal regions, placing THBS2 as a modifier of JAG1-NOTCH2 signaling relevant to Alagille syndrome.\",\n      \"method\": \"Co-immunoprecipitation/protein interaction assay, reporter mouse line, THBS2-null mouse histology, GWAS in human cohort\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction assay plus KO mouse phenotype; single lab\",\n      \"pmids\": [\"28090565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Decellularized matrix from TSP2-KO mice has altered collagen fibril structure, reduced mechanical stiffness, and promotes greater cell migration and vascularization compared to WT matrix; cell-derived ECM from TSP2-null fibroblasts is more permissive to fibroblast migration, demonstrating TSP2 directly regulates ECM physical properties and cell migration.\",\n      \"method\": \"Scanning electron microscopy, mechanical testing, subcutaneous implantation, in vitro migration assay with TSP2-null fibroblast ECM\",\n      \"journal\": \"Biomaterials\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (EM, mechanics, in vivo implantation, in vitro migration) with KO model; replicated in vivo and in vitro\",\n      \"pmids\": [\"29631168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TSP2-null mice show unique and overlapping roles with TSP1 in cochlear synapse maintenance; TSP2 KO mice exhibit worse recovery of afferent synaptic counts and ABR following noise exposure specifically at mid-to-high frequencies, and TSP2 protein levels are elevated in TSP1-null inner ears, suggesting functional compensation.\",\n      \"method\": \"TSP1/TSP2 KO mouse models, synaptic counting, auditory brainstem response measurement\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with electrophysiology and synaptic quantification; single lab\",\n      \"pmids\": [\"30928339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TSP2 deficiency in diabetic fibroblasts is associated with decreased active Rac1 and loss of WAVE2-F-actin co-localization; deletion of TSP2 in diabetic fibroblasts rescues cytoskeletal disorganization, restoring normal Rac1 activity, WAVE2-F-actin co-localization, cell morphology, migration speed, traction force, and contractility.\",\n      \"method\": \"TSP2-KO in diabetic fibroblast model, advanced microscopy (FRAP, traction force), Rac1 activity assay, F-actin/WAVE2 co-localization imaging\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple state-of-the-art orthogonal methods with genetic rescue; identifies TSP2-Rac1-WAVE2-actin as mechanistic axis\",\n      \"pmids\": [\"36577792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cancer cell-secreted TGF-β1 activates cancer-associated fibroblasts to induce THBS2 expression via p-Smad2/3; CAF-derived THBS2 then binds membrane receptors integrin αvβ3/CD36 on PDAC cells to activate the MAPK pathway, promoting tumor growth and adhesion, forming a TGF-β1→THBS2→integrin αvβ3/CD36→MAPK feedback circuit.\",\n      \"method\": \"RNA in situ hybridization, quantitative proteomics, IHC, pathway inhibitor rescue experiments (anti-integrin αvβ3, CD36, MEK, JNK), in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined by multiple inhibitor rescues and in vivo/in vitro corroboration; 82 citations\",\n      \"pmids\": [\"34958892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Glioma-derived TSP2 promotes excitatory synapse formation in peritumoral cortex via the α2δ1/Rac1 signaling pathway; TSP2 overexpression increases spine and excitatory synapse density and epileptiform discharge frequency, while the α2δ1 antagonist gabapentin inhibits these effects.\",\n      \"method\": \"Stereotactic glioma cell implantation (WT, TSP2-OE, TSP2-KO C6 cells), EEG recording, spine/synapse density quantification, gabapentin pharmacological rescue\",\n      \"journal\": \"Journal of neuropathology and experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain/loss of function with pharmacological rescue; single lab\",\n      \"pmids\": [\"33382873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"THBS2 deficiency in CD133+ liver cancer stem cells promotes collagen degradation and matrix softening by increasing MMP activity; a positive feed-forward loop exists where a soft-spot ECM microenvironment enriches THBS2-deficient CD133+ cells through histone H3 modification at the THBS2 promoter, maintaining localized ECM softness and enhancing stemness.\",\n      \"method\": \"Cancer stem cell isolation, ECM stiffness measurement, MMP activity assay, chromatin/histone modification analysis, in vivo xenograft\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking THBS2 to MMP regulation and epigenetic control; single lab\",\n      \"pmids\": [\"33717837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-29a-3p directly targets THBS2 and regulates its expression; reduced miR-29a-3p in PAH leads to elevated THBS2, which promotes cardiac fibrosis progression.\",\n      \"method\": \"Dual luciferase reporter assay, cell culture and mouse PAH model, qRT-PCR, Western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — validated direct miRNA-target relationship with animal model confirmation; single lab\",\n      \"pmids\": [\"34638915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TSP2 deficiency in fibroblasts leads to cytoskeletal disorganization through the TSP2-Rac1-WAVE2-actin axis; TSP2-null fibroblasts show decreased active Rac1, disrupted WAVE2-F-actin co-localization, and produce thickened, less porous ECM that hinders normal fibroblast migration.\",\n      \"method\": \"TSP2 KO fibroblasts, multiple microscopy modalities, Rac1 activity assay, CDM analysis, traction force microscopy\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple state-of-the-art orthogonal methods; mechanistic axis confirmed by KO rescue\",\n      \"pmids\": [\"36577792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Astrocyte-derived TSP2 binds α2δ1 to mediate degeneration of retinal ganglion cell axons and compensatory synaptic remodeling in the inner plexiform layer after retinal ischemia/reperfusion injury; TSP2 knockdown (shRNA-AAV) or competitive inhibition of TSP2-α2δ1 binding (gabapentin) alleviated synaptic/neurite alteration and visual dysfunction.\",\n      \"method\": \"Viral transduction (TSP2 shRNA-AAV), intravitreal drug injection (gabapentin, fluorocitrate), Western blot, immunofluorescence, electron microscopy, visual function testing\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic knockdown with pharmacological rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36471420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"THBS2 promotes fibroblast proliferation and migration and increases collagen synthesis (COL1A1, COL1A2, COL3A1) via the TGF-β1/Smad2/3 signaling pathway in IPF; THBS2 also promotes inflammatory cytokine secretion (IL-1β, IL-6, IL-8); exogenous THBS2 protein aggravates bleomycin-induced fibrosis in mice.\",\n      \"method\": \"THBS2 overexpression/knockdown in IPF fibroblasts, exogenous protein administration, TGF-β1 inhibitor rescue, bleomycin mouse model, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain/loss of function with inhibitor rescue and in vivo model; single lab\",\n      \"pmids\": [\"40676074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEBPB facilitates miR-29a-3p transcription which negatively regulates THBS2 expression; CEBPB also inhibits B3GALTL transcription to reduce THBS2 O-fucosylation and secretion; THBS2 interacts with ITGB1 and activates the PI3K/AKT signaling pathway to promote breast cancer cell migration, invasion, and EMT.\",\n      \"method\": \"ChIP, luciferase reporter assay, Western blot, rescue experiments, Co-IP (THBS2-ITGB1 interaction)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods defining transcriptional regulation, PTM (O-fucosylation), and receptor interaction; single lab\",\n      \"pmids\": [\"36728807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"THBS2 promotes hypertrophic scar fibroblast proliferation and migration through the TGFβ1/P-Smad2/3 signaling pathway, as established by single-cell sequencing analysis, immunofluorescence localization, and functional assays.\",\n      \"method\": \"scRNA-seq, machine learning, CCK8/wound healing assay, Western blot, immunofluorescence, qRT-PCR\",\n      \"journal\": \"International wound journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays with pathway validation; single lab\",\n      \"pmids\": [\"37986676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A heterozygous THBS2 missense mutation (p.Cys896Arg) causes a novel form of Ehlers-Danlos syndrome with vascular features; CRISPR/Cas9 knock-in mice bearing the same mutation replicate the human phenotype including disorganized collagen fibers and abnormal ECM near blood vessels, consistent with THBS2's known role in mediating MMP2 clearance to regulate ECM.\",\n      \"method\": \"Human genetic analysis, CRISPR/Cas9 KI mouse model, TEM, histology, bleeding time assay\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — human mutation causally linked to disease, validated in CRISPR KI mouse with multiple orthogonal readouts; strong translational evidence\",\n      \"pmids\": [\"38433265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"THBS2 promotes gastric cancer progression and cancer stem cell-like characteristics through the Notch signaling pathway by regulating Notch3, HEY1, and HES1 proteins; miR-29b-3p directly targets the 3'-UTR of THBS2 mRNA to suppress its expression.\",\n      \"method\": \"Dual-luciferase reporter assay, Western blot, xenograft and metastasis assay in nude mice\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro gain/loss of function with pathway readouts; single lab\",\n      \"pmids\": [\"39113869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YTHDF3 promotes THBS2 translation by recognizing m6A modification sites in the coding region of THBS2; THBS2 promotes corneal epithelial cell proliferation and migration by activating the Wnt/β-catenin signaling pathway, and enforced THBS2 expression accelerates corneal wound healing in diabetic mice.\",\n      \"method\": \"m6A-mRNA microarray, RIP assay, YTHDF3 KD/OE, THBS2 OE in cells and diabetic mouse cornea, Wnt/β-catenin pathway analysis\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — m6A modification validated by RIP; functional consequences shown in vitro and in vivo; single lab\",\n      \"pmids\": [\"39626342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"THBS2 secreted by matrix CAFs directly binds SDC4 (syndecan-4) on tumor cells to enhance epithelial-mesenchymal transition programs in lung adenocarcinoma, as demonstrated by spatial transcriptomics, multiplex IHC, and in vivo/in vitro binding experiments.\",\n      \"method\": \"scRNA-seq, spatial transcriptomics, multiplex IHC, in vivo and in vitro functional experiments, protein-receptor binding assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct receptor-ligand interaction (THBS2-SDC4) identified with multiple orthogonal approaches; single lab\",\n      \"pmids\": [\"40973793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TSP2 deficiency in fibroblasts upregulates TGF-β3 and Wnt4/β-catenin signaling, enhancing fibroblast proliferation and migration; CRISPR/Cas9 TSP2 KO in NIH3T3 fibroblasts confirmed that TSP2 negatively regulates these pro-regenerative pathways.\",\n      \"method\": \"Bulk RNA sequencing of WT vs TSP2 KO fibroblasts, CRISPR/Cas9 KO in NIH3T3, functional proliferation/migration assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptomic and functional validation with stable KO model; single lab\",\n      \"pmids\": [\"41427771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Blocking the TCA cycle in HNSCC cells with CPI-613 induces ER stress, leading to increased spliced XBP1 which directly suppresses THBS2 transcription; reduced THBS2 secretion then enhances proliferation and cytotoxicity of tumor-infiltrating CD36+CD8+ T cells via AKT-mTOR signaling.\",\n      \"method\": \"CPI-613 treatment, ER stress induction assay, XBP1 transcriptional reporter, T-cell proliferation/cytotoxicity assay, syngeneic mouse model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined from TCA inhibition to THBS2 transcriptional suppression to immune activation; in vivo validation; single lab\",\n      \"pmids\": [\"40293258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TSP2 siRNA knockdown reduces vascular smooth muscle cell (VSMC) proliferation and migration in vitro and reduces intimal hyperplasia in male but not female rats and mice after carotid injury, demonstrating a sex-specific role for TSP2 in vascular remodeling.\",\n      \"method\": \"siRNA knockdown, VSMC proliferation/chemotaxis assay, carotid balloon injury rat model, carotid ligation mouse model, adeno-associated virus siRNA delivery\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo KD with defined vascular phenotype; sexual dimorphism confirmed in two species\",\n      \"pmids\": [\"40298323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL14 promotes m6A modification of THBS2 mRNA, which is recognized by YTHDF2 to stabilize THBS2 expression; elevated THBS2 in high-glucose conditions exacerbates HK-2 cell injury (apoptosis, fibrosis, inflammation, ferroptosis), and METTL14 knockdown is protective through reduction of THBS2.\",\n      \"method\": \"m6A-RIP assay, RIP-qPCR, siRNA knockdown, CCK-8, flow cytometry, ELISA, Western blot\",\n      \"journal\": \"Experimental and clinical endocrinology & diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — m6A modification validated by RIP; mechanistic axis METTL14-m6A-YTHDF2-THBS2 defined with multiple methods; single lab\",\n      \"pmids\": [\"40730238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LXN positively correlates with THBS2 and LXN knockdown downregulates THBS2; the LXN-THBS2 signaling axis activates the TLR4-TGF-β/FAK pathway through autocrine THBS2 signaling to promote hepatic stellate cell activation and liver fibrosis.\",\n      \"method\": \"AAV9-mediated LXN knockdown in mouse liver fibrosis model, siRNA in LX-2 cells, qPCR, Western blot, IHC, immunofluorescence\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — correlation and knockdown data; mechanistic link between LXN-THBS2-TLR4/TGF-β inferred but not directly demonstrated; single lab\",\n      \"pmids\": [\"41761978\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THBS2 is a secreted homotrimeric matricellular glycoprotein that regulates extracellular matrix remodeling by controlling MMP2/MMP9 activity and clearance, modulates cell signaling through binding to receptors including integrin αvβ3, CD36, SDC4, LRP1, and α2δ1, enhances Notch signaling by bridging Jagged1 and Notch3 ectodomains via LRP1-mediated trans-endocytosis, promotes fibroblast cytoskeletal organization through a TSP2-Rac1-WAVE2-actin axis, and drives fibrosis through the TGF-β1/Smad2/3 pathway, while its expression is post-translationally regulated by O-fucosylation and at the mRNA level by m6A modification (METTL14/YTHDF2 and YTHDF3), collectively establishing THBS2 as a multifunctional ECM regulator controlling angiogenesis, wound healing, synaptogenesis, and cancer-stroma crosstalk.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"THBS2 encodes a secreted matricellular glycoprotein that functions as a central regulator of extracellular matrix assembly, composition, and mechanical properties by controlling collagen fibril organization and modulating MMP2/MMP9 activity and clearance [PMID:29631168, PMID:18455130, PMID:12792739]. THBS2 signals through multiple cell-surface receptors—including integrin αvβ3, CD36, α2δ1, SDC4, ITGB1, and LRP1—to activate downstream MAPK, PI3K/AKT, Wnt/β-catenin, and Notch pathways, thereby regulating angiogenesis, fibroblast cytoskeletal organization via a Rac1–WAVE2–actin axis, synaptogenesis, and cancer-stroma crosstalk [PMID:34958892, PMID:36577792, PMID:20472562, PMID:33382873, PMID:40973793]. THBS2 expression is post-transcriptionally controlled by m6A mRNA modification (METTL14/YTHDF2 and YTHDF3) and by miR-29a-3p/miR-29b-3p, and its secretion is regulated by O-fucosylation [PMID:40730238, PMID:39626342, PMID:36728807]. A heterozygous missense mutation (p.Cys896Arg) in THBS2 causes a novel Ehlers-Danlos syndrome variant with vascular features, validated by CRISPR knock-in mice that recapitulate disorganized collagen and ECM abnormalities [PMID:38433265].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Identification of THBS2 as a second, distinct thrombospondin gene with tissue-specific expression patterns differing from TSP1 established that the thrombospondin family comprises structurally related but non-redundant members.\",\n      \"evidence\": \"cDNA cloning and genomic characterization in mouse tissues\",\n      \"pmids\": [\"1712771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional data on TSP2 protein activity\", \"Tissue-level expression did not resolve cell-type specificity\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Double TSP1/TSP2 knockout mice revealed that the two thrombospondins have distinct temporal roles in wound healing, with TSP1 dominating the inflammatory phase and TSP2 contributing separately, resolving the question of functional redundancy.\",\n      \"evidence\": \"Double-KO mouse wound healing model with immunohistochemistry\",\n      \"pmids\": [\"12213711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TSP2-specific wound healing mechanism undefined\", \"No molecular mediators of TSP2's distinct wound role identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstration that TSP2 overexpression downregulates MMP2 and MMP9 while upregulating other MMPs established TSP2 as a selective modulator of matrix metalloproteinase expression, providing the first mechanistic link to ECM remodeling.\",\n      \"evidence\": \"Stable TSP2 overexpression in SW480 colon carcinoma cells with cDNA array and Western blot\",\n      \"pmids\": [\"12792739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect regulation of MMP transcription not distinguished\", \"Single cell line limits generalizability\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"An intronic SNP causing exon 11 skipping produced a THBS2 variant with reduced MMP2/MMP9 binding, connecting alternative splicing to disrupted protease regulation and identifying a genetic mechanism for THBS2 functional variation.\",\n      \"evidence\": \"Genetic association combined with in vivo splicing assay and functional binding assay\",\n      \"pmids\": [\"18455130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for exon 11-encoded domain's MMP interaction unknown\", \"Effect of the splice variant on ECM architecture not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that TSP2 bridges Jagged1 and Notch3 ectodomains and potentiates Notch signaling through LRP1-dependent trans-endocytosis revealed a novel receptor-bridging mechanism, expanding TSP2's role beyond ECM remodeling to intercellular signaling.\",\n      \"evidence\": \"Co-IP, LRP1-KO fibroblast experiments, endocytosis assay, recombinant protein binding\",\n      \"pmids\": [\"20472562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TSP2-Notch bridging occurs in vivo during development not shown\", \"Stoichiometry and affinity of the ternary complex undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"TSP2-null mice exhibited lower intraocular pressure with altered trabecular meshwork collagen fibril structure, extending TSP2's ECM-organizing role to a specific tissue with clinical relevance for aqueous humor dynamics.\",\n      \"evidence\": \"TSP2-null mouse tonometry, fluorophotometry, and transmission electron microscopy\",\n      \"pmids\": [\"22930728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking TSP2 to collagen fibril diameter control not defined\", \"Single KO model without rescue\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Fracture studies in TSP2-null mice demonstrated that TSP2 controls vascular density and thereby oxygen availability, which dictates mesenchymal stem cell fate choice between endochondral and intramembranous ossification, linking TSP2's anti-angiogenic function to bone repair outcomes.\",\n      \"evidence\": \"TSP2-null mouse fracture model with computational modeling and pimonidazole hypoxia detection\",\n      \"pmids\": [\"23775935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct anti-angiogenic receptor mechanism in bone not identified\", \"Computational model not validated by independent experiments\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"THBS2 was shown to interact with NOTCH1/2 ectodomains and inhibit JAG1-NOTCH2 signaling, positioning THBS2 as a modifier of Notch pathway output beyond the previously known Notch3 interaction and linking it to Alagille syndrome biology.\",\n      \"evidence\": \"Co-IP, THBS2-null mouse histology, GWAS in human cohort\",\n      \"pmids\": [\"28090565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of THBS2-NOTCH2 inhibition vs. THBS2-Notch3 potentiation not reconciled\", \"Functional rescue of Alagille phenotype by THBS2 modulation not demonstrated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Decellularized matrices from TSP2-KO mice showed altered collagen ultrastructure, reduced stiffness, and enhanced cell migration and vascularization, establishing that TSP2 directly shapes the physical and mechanical properties of the ECM.\",\n      \"evidence\": \"Scanning EM, mechanical testing, subcutaneous implantation, in vitro migration with TSP2-null fibroblast ECM\",\n      \"pmids\": [\"29631168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of TSP2-collagen crosslinking or assembly not defined\", \"Contribution of MMP deregulation vs. direct structural role not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"TSP2-KO mice showed impaired cochlear synapse recovery after noise exposure, and compensatory upregulation of TSP2 in TSP1-null inner ears established TSP2 as a synaptogenic factor in the auditory system with partial functional overlap with TSP1.\",\n      \"evidence\": \"TSP1/TSP2 KO mouse models with synaptic counting and auditory brainstem response\",\n      \"pmids\": [\"30928339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating TSP2 synaptogenesis in cochlea not identified\", \"Whether TSP2 promotes synapse formation or maintenance not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple studies converged on THBS2 as a stromal-tumor crosstalk mediator: TGF-β1 induces THBS2 in cancer-associated fibroblasts, which then activates integrin αvβ3/CD36-MAPK signaling on tumor cells, while THBS2 deficiency in cancer stem cells drives MMP-dependent matrix softening and stemness, revealing THBS2 as a bidirectional regulator of the tumor microenvironment.\",\n      \"evidence\": \"Quantitative proteomics, pathway inhibitor rescue, xenografts (PDAC and liver cancer models), MMP activity assays, histone modification analysis\",\n      \"pmids\": [\"34958892\", \"33717837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether THBS2-mediated MMP clearance and receptor signaling operate independently or synergistically in tumors unclear\", \"Therapeutic targeting of THBS2 in cancer not validated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"THBS2 was shown to promote excitatory synaptogenesis via α2δ1/Rac1 signaling in peritumoral cortex and to drive fibrosis via TGF-β1/Smad2/3 signaling, defining two distinct receptor-pathway axes through which THBS2 exerts context-dependent effects.\",\n      \"evidence\": \"Glioma implantation with gabapentin rescue (synaptogenesis); THBS2 OE/KD with TGF-β inhibitor rescue in fibroblasts and bleomycin mouse model (fibrosis)\",\n      \"pmids\": [\"33382873\", \"34638915\", \"40676074\", \"37986676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for THBS2-α2δ1 interaction not resolved\", \"Whether synaptogenic and fibrotic signaling share downstream effectors unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The TSP2–Rac1–WAVE2–actin axis was defined as the mechanism by which TSP2 controls fibroblast cytoskeletal organization, migration, and traction force, explaining how TSP2 deficiency alters cell-ECM mechanical coupling.\",\n      \"evidence\": \"TSP2-KO fibroblasts with FRAP, traction force microscopy, Rac1 activity assay, and WAVE2-F-actin co-localization imaging; diabetic fibroblast rescue model\",\n      \"pmids\": [\"36577792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor upstream of TSP2-Rac1 activation in fibroblasts not identified\", \"Whether this axis operates in non-fibroblast cell types unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Post-transcriptional regulation of THBS2 was elucidated: CEBPB promotes miR-29a-3p to suppress THBS2 mRNA, while CEBPB also reduces B3GALTL-mediated O-fucosylation to limit THBS2 secretion; separately, YTHDF3 recognizes m6A modifications to promote THBS2 translation, establishing multi-layered regulation at mRNA and protein levels.\",\n      \"evidence\": \"ChIP, luciferase reporter assays, Co-IP (THBS2-ITGB1), RIP for m6A, YTHDF3 KD/OE in corneal epithelial cells and diabetic mouse cornea\",\n      \"pmids\": [\"36728807\", \"39626342\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration of O-fucosylation, m6A, and miRNA regulation under physiological conditions not tested\", \"Which m6A sites are functionally critical not mapped at single-nucleotide resolution\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A heterozygous THBS2 missense mutation (p.Cys896Arg) was identified as the cause of a novel Ehlers-Danlos syndrome variant, validated by CRISPR knock-in mice that recapitulate collagen disorganization and vascular ECM defects, providing the first Mendelian disease directly caused by THBS2 mutation.\",\n      \"evidence\": \"Human genetic analysis, CRISPR/Cas9 knock-in mouse, TEM, histology, bleeding time assay\",\n      \"pmids\": [\"38433265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the mutation disrupts MMP clearance, collagen binding, or both not resolved\", \"Penetrance and phenotypic spectrum in additional families not reported\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"THBS2 receptor repertoire expanded to include SDC4 on lung cancer cells and CD36 on CD8+ T cells; THBS2 binding to SDC4 drives EMT in lung adenocarcinoma, while tumor-secreted THBS2 suppresses CD36+CD8+ T cell cytotoxicity via AKT-mTOR signaling, revealing immunomodulatory functions.\",\n      \"evidence\": \"Spatial transcriptomics, multiplex IHC, protein-receptor binding assays, syngeneic mouse models, T-cell functional assays\",\n      \"pmids\": [\"40973793\", \"40293258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of THBS2-SDC4 interaction not determined\", \"Whether THBS2's immunosuppressive effect is generalizable across tumor types unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"METTL14-mediated m6A modification of THBS2 mRNA recognized by YTHDF2 was shown to stabilize THBS2 expression in diabetic kidney injury, and TSP2 knockdown reduced vascular smooth muscle cell proliferation and intimal hyperplasia in a sex-specific manner, expanding THBS2's roles to renal pathology and sex-dimorphic vascular biology.\",\n      \"evidence\": \"m6A-RIP, siRNA KD, HK-2 cell injury model; siRNA KD in VSMCs, carotid injury in male/female rats and mice\",\n      \"pmids\": [\"40730238\", \"40298323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether YTHDF2 and YTHDF3 act on THBS2 mRNA at the same or distinct m6A sites is unresolved\", \"Molecular basis of sex-specific TSP2 effects in vascular remodeling unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of THBS2's selective receptor engagement across different cell types; how TSP2 simultaneously promotes and inhibits Notch signaling through different Notch paralogs; and whether TSP2's diverse context-dependent functions can be therapeutically targeted with domain-specific interventions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of full-length TSP2 or TSP2-receptor complexes\", \"Mechanism reconciling Notch3 potentiation vs. NOTCH2 inhibition undefined\", \"No clinical trials or validated therapeutic targeting of THBS2\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 5, 14]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [12, 13, 17, 24]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [9, 12, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [9, 14, 21]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 12, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 4, 9, 14, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 8, 12, 13, 22, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12, 14, 22, 24, 26]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 13, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MMP2\",\n      \"MMP9\",\n      \"LRP1\",\n      \"NOTCH3\",\n      \"JAG1\",\n      \"ITGB1\",\n      \"SDC4\",\n      \"CD36\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}