{"gene":"SPP1","run_date":"2026-06-10T07:46:40","timeline":{"discoveries":[{"year":1996,"finding":"Osteopontin (SPP1/Eta-1) is a protein ligand of CD44. Binding of osteopontin to CD44 induces cellular chemotaxis but not homotypic aggregation, whereas CD44 ligation by hyaluronate induces homotypic aggregation but not chemotaxis, indicating that different CD44 ligands trigger distinct downstream cellular responses.","method":"Receptor-ligand binding assay, chemotaxis assay, homotypic aggregation assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct receptor-ligand interaction established with functional cellular readouts, replicated by multiple subsequent studies","pmids":["8560266"],"is_preprint":false},{"year":2000,"finding":"Eta-1/OPN promotes type-1 immunity through two receptor-dependent mechanisms: (1) a phosphorylation-dependent interaction between the amino-terminal portion of OPN and its integrin receptor stimulates IL-12 expression in macrophages; (2) a phosphorylation-independent interaction with CD44 inhibits IL-10 expression in macrophages. Mice deficient in OPN have severely impaired IL-12 and IFN-γ production and increased IL-10 production during viral and bacterial infection.","method":"OPN knockout mice, infection models (HSV-1, Listeria monocytogenes), cytokine measurement, phosphorylation-dependent binding assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function genetic model with defined molecular mechanism (phosphorylation-dependent integrin vs. CD44 interaction), multiple orthogonal readouts","pmids":["10657301"],"is_preprint":false},{"year":2003,"finding":"OPN/Eta-1 acts downstream of FGF2 signaling in endothelial cells; FGF2 induces OPN overexpression in endothelial cells in vitro and in vivo. Recombinant OPN drives angiogenesis independently of αvβ3 integrin engagement by recruiting proangiogenic monocytes and inducing TNF-α and IL-8 expression in monocytes.","method":"Subtractive suppression hybridization, Northern/Western blotting, CAM angiogenesis assay, Matrigel plug assay, chemotaxis assay, RGD-deletion mutant (GST-ΔRGDo-OPN), cytokine induction assay in human monocytes","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstitution with deletion mutants, multiple in vitro and in vivo assays in one study establishing mechanism","pmids":["12847283"],"is_preprint":false},{"year":2013,"finding":"BRD4 regulates SPP1 expression in melanoma not by direct binding to the SPP1 promoter but via the non-canonical NF-κB pathway through NFKB2; silencing NFKB2 phenocopies BET inhibitor treatment and SPP1 silencing in suppressing melanoma proliferation, migration, and invasion.","method":"ChIP assay, siRNA knockdown, BET inhibitor treatment, cell proliferation/migration/invasion assays, xenograft mouse model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay and epistasis (NFKB2 knockdown phenocopying) plus in vivo validation, single lab","pmids":["33052224"],"is_preprint":false},{"year":2021,"finding":"SPP1/OPN secreted by cancer-associated fibroblasts (CAFs) activates CD44 on pancreatic cancer cells to promote cancer stemness. Knockdown of SPP1 in CAF-conditioned media significantly reduced stemness characteristics (CD44+, ALDH+, tumorsphere formation) in pancreatic cancer cells.","method":"Conditioned media treatment, gene knockdown (siRNA), 3D co-culture, stemness assays (tumorsphere, ALDH, CD44 FACS), 3D sodium alginate bead co-culture","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific cellular phenotype readout and multiple orthogonal stemness assays, single lab","pmids":["34418441"],"is_preprint":false},{"year":2023,"finding":"Macrophage-derived OPN (SPP1) protects from NASH by inducing oncostatin-M (OSM) secretion from macrophages; OSM activates STAT3 signaling in hepatocytes, which upregulates arginase-2 (ARG2), thereby enhancing fatty acid oxidation (FAO) and reducing steatosis. Conditional knockout of Spp1 in myeloid cells worsened NASH while conditional knockin conferred protection.","method":"Conditional myeloid Spp1 knockin and knockout mouse models, Western blot, STAT3 pathway analysis, FAO measurement, high-fat/fructose/cholesterol diet NASH model","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — both gain- and loss-of-function conditional mouse models with defined OPN→OSM→STAT3→ARG2 molecular pathway and multiple orthogonal readouts","pmids":["37028770"],"is_preprint":false},{"year":2021,"finding":"SPP1 mediates crosstalk between hepatocellular carcinoma cells and macrophages via SPP1-CD44 and SPP1-PTGER4 receptor-ligand axes, and can trigger polarization of macrophages to an M2-phenotype (tumor-associated macrophage phenotype).","method":"Receptor-ligand pair analysis from single-cell RNA-seq, in vitro macrophage polarization assay","journal":"Cancer Immunology, Immunotherapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — receptor-ligand interaction supported by scRNA-seq analysis plus in vitro polarization assay validation, single lab","pmids":["34028567"],"is_preprint":false},{"year":2022,"finding":"SPP1 facilitates lung adenocarcinoma cell migration and invasion by upregulating COL11A1 expression; COL11A1 overexpression rescues the suppression of migration/invasion and EMT marker changes caused by SPP1 knockdown, establishing COL11A1 as a downstream effector of SPP1.","method":"SPP1 siRNA knockdown, COL11A1 overexpression rescue experiments, Western blot, in vitro and in vivo migration/invasion assays","journal":"Cancer Cell International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue experiment (COL11A1 overexpression reverting SPP1 knockdown phenotype) with in vivo validation, single lab","pmids":["36266702"],"is_preprint":false},{"year":2023,"finding":"CXCL4 (from platelets, the major in vivo source of CXCL4) drives differentiation of profibrotic Spp1+ macrophages (marked by Spp1, Fn1, Arg1). Loss of Cxcl4 abrogates Spp1 macrophage differentiation and ameliorates fibrosis. These macrophages orchestrate fibroblast activation via Spp1, Fn1, and Sema3 crosstalk.","method":"In vitro and in vivo Cxcl4 loss-of-function, single nuclear RNA sequencing, ligand-receptor interaction analysis, heart and kidney injury models","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo loss-of-function, single nuclear RNA-seq ligand-receptor analysis, multiple organ injury models, identification of platelet CXCL4 as upstream driver","pmids":["36807143"],"is_preprint":false},{"year":2021,"finding":"SPP1 derived from silica-exposed macrophage exosomes triggers fibroblast transdifferentiation into myofibroblasts. Knockdown of SPP1 in exosomes decreases fibrosis-related indicators, establishing exosomal SPP1 as a paracrine mediator of macrophage-to-fibroblast communication.","method":"Proteomic analysis of macrophage-derived exosomes, SPP1 knockdown in exosomes, fibrosis marker assays","journal":"Toxicology and Applied Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (SPP1 knockdown in exosomes) with specific fibrosis phenotype, single lab, single mechanism","pmids":["33961903"],"is_preprint":false},{"year":2015,"finding":"OPN isoforms OPNb and OPNc have distinct pro-invasion mechanisms in esophageal adenocarcinoma: OPNb enhances cell migration, adhesion to laminin, and invasion through integrin RGD-dependent signaling; OPNc decreases migration yet increases cell detachment through integrin-independent mechanisms. Inhibition of RGD integrins abrogates OPNb but not OPNc phenotypes.","method":"Stable transfection of OPN isoforms, RGD integrin inhibition, migration assay, adhesion assay, invasion assay in vitro and in vivo","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific gain-of-function with pharmacological inhibition to delineate integrin-dependent vs. independent mechanisms, in vitro and in vivo, single lab","pmids":["26068949"],"is_preprint":false},{"year":2020,"finding":"OPN inhibits autophagy in osteoarthritic chondrocytes through CD44 and αvβ3 integrin receptors via the ERK MAPK signaling pathway. Blocking CD44 or αvβ3 integrin with antibodies, or inhibiting ERK, reverses OPN-mediated suppression of LC3II and Beclin1 expression. OPN also promotes chondrocyte proliferation.","method":"Recombinant human OPN treatment, anti-CD44 and anti-CD51/61 blocking antibodies, ERK inhibitor, Western blot, mRFP-GFP-LC3 confocal imaging, transmission electron microscopy, CCK-8 assay","journal":"Frontiers in Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and antibody blocking experiments with multiple orthogonal autophagy readouts, single lab","pmids":["36034459"],"is_preprint":false},{"year":2020,"finding":"OPN activates intracellular PI3K signaling by binding to CD44 on the chondrocyte cell surface, leading to downstream cascade effects that inhibit OA progression. Blocking CD44 or overexpressing OPN alters PI3K, HAS, and hyaluronic acid synthesis in OA chondrocytes.","method":"OPN overexpression and siRNA depletion, GRGDSP integrin blocking peptide, integrin αvβ3 antibody blocking, Western blot, HA synthesis assay, in vivo mouse OA model","journal":"Genes & Diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with receptor blocking, multiple readouts in vitro and in vivo, single lab","pmids":["35005113"],"is_preprint":false},{"year":2020,"finding":"OPN interaction with integrin αvβ3 predominantly regulates hyaluronic acid synthase (HAS) expression and hyaluronic acid synthesis in OA chondrocytes. Both non-specific (GRGDSP) and integrin αvβ3-specific blocking downregulate HAS and HA to similar extents.","method":"OPN overexpression and depletion, GRGDSP peptide blocking, integrin αvβ3 antibody, HAS expression, HA measurement","journal":"BioMed Research International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological blocking and gain/loss-of-function with specific molecular readouts, single lab","pmids":["33134374"],"is_preprint":false},{"year":2022,"finding":"SPP1 promotes radiation resistance in esophageal carcinoma by increasing phosphorylation of JAK2 and STAT3 downstream of SPP1. SPP1 knockdown reduces DNA damage repair and tumor cell survival post-irradiation; pharmacological inhibition of JAK2-STAT3 synergizes with radiotherapy to reduce tumor volume in vivo.","method":"SPP1 knockdown and overexpression, Western blot (JAK2/STAT3 phosphorylation), colony formation, flow cytometry, xenograft mouse model, pharmacological JAK2-STAT3 inhibitor","journal":"Cancer Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined signaling pathway readouts and in vivo validation, single lab","pmids":["35593388"],"is_preprint":false},{"year":2024,"finding":"SPP1 promotes tumor progression in esophageal carcinoma by activating the focal adhesion kinase (FAK)/ERK pathway. SPP1 knockdown reduces cell adhesion and p-FAK and p-ERK expression; pharmacological FAK inhibition (Y15) reduces tumor proliferation, migration, and invasion.","method":"SPP1 knockdown, Western blot (p-FAK, p-ERK), GSEA, cell adhesion and spreading assays, FAK inhibitor Y15, in vitro proliferation/migration/invasion assays","journal":"Journal of Gastrointestinal Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and pharmacological inhibition with defined pathway readouts, single lab","pmids":["38989403"],"is_preprint":false},{"year":2013,"finding":"BAFF induces OPN secretion from splenic CD21-CD23+ B cells via an NF-κB-dependent signaling pathway. B cell-derived OPN in turn upregulates Bcl2 expression in T cells, promoting T cell survival and resistance to apoptosis.","method":"TACI-IgG BAFF blockade in EAE model, in vitro B cell stimulation, NF-κB pathway analysis, T cell apoptosis assay, Bcl2 expression measurement","journal":"Molecular Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological blockade and in vitro mechanistic dissection, defined NF-κB pathway and Bcl2 downstream effector, single lab","pmids":["24084099"],"is_preprint":false},{"year":2024,"finding":"SPP1 secreted by tumor cells binds CD44 on hepatic stellate cells (HSCs), activating the PI3K/AKT signaling pathway to promote HSC differentiation into cancer-associated fibroblasts (CAFs). CD44 receptor blockade abrogates this interaction, and in vivo SPP1 silencing impairs HSC-to-CAF differentiation, reducing tumor volume and collagen deposition.","method":"Spatial transcriptomics, scRNA-seq, CD44 receptor blockade, in vivo SPP1 silencing, PI3K/AKT pathway analysis, collagen deposition measurement","journal":"Journal of Translational Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blockade plus in vivo loss-of-function with defined PI3K/AKT pathway and fibrosis readouts, single lab","pmids":["39267037"],"is_preprint":false},{"year":2024,"finding":"OPN secreted by SPP1+ macrophages in coronary PVAT interacts with CD44/integrin on fibroadipogenic progenitor cells to promote their migration and proliferation, driving PVAT fibrosis. Blocking CD44 or integrin prevents conditioned medium-induced migration and proliferation of fibroadipogenic progenitor cells.","method":"In vitro conditioned medium experiments, CD44 and integrin blocking, scRNA-seq, spatial transcriptomics, multiplex immunofluorescence","journal":"Arteriosclerosis, Thrombosis, and Vascular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blocking in vitro with defined cellular phenotype, validated spatially, single lab","pmids":["37706320"],"is_preprint":false},{"year":2025,"finding":"SPP1 (osteopontin) is required for maintaining mesenchymal cell fate in pancreatic cancer. SPP1 binds the CD61 receptor on mesenchymal PDAC cells to induce Bmp2 and Grem1 expression. GREM1 inhibits BMP signaling, which is required for Spp1 expression in epithelial cells, forming an intercellular regulatory loop. Spp1 inactivation converts mesenchymal PDAC cells to an epithelial phenotype and abolishes metastasis.","method":"Spp1 knockout mouse PDAC models, Grem1 conditional heterozygosity genetic epistasis, proteomic analysis of patient plasma, in vivo tumorigenesis assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo loss-of-function with defined receptor (CD61), downstream signaling (BMP2/GREM1), intercellular regulatory loop confirmed by double-mutant epistasis, replicated across multiple genetic combinations","pmids":["40993391"],"is_preprint":false},{"year":2024,"finding":"SPP1 secreted by SPP1+ macrophages drives T-cell exhaustion via the SPP1-CD44 axis. Blocking either SPP1 or CD44 reverses T-cell exhaustion and restores CD8+ T-cell functionality, suppressing tumor growth in vivo in ovarian cancer models.","method":"Functional T-cell exhaustion assays, SPP1 and CD44 blocking antibodies, in vivo tumor growth assay, scRNA-seq analysis, molecular docking","journal":"International Immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blocking in vitro and in vivo with defined T-cell exhaustion phenotype readout, single lab","pmids":["40446696"],"is_preprint":false},{"year":2023,"finding":"Microglia-derived Spp1 promotes pathological retinal neovascularization by activating endothelial Kit/Akt/mTOR signaling. Spp1 expression in microglia is regulated by NF-κB and HIF-1α pathways. Spp1 neutralizing antibody reduces endothelial proliferation and migration in vitro and attenuates pathological retinal neovascularization and improves visual function in vivo.","method":"scRNA-seq, BV2 conditioned medium assays with/without Spp1 neutralization, recombinant Spp1 treatment, RNA sequencing of endothelial cells, intravitreal injection of neutralizing antibody, in vitro (BV2, bEnd.3) and in vivo OIR mouse model","journal":"Journal of Personalized Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neutralizing antibody in vitro and in vivo, RNA-seq defining Kit/Akt/mTOR pathway, NF-κB/HIF-1α regulation confirmed in vitro, single lab","pmids":["36675807"],"is_preprint":false},{"year":2024,"finding":"SOCS3 in myeloid cells directly regulates Spp1 as a transcriptional target of STAT3. Loss of myeloid SOCS3 leads to increased STAT3 activation and elevated Spp1 expression in microglia/macrophages, promoting pathological retinal neovascularization. Pharmaceutical SOCS3 activation or SPP1 blocking reduces pathological neovascularization.","method":"scRNA-seq, SOCS3 conditional knockout mice, STAT3 pathway analysis, SPP1 blocking, angiogenesis mouse models","journal":"Molecular Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional loss-of-function with defined SOCS3/STAT3/SPP1 transcriptional axis confirmed in vivo, single lab","pmids":["38504518"],"is_preprint":false},{"year":2022,"finding":"miR-433 directly binds to the 3'-UTR of SPP1 mRNA to suppress SPP1 expression. Overexpression of miR-433 in human osteoblast cells (hFOB1.19) decreases SPP1 mRNA and protein levels. In patients with tibial fracture combined with TBI, reduced miR-433 correlates with elevated SPP1.","method":"Dual luciferase reporter assay, agomiR-433 overexpression in hFOB1.19 cells, RT-qPCR, Western blot","journal":"Experimental and Therapeutic Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual luciferase reporter assay establishes direct miR-433/SPP1 3'-UTR interaction, confirmed by functional overexpression, single lab","pmids":["34306197"],"is_preprint":false},{"year":2022,"finding":"OPN N-glycosylation at asparagine-79 promotes osteoclast proliferation and modulates OPN function. N-glycosylation of OPN activates the NF-κB signaling pathway and promotes nuclear translocation of NF-κB in both osteoclasts and osteoblasts. Mutation of N79 prevents OPN from increasing osteoblast proliferation but retains effects on osteoclasts.","method":"Site-directed mutagenesis (N79Q), plasmid transfection into osteoblasts and osteoclasts, mass spectrometry for glycosylation site identification, CCK-8 proliferation assay, Western blot, NF-κB nuclear translocation assay","journal":"Oral Diseases","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis of post-translational modification site combined with cellular functional assays, single lab","pmids":["35451542"],"is_preprint":false},{"year":2022,"finding":"The β-catenin/TCF-4 pathway regulates OPN expression in human chondrocytes. TCF4 shRNA knockdown downregulates OPN expression; treatment with the Wnt/β-catenin inhibitor DKK1 decreases both β-catenin and OPN mRNA and protein in OA chondrocytes.","method":"TCF4 shRNA knockdown, DKK1 inhibitor treatment, RT-PCR, Western blot in human chondrocytes","journal":"Journal of Orthopaedic Surgery and Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (shRNA) and pharmacological inhibition establishing β-catenin/TCF4→OPN transcriptional regulation, single lab","pmids":["32819387"],"is_preprint":false},{"year":2025,"finding":"H4K12 lactylation (H4K12la) promotes transcription of Spp1 in reprogrammed microglia after spinal cord injury. DNA-pulldown experiments identified H4K12la as an upstream epigenetic regulator of Spp1. Recombinant SPP1 (rSPP1) promotes neuronal maturation, enhances mitochondrial function in axons, and improves functional recovery after SCI.","method":"DNA-pulldown assay, scRNA-seq, pseudotime analysis, recombinant SPP1 injection in vivo, mitochondrial function assays, behavioral functional recovery assays","journal":"CNS Neuroscience & Therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DNA-pulldown identifies H4K12la as SPP1 transcriptional regulator; rSPP1 gain-of-function in vivo with defined neuronal and mitochondrial readouts; single lab","pmids":["39939834"],"is_preprint":false},{"year":2010,"finding":"The ATX-LPA axis induces OPN expression in hepatic cancer cells (SMMC7721) via activation of the PI3K/Akt pathway through LPA receptors. OPN is required for cell migration induced by the ATX-LPA axis; LPA receptor or PI3K/Akt inhibitors block ATX/LPC-induced OPN expression.","method":"Western blot, RT-qPCR, PI3K/Akt inhibitors, LPA receptor inhibitors, Transwell migration assay","journal":"Anatomical Record","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway inhibition establishing LPA receptor→PI3K/Akt→OPN induction axis with functional migration readout, single lab","pmids":["21337710"],"is_preprint":false},{"year":2024,"finding":"SPP1 secreted by SPP1+ macrophages inhibits CD8+ T cell proliferation. Targeting SPP1 in tumor-associated macrophages shifts their phenotype toward a favorable (less immunosuppressive) state in hepatocellular carcinoma. In vitro, SPP1 overexpression in macrophages upregulates CD73, IL-10, and TGF-β, impairing CD8+ T cell function via A2AR signaling; anti-SPP1 or anti-A2AR treatment restores CD8+ T cell activity.","method":"scRNA-seq, bulk RNA-seq, in vitro co-culture of SPP1-overexpressing macrophages and CD8+ T cells, flow cytometry, Western blot, anti-SPP1 and anti-A2AR neutralization, CD8+ T cell proliferation and cytokine assays","journal":"Frontiers in Immunology / Cancer Immunology Immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro co-culture with SPP1 overexpression and receptor neutralization establishing SPP1→A2AR→CD8+ T cell suppression axis, single lab","pmids":["39691723","41021043"],"is_preprint":false},{"year":2024,"finding":"Glycosyltransferase B4GALNT1 upregulates SPP1 synthesis and secretion in HCC tumor cells by increasing phosphorylation of HES4 via p38/JNK signaling, thereby increasing HES4 transcriptional activity which drives SPP1 expression and reshapes the immunosuppressive microenvironment (TAMs, Th2 cells).","method":"B4GALNT1 and HES4 manipulation, Western blot (p38/JNK/HES4 phosphorylation), transcriptional activity assay, SPP1 secretion measurement, immune cell composition analysis in mouse model","journal":"Molecular Biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined B4GALNT1→p38/JNK→HES4→SPP1 signaling cascade, single lab","pmids":["39616302"],"is_preprint":false},{"year":2025,"finding":"Macrophage-derived Spp1 promotes accumulation of adipogenic stromal cells (PDGFRα+ Lifr+ and Procr+ populations) in dystrophic (mdx) muscles, leading to intramuscular fat accumulation. Macrophage-specific Spp1 conditional knockout reduces these adipogenic progenitor populations, decreases intramuscular diaphragmatic fat, and improves diaphragm function.","method":"Macrophage-specific Spp1 conditional knockout (cKO), single-cell transcriptional profiling, cell sorting, in vitro adipogenesis assay, diaphragm function measurement","journal":"JCI Insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional knockout with scRNA-seq defining target cell populations and in vitro adipogenesis confirmation, single lab","pmids":["40626359"],"is_preprint":false},{"year":2024,"finding":"TGF-β instructs tumor-associated macrophages to induce SPP1 expression. SPP1, in turn, promotes collagen deposition and accumulation of tumor-associated macrophages and fibroblasts, creating an immunosuppressive barrier that blocks clonal expansion of newly arrived T cells, thereby driving immune checkpoint blockade resistance in colorectal cancer liver metastases.","method":"Mouse models of colorectal cancer, patient-derived data, genetic epistasis (TGF-β pathway manipulation), T cell recruitment assays, collagen deposition measurement","journal":"Nature Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models establishing TGF-β→SPP1 induction and SPP1→collagen/immune suppression with defined cellular and functional readouts, single lab","pmids":["41203813"],"is_preprint":false},{"year":2025,"finding":"Spp1+ macrophages in viral myocarditis promote fibroblast conversion to an inflammatory phenotype with high Ccl2/Ccl7 expression, which in turn increases monocyte chemotaxis to the heart. Inhibition of SPP1 reduces cardiac macrophage infiltration, attenuates myocardial inflammation, and improves cardiac function in CVB3-induced VMC mice.","method":"scRNA-seq, indirect co-culture of macrophages and cardiac fibroblasts in vitro, CellPhoneDB ligand-receptor analysis, macrophage depletion, SPP1 inhibition in vivo, cardiac function measurement","journal":"Biology Direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro co-culture establishing SPP1→fibroblast Ccl2/Ccl7 induction plus in vivo SPP1 inhibition with cardiac functional readout, single lab","pmids":["40087693"],"is_preprint":false},{"year":2024,"finding":"Therapeutic silencing of Spp1 in TREM2+ cardiac macrophages using an antibody-siRNA conjugate reduces atrial fibrosis and suppresses atrial fibrillation in mice, demonstrating that macrophage-secreted osteopontin (encoded by Spp1) drives atrial fibrosis and arrhythmia.","method":"Antibody-siRNA conjugate for macrophage-specific Spp1 silencing in vivo, atrial fibrosis measurement, atrial fibrillation induction assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific in vivo loss-of-function with defined fibrosis and electrophysiological readouts; preprint, not yet peer-reviewed","pmids":["39149373"],"is_preprint":true},{"year":2025,"finding":"SPP1 macrophage-derived SPP1 mediates immune suppression in colon cancer liver metastasis via the SPP1/CD44/PI3K/AKT signaling pathway, inducing T-cell stress (HSPA1A/HSPA1Bhigh T cells). Combination treatment with anti-SPP1 and anti-PD-1 antibodies inhibits liver metastasis growth and restores T-cell infiltration and function.","method":"scRNA-seq, in vitro co-culture of Macro_SPP1high cells with T cells, CD44 blocking, PI3K/AKT pathway analysis, anti-SPP1/anti-PD-1 combination therapy in vivo","journal":"Journal for Immunotherapy of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic dissection with CD44 blocking and defined PI3K/AKT pathway, in vivo combination therapy validation, single lab","pmids":["41120125"],"is_preprint":false},{"year":2022,"finding":"Magnesium ions promote OPN expression in osteoblastic cells through the CaM/CaMKIV/CREB1 signaling pathway. Phosphorylated CREB1 directly binds the OPN promoter to upregulate OPN transcription. Knockdown of CaMKIV or CREB1 reduces Mg2+-induced OPN expression and mineralization.","method":"Dual-luciferase reporter assay (p-CREB1 binding to OPN promoter), shCaMKIV and shCREB1 knockdown, KN93 CaMKIV inhibitor, Western blot, in vivo Mg screw implantation","journal":"Journal of Biomedical Materials Research Part B","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — luciferase reporter assay for direct transcription factor binding to OPN promoter, shRNA knockdown, pharmacological inhibitor, in vivo validation, single lab","pmids":["35106922"],"is_preprint":false}],"current_model":"SPP1 (osteopontin/OPN) is a secreted, multifunctional phosphoglycoprotein that signals through cell-surface receptors—primarily CD44 and integrins (αvβ3, RGD-binding)—to regulate immunity, cell migration, adhesion, fibrosis, and cancer progression; its phosphorylation state determines receptor selectivity (phosphorylation-dependent integrin engagement stimulates IL-12, phosphorylation-independent CD44 binding suppresses IL-10), and its expression is controlled transcriptionally by NF-κB/NFKB2, β-catenin/TCF-4, STAT3, and CREB1 (via CaM/CaMKIV), post-translationally by N-glycosylation at N79 and H4K12 lactylation, and post-transcriptionally by miR-433, while acting downstream of FGF2, ATX-LPA/PI3K-Akt, CXCL4 (from platelets), and TGF-β to drive angiogenesis, macrophage polarization, T-cell exhaustion, fibroblast activation, and cancer cell invasion via COL11A1 upregulation and FAK/ERK or PI3K/AKT/JAK2-STAT3 signaling."},"narrative":{"mechanistic_narrative":"SPP1 (osteopontin/OPN) is a secreted phosphoglycoprotein that acts as an extracellular signaling ligand to coordinate immunity, fibrosis, tissue remodeling, and cancer progression through engagement of cell-surface receptors [PMID:8560266, PMID:10657301]. Receptor selectivity is dictated by its phosphorylation and isoform state: a phosphorylation-dependent interaction between the N-terminal region of OPN and its integrin receptor stimulates IL-12 in macrophages, whereas a phosphorylation-independent interaction with CD44 suppresses IL-10, together promoting type-1 immunity [PMID:10657301], and binding to CD44 versus hyaluronate elicits distinct cellular responses such as chemotaxis [PMID:8560266]. Splice isoforms further diversify output, with OPNb signaling through RGD-dependent integrins while OPNc acts integrin-independently [PMID:26068949]. Across diverse tissues, OPN signals through CD44 and αvβ3/CD61 integrins to drive PI3K/AKT, FAK/ERK, JAK2-STAT3, and ERK MAPK cascades, controlling chondrocyte autophagy and hyaluronan synthesis [PMID:36034459, PMID:35005113, PMID:33134374], cancer cell migration and invasion via COL11A1 induction [PMID:36266702], radioresistance through JAK2-STAT3 [PMID:35593388], and adhesion-dependent progression via FAK/ERK [PMID:38989403]. A recurrent theme is OPN produced by SPP1+ macrophages acting on stromal and immune cells: it converts hepatic stellate cells and fibroadipogenic progenitors into activated fibroblasts via CD44/integrin-PI3K/AKT [PMID:39267037, PMID:37706320], drives profibrotic crosstalk in heart, kidney, and muscle downstream of platelet CXCL4 [PMID:36807143, PMID:40626359], polarizes tumor-associated macrophages to an M2 state [PMID:34028567], and enforces CD8+ T-cell exhaustion and immune-checkpoint resistance through the SPP1-CD44 axis and A2AR signaling [PMID:40446696, PMID:39691723, PMID:41021043, PMID:41120125]. In pancreatic cancer, SPP1 binding to CD61 sustains a mesenchymal, metastatic cell state through a BMP2/GREM1 intercellular regulatory loop [PMID:40993391]. SPP1 expression is controlled transcriptionally by non-canonical NF-κB/NFKB2, β-catenin/TCF-4, STAT3 (via SOCS3 and B4GALNT1/HES4), and CaM/CaMKIV/CREB1 [PMID:33052224, PMID:32819387, PMID:38504518, PMID:39616302, PMID:35106922], post-transcriptionally by miR-433 [PMID:34306197], and by the epigenetic and post-translational modifications H4K12 lactylation and N79 N-glycosylation [PMID:39939834, PMID:35451542].","teleology":[{"year":1996,"claim":"Establishing that OPN is a functional ligand of CD44 defined a receptor-based mechanism for its biological activity and showed that different CD44 ligands route distinct responses.","evidence":"Receptor-ligand binding, chemotaxis, and homotypic aggregation assays","pmids":["8560266"],"confidence":"High","gaps":["Did not resolve integrin contribution","Downstream intracellular cascade not mapped"]},{"year":2000,"claim":"Knockout and infection models revealed that OPN promotes type-1 immunity through two molecularly separable arms, defining phosphorylation state as the switch for receptor choice.","evidence":"OPN knockout mice in HSV-1/Listeria infection with phosphorylation-dependent binding assays and cytokine readouts","pmids":["10657301"],"confidence":"High","gaps":["Specific integrin partner not pinned down","Phosphosite mapping incomplete"]},{"year":2003,"claim":"Placing OPN downstream of FGF2 in endothelium and showing RGD-independent angiogenesis broadened OPN's role beyond integrin engagement to monocyte recruitment.","evidence":"FGF2 induction, RGD-deletion mutant, CAM and Matrigel angiogenesis assays, monocyte cytokine induction","pmids":["12847283"],"confidence":"High","gaps":["RGD-independent receptor not identified","In vivo source of OPN not defined"]},{"year":2010,"claim":"Linking the ATX-LPA axis to OPN induction via PI3K/Akt identified an upstream lipid-signaling route controlling OPN-dependent migration.","evidence":"Pharmacological LPA receptor and PI3K/Akt inhibition with Transwell migration in hepatic cancer cells","pmids":["21337710"],"confidence":"Medium","gaps":["Transcription factor mediating induction not identified","Single cell line"]},{"year":2013,"claim":"Two studies defined upstream transcriptional control of SPP1, through non-canonical NF-κB/NFKB2 in melanoma and through BAFF/NF-κB in B cells feeding T-cell survival.","evidence":"ChIP, siRNA/BET inhibition with xenografts; BAFF blockade and B-cell stimulation with Bcl2 readout","pmids":["33052224","24084099"],"confidence":"Medium","gaps":["Direct promoter elements not fully mapped","Single-lab findings"]},{"year":2015,"claim":"Isoform-resolved analysis showed OPNb and OPNc use integrin-dependent versus integrin-independent mechanisms, explaining functional heterogeneity of OPN outputs.","evidence":"Stable isoform transfection with RGD integrin inhibition in esophageal adenocarcinoma","pmids":["26068949"],"confidence":"Medium","gaps":["OPNc integrin-independent receptor unknown","Single lab"]},{"year":2020,"claim":"Chondrocyte studies established that OPN signals through both CD44 and αvβ3 to control autophagy (ERK MAPK) and hyaluronan synthesis (PI3K/HAS), connecting receptor usage to specific intracellular cascades.","evidence":"Recombinant OPN, anti-CD44/anti-αvβ3 and RGD-peptide blocking, ERK inhibition, autophagy and HA assays in vitro and in vivo","pmids":["36034459","35005113","33134374"],"confidence":"Medium","gaps":["Receptor cross-talk quantitation incomplete","Single-lab series"]},{"year":2021,"claim":"Tumor-microenvironment studies showed SPP1 from CAFs and tumor cells engages CD44 (and PTGER4) to drive stemness and M2 macrophage polarization, framing SPP1 as a stromal-immune crosstalk node.","evidence":"Conditioned media, siRNA knockdown, 3D co-culture, stemness assays, scRNA-seq receptor-ligand analysis with polarization assays","pmids":["34418441","34028567"],"confidence":"Medium","gaps":["PTGER4 axis not functionally validated","Single-lab findings"]},{"year":2021,"claim":"Exosomal delivery of SPP1 from silica-exposed macrophages was shown to drive fibroblast-to-myofibroblast transdifferentiation, identifying a paracrine vehicle for OPN-mediated fibrosis.","evidence":"Exosome proteomics with SPP1 knockdown and fibrosis marker assays","pmids":["33961903"],"confidence":"Medium","gaps":["Receptor on fibroblasts not defined","Single mechanism"]},{"year":2022,"claim":"Mechanistic dissection in cancer defined SPP1 downstream effectors and signaling, including COL11A1 induction for invasion and JAK2-STAT3 for radioresistance.","evidence":"SPP1 knockdown with COL11A1 rescue; JAK2/STAT3 phosphorylation with pharmacological inhibition and xenografts","pmids":["36266702","35593388"],"confidence":"Medium","gaps":["Receptor upstream of these cascades not specified in each system","Single-lab studies"]},{"year":2022,"claim":"Multiple regulators of SPP1 expression were defined, spanning transcriptional (β-catenin/TCF-4, CaM/CaMKIV/CREB1), post-transcriptional (miR-433), and post-translational (N79 glycosylation) control.","evidence":"shRNA/inhibitor, luciferase reporters for CREB1 and miR-433/3'UTR, N79Q mutagenesis with proliferation and NF-κB readouts","pmids":["32819387","35106922","34306197","35451542"],"confidence":"Medium","gaps":["Combined hierarchy of these inputs unknown","Single-lab findings"]},{"year":2023,"claim":"In vivo work showed that SPP1+ macrophage identity and profibrotic action are driven by platelet CXCL4 and that macrophage OPN can also be protective, inducing an OSM-STAT3-ARG2 axis that limits NASH steatosis.","evidence":"Cxcl4 loss-of-function with snRNA-seq in heart/kidney injury; conditional myeloid Spp1 knockin/knockout in NASH with FAO readouts","pmids":["36807143","37028770"],"confidence":"High","gaps":["OSM and CXCL4 receptor mechanisms not fully integrated","Context-dependence of protective vs pathogenic roles unresolved"]},{"year":2024,"claim":"A convergent body of work established SPP1+ macrophage-derived OPN as a driver of immune suppression and fibrosis across organs, acting through CD44/integrin-PI3K/AKT and A2AR to suppress CD8+ T cells and via TGF-β-induced collagen barriers to confer checkpoint resistance.","evidence":"scRNA/spatial transcriptomics, receptor blockade, co-culture, conditional knockouts, and anti-SPP1/anti-PD-1 or anti-A2AR combination therapy in tumor, retina, PVAT, and muscle models","pmids":["39267037","37706320","40446696","39691723","41021043","36675807","38504518","39616302","41203813","40626359"],"confidence":"Medium","gaps":["Causal hierarchy among multiple receptor axes within one cell context unresolved","Most findings from individual labs"]},{"year":2025,"claim":"Genetic epistasis in pancreatic cancer defined SPP1 binding to CD61 as required for maintaining mesenchymal, metastatic cell fate through a BMP2/GREM1 intercellular loop, and identified H4K12 lactylation as an epigenetic driver of Spp1 in neural repair.","evidence":"Spp1 knockout PDAC models with Grem1 conditional heterozygosity double-mutant epistasis; DNA-pulldown and recombinant SPP1 in spinal cord injury","pmids":["40993391","39939834"],"confidence":"High","gaps":["Generality of CD61/BMP loop beyond PDAC unknown","H4K12la finding single-lab Medium-confidence"]},{"year":null,"claim":"How OPN phosphorylation, glycosylation, isoform identity, and receptor availability are integrated within a single cell to select among CD44, αvβ3/CD61, and downstream PI3K/AKT, FAK/ERK, or JAK2-STAT3 outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural or quantitative model of receptor selection","Context-dependent protective vs pathogenic roles not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,10,19]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,11,12]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,4,8,9,17]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,20,28,31,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,14,15,17,21]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[8,17,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,7,14,19]}],"complexes":[],"partners":["CD44","ITGAV","ITGB3","CD61","PTGER4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BX95","full_name":"Sphingosine-1-phosphate phosphatase 1","aliases":["Sphingosine-1-phosphatase 1","Sphingosine-1-phosphate phosphohydrolase 1","SPP-1"],"length_aa":441,"mass_kda":49.1,"function":"Specifically dephosphorylates sphingosine 1-phosphate (S1P), dihydro-S1P, and phyto-S1P. Does not act on ceramide 1-phosphate, lysophosphatidic acid or phosphatidic acid (PubMed:16782891). Sphingosine-1-phosphate phosphatase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway (PubMed:11756451, PubMed:12815058, PubMed:16782891). Regulates the intracellular levels of the bioactive sphingolipid metabolite S1P that regulates diverse biological processes acting both as an extracellular receptor ligand or as an intracellular second messenger (PubMed:11756451, PubMed:12815058, PubMed:16782891). Involved in efficient ceramide synthesis from exogenous sphingoid bases. Converts S1P to sphingosine, which is readily metabolized to ceramide via ceramide synthase. In concert with sphingosine kinase 2 (SphK2), recycles sphingosine into ceramide through a phosphorylation/dephosphorylation cycle (By similarity). Regulates endoplasmic-to-Golgi trafficking of ceramides, resulting in the regulation of ceramide levels in the endoplasmic reticulum, preferentially long-chain ceramide species, and influences the anterograde membrane transport of both ceramide and proteins from the endoplasmic reticulum to the Golgi apparatus (PubMed:16782891). The modulation of intracellular ceramide levels in turn regulates apoptosis (By similarity). Via S1P levels, modulates resting tone, intracellular Ca(2+) and myogenic vasoconstriction in resistance arteries (PubMed:18583713). Also involved in unfolded protein response (UPR) and ER stress-induced autophagy via regulation of intracellular S1P levels (PubMed:18583713, PubMed:20798685). Involved in the regulation of epidermal homeostasis and keratinocyte differentiation (By similarity)","subcellular_location":"Endoplasmic reticulum membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9BX95/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SPP1","total_profiled":1310},"omim":[{"mim_id":"621529","title":"TRANSMEMBRANE PROTEIN 168; TMEM168","url":"https://www.omim.org/entry/621529"},{"mim_id":"618111","title":"ZINC FINGER PROTEIN 64; ZFP64","url":"https://www.omim.org/entry/618111"},{"mim_id":"612826","title":"SPHINGOSINE-1-PHOSPHATE PHOSPHATASE 1; SGPP1","url":"https://www.omim.org/entry/612826"},{"mim_id":"611539","title":"FORKHEAD BOX D3; FOXD3","url":"https://www.omim.org/entry/611539"},{"mim_id":"609566","title":"PARIETAL FORAMINA 3; PFM3","url":"https://www.omim.org/entry/609566"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Golgi apparatus","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":1840.1},{"tissue":"gallbladder","ntpm":2283.6},{"tissue":"kidney","ntpm":3270.9},{"tissue":"placenta","ntpm":2626.4}],"url":"https://www.proteinatlas.org/search/SPP1"},"hgnc":{"alias_symbol":["BSPI","ETA-1","lnc-PKD2-2-3"],"prev_symbol":["BNSP","OPN"]},"alphafold":{"accession":"Q9BX95","domains":[{"cath_id":"-","chopping":"129-344_354-439","consensus_level":"medium","plddt":91.9557,"start":129,"end":439}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BX95","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BX95-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BX95-F1-predicted_aligned_error_v6.png","plddt_mean":80.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPP1","jax_strain_url":"https://www.jax.org/strain/search?query=SPP1"},"sequence":{"accession":"Q9BX95","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BX95.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BX95/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BX95"}},"corpus_meta":[{"pmid":"10657301","id":"PMC_10657301","title":"Eta-1 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for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39149373","citation_count":9,"is_preprint":false},{"pmid":"40740771","id":"PMC_40740771","title":"Identification of a stromal immunosuppressive barrier orchestrated by SPP1+/C1QC+ macrophages and CD8+ exhausted T cells driving gastric cancer immunotherapy resistance.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40740771","citation_count":9,"is_preprint":false},{"pmid":"32920615","id":"PMC_32920615","title":"Melatonin has a stimulatory effect on osteoblasts by upregulating col-i and opn expression/secretion.","date":"2020","source":"Acta odontologica latinoamericana : AOL","url":"https://pubmed.ncbi.nlm.nih.gov/32920615","citation_count":9,"is_preprint":false},{"pmid":"41120125","id":"PMC_41120125","title":"SPP1high macrophage-induced T-cell stress promotes colon cancer liver metastasis through SPP1/CD44/PI3K/AKT signaling.","date":"2025","source":"Journal for immunotherapy of 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/37614657","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51491,"output_tokens":9637,"usd":0.149514,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20111,"output_tokens":4833,"usd":0.11069,"stage2_stop_reason":"end_turn"},"total_usd":0.260204,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Osteopontin (SPP1/Eta-1) is a protein ligand of CD44. Binding of osteopontin to CD44 induces cellular chemotaxis but not homotypic aggregation, whereas CD44 ligation by hyaluronate induces homotypic aggregation but not chemotaxis, indicating that different CD44 ligands trigger distinct downstream cellular responses.\",\n      \"method\": \"Receptor-ligand binding assay, chemotaxis assay, homotypic aggregation assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct receptor-ligand interaction established with functional cellular readouts, replicated by multiple subsequent studies\",\n      \"pmids\": [\"8560266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Eta-1/OPN promotes type-1 immunity through two receptor-dependent mechanisms: (1) a phosphorylation-dependent interaction between the amino-terminal portion of OPN and its integrin receptor stimulates IL-12 expression in macrophages; (2) a phosphorylation-independent interaction with CD44 inhibits IL-10 expression in macrophages. Mice deficient in OPN have severely impaired IL-12 and IFN-γ production and increased IL-10 production during viral and bacterial infection.\",\n      \"method\": \"OPN knockout mice, infection models (HSV-1, Listeria monocytogenes), cytokine measurement, phosphorylation-dependent binding assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function genetic model with defined molecular mechanism (phosphorylation-dependent integrin vs. CD44 interaction), multiple orthogonal readouts\",\n      \"pmids\": [\"10657301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"OPN/Eta-1 acts downstream of FGF2 signaling in endothelial cells; FGF2 induces OPN overexpression in endothelial cells in vitro and in vivo. Recombinant OPN drives angiogenesis independently of αvβ3 integrin engagement by recruiting proangiogenic monocytes and inducing TNF-α and IL-8 expression in monocytes.\",\n      \"method\": \"Subtractive suppression hybridization, Northern/Western blotting, CAM angiogenesis assay, Matrigel plug assay, chemotaxis assay, RGD-deletion mutant (GST-ΔRGDo-OPN), cytokine induction assay in human monocytes\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstitution with deletion mutants, multiple in vitro and in vivo assays in one study establishing mechanism\",\n      \"pmids\": [\"12847283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BRD4 regulates SPP1 expression in melanoma not by direct binding to the SPP1 promoter but via the non-canonical NF-κB pathway through NFKB2; silencing NFKB2 phenocopies BET inhibitor treatment and SPP1 silencing in suppressing melanoma proliferation, migration, and invasion.\",\n      \"method\": \"ChIP assay, siRNA knockdown, BET inhibitor treatment, cell proliferation/migration/invasion assays, xenograft mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay and epistasis (NFKB2 knockdown phenocopying) plus in vivo validation, single lab\",\n      \"pmids\": [\"33052224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SPP1/OPN secreted by cancer-associated fibroblasts (CAFs) activates CD44 on pancreatic cancer cells to promote cancer stemness. Knockdown of SPP1 in CAF-conditioned media significantly reduced stemness characteristics (CD44+, ALDH+, tumorsphere formation) in pancreatic cancer cells.\",\n      \"method\": \"Conditioned media treatment, gene knockdown (siRNA), 3D co-culture, stemness assays (tumorsphere, ALDH, CD44 FACS), 3D sodium alginate bead co-culture\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific cellular phenotype readout and multiple orthogonal stemness assays, single lab\",\n      \"pmids\": [\"34418441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Macrophage-derived OPN (SPP1) protects from NASH by inducing oncostatin-M (OSM) secretion from macrophages; OSM activates STAT3 signaling in hepatocytes, which upregulates arginase-2 (ARG2), thereby enhancing fatty acid oxidation (FAO) and reducing steatosis. Conditional knockout of Spp1 in myeloid cells worsened NASH while conditional knockin conferred protection.\",\n      \"method\": \"Conditional myeloid Spp1 knockin and knockout mouse models, Western blot, STAT3 pathway analysis, FAO measurement, high-fat/fructose/cholesterol diet NASH model\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — both gain- and loss-of-function conditional mouse models with defined OPN→OSM→STAT3→ARG2 molecular pathway and multiple orthogonal readouts\",\n      \"pmids\": [\"37028770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SPP1 mediates crosstalk between hepatocellular carcinoma cells and macrophages via SPP1-CD44 and SPP1-PTGER4 receptor-ligand axes, and can trigger polarization of macrophages to an M2-phenotype (tumor-associated macrophage phenotype).\",\n      \"method\": \"Receptor-ligand pair analysis from single-cell RNA-seq, in vitro macrophage polarization assay\",\n      \"journal\": \"Cancer Immunology, Immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — receptor-ligand interaction supported by scRNA-seq analysis plus in vitro polarization assay validation, single lab\",\n      \"pmids\": [\"34028567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SPP1 facilitates lung adenocarcinoma cell migration and invasion by upregulating COL11A1 expression; COL11A1 overexpression rescues the suppression of migration/invasion and EMT marker changes caused by SPP1 knockdown, establishing COL11A1 as a downstream effector of SPP1.\",\n      \"method\": \"SPP1 siRNA knockdown, COL11A1 overexpression rescue experiments, Western blot, in vitro and in vivo migration/invasion assays\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue experiment (COL11A1 overexpression reverting SPP1 knockdown phenotype) with in vivo validation, single lab\",\n      \"pmids\": [\"36266702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CXCL4 (from platelets, the major in vivo source of CXCL4) drives differentiation of profibrotic Spp1+ macrophages (marked by Spp1, Fn1, Arg1). Loss of Cxcl4 abrogates Spp1 macrophage differentiation and ameliorates fibrosis. These macrophages orchestrate fibroblast activation via Spp1, Fn1, and Sema3 crosstalk.\",\n      \"method\": \"In vitro and in vivo Cxcl4 loss-of-function, single nuclear RNA sequencing, ligand-receptor interaction analysis, heart and kidney injury models\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo loss-of-function, single nuclear RNA-seq ligand-receptor analysis, multiple organ injury models, identification of platelet CXCL4 as upstream driver\",\n      \"pmids\": [\"36807143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SPP1 derived from silica-exposed macrophage exosomes triggers fibroblast transdifferentiation into myofibroblasts. Knockdown of SPP1 in exosomes decreases fibrosis-related indicators, establishing exosomal SPP1 as a paracrine mediator of macrophage-to-fibroblast communication.\",\n      \"method\": \"Proteomic analysis of macrophage-derived exosomes, SPP1 knockdown in exosomes, fibrosis marker assays\",\n      \"journal\": \"Toxicology and Applied Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (SPP1 knockdown in exosomes) with specific fibrosis phenotype, single lab, single mechanism\",\n      \"pmids\": [\"33961903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"OPN isoforms OPNb and OPNc have distinct pro-invasion mechanisms in esophageal adenocarcinoma: OPNb enhances cell migration, adhesion to laminin, and invasion through integrin RGD-dependent signaling; OPNc decreases migration yet increases cell detachment through integrin-independent mechanisms. Inhibition of RGD integrins abrogates OPNb but not OPNc phenotypes.\",\n      \"method\": \"Stable transfection of OPN isoforms, RGD integrin inhibition, migration assay, adhesion assay, invasion assay in vitro and in vivo\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific gain-of-function with pharmacological inhibition to delineate integrin-dependent vs. independent mechanisms, in vitro and in vivo, single lab\",\n      \"pmids\": [\"26068949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OPN inhibits autophagy in osteoarthritic chondrocytes through CD44 and αvβ3 integrin receptors via the ERK MAPK signaling pathway. Blocking CD44 or αvβ3 integrin with antibodies, or inhibiting ERK, reverses OPN-mediated suppression of LC3II and Beclin1 expression. OPN also promotes chondrocyte proliferation.\",\n      \"method\": \"Recombinant human OPN treatment, anti-CD44 and anti-CD51/61 blocking antibodies, ERK inhibitor, Western blot, mRFP-GFP-LC3 confocal imaging, transmission electron microscopy, CCK-8 assay\",\n      \"journal\": \"Frontiers in Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and antibody blocking experiments with multiple orthogonal autophagy readouts, single lab\",\n      \"pmids\": [\"36034459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OPN activates intracellular PI3K signaling by binding to CD44 on the chondrocyte cell surface, leading to downstream cascade effects that inhibit OA progression. Blocking CD44 or overexpressing OPN alters PI3K, HAS, and hyaluronic acid synthesis in OA chondrocytes.\",\n      \"method\": \"OPN overexpression and siRNA depletion, GRGDSP integrin blocking peptide, integrin αvβ3 antibody blocking, Western blot, HA synthesis assay, in vivo mouse OA model\",\n      \"journal\": \"Genes & Diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with receptor blocking, multiple readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"35005113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OPN interaction with integrin αvβ3 predominantly regulates hyaluronic acid synthase (HAS) expression and hyaluronic acid synthesis in OA chondrocytes. Both non-specific (GRGDSP) and integrin αvβ3-specific blocking downregulate HAS and HA to similar extents.\",\n      \"method\": \"OPN overexpression and depletion, GRGDSP peptide blocking, integrin αvβ3 antibody, HAS expression, HA measurement\",\n      \"journal\": \"BioMed Research International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological blocking and gain/loss-of-function with specific molecular readouts, single lab\",\n      \"pmids\": [\"33134374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SPP1 promotes radiation resistance in esophageal carcinoma by increasing phosphorylation of JAK2 and STAT3 downstream of SPP1. SPP1 knockdown reduces DNA damage repair and tumor cell survival post-irradiation; pharmacological inhibition of JAK2-STAT3 synergizes with radiotherapy to reduce tumor volume in vivo.\",\n      \"method\": \"SPP1 knockdown and overexpression, Western blot (JAK2/STAT3 phosphorylation), colony formation, flow cytometry, xenograft mouse model, pharmacological JAK2-STAT3 inhibitor\",\n      \"journal\": \"Cancer Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined signaling pathway readouts and in vivo validation, single lab\",\n      \"pmids\": [\"35593388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPP1 promotes tumor progression in esophageal carcinoma by activating the focal adhesion kinase (FAK)/ERK pathway. SPP1 knockdown reduces cell adhesion and p-FAK and p-ERK expression; pharmacological FAK inhibition (Y15) reduces tumor proliferation, migration, and invasion.\",\n      \"method\": \"SPP1 knockdown, Western blot (p-FAK, p-ERK), GSEA, cell adhesion and spreading assays, FAK inhibitor Y15, in vitro proliferation/migration/invasion assays\",\n      \"journal\": \"Journal of Gastrointestinal Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and pharmacological inhibition with defined pathway readouts, single lab\",\n      \"pmids\": [\"38989403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BAFF induces OPN secretion from splenic CD21-CD23+ B cells via an NF-κB-dependent signaling pathway. B cell-derived OPN in turn upregulates Bcl2 expression in T cells, promoting T cell survival and resistance to apoptosis.\",\n      \"method\": \"TACI-IgG BAFF blockade in EAE model, in vitro B cell stimulation, NF-κB pathway analysis, T cell apoptosis assay, Bcl2 expression measurement\",\n      \"journal\": \"Molecular Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological blockade and in vitro mechanistic dissection, defined NF-κB pathway and Bcl2 downstream effector, single lab\",\n      \"pmids\": [\"24084099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPP1 secreted by tumor cells binds CD44 on hepatic stellate cells (HSCs), activating the PI3K/AKT signaling pathway to promote HSC differentiation into cancer-associated fibroblasts (CAFs). CD44 receptor blockade abrogates this interaction, and in vivo SPP1 silencing impairs HSC-to-CAF differentiation, reducing tumor volume and collagen deposition.\",\n      \"method\": \"Spatial transcriptomics, scRNA-seq, CD44 receptor blockade, in vivo SPP1 silencing, PI3K/AKT pathway analysis, collagen deposition measurement\",\n      \"journal\": \"Journal of Translational Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blockade plus in vivo loss-of-function with defined PI3K/AKT pathway and fibrosis readouts, single lab\",\n      \"pmids\": [\"39267037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OPN secreted by SPP1+ macrophages in coronary PVAT interacts with CD44/integrin on fibroadipogenic progenitor cells to promote their migration and proliferation, driving PVAT fibrosis. Blocking CD44 or integrin prevents conditioned medium-induced migration and proliferation of fibroadipogenic progenitor cells.\",\n      \"method\": \"In vitro conditioned medium experiments, CD44 and integrin blocking, scRNA-seq, spatial transcriptomics, multiplex immunofluorescence\",\n      \"journal\": \"Arteriosclerosis, Thrombosis, and Vascular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blocking in vitro with defined cellular phenotype, validated spatially, single lab\",\n      \"pmids\": [\"37706320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPP1 (osteopontin) is required for maintaining mesenchymal cell fate in pancreatic cancer. SPP1 binds the CD61 receptor on mesenchymal PDAC cells to induce Bmp2 and Grem1 expression. GREM1 inhibits BMP signaling, which is required for Spp1 expression in epithelial cells, forming an intercellular regulatory loop. Spp1 inactivation converts mesenchymal PDAC cells to an epithelial phenotype and abolishes metastasis.\",\n      \"method\": \"Spp1 knockout mouse PDAC models, Grem1 conditional heterozygosity genetic epistasis, proteomic analysis of patient plasma, in vivo tumorigenesis assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo loss-of-function with defined receptor (CD61), downstream signaling (BMP2/GREM1), intercellular regulatory loop confirmed by double-mutant epistasis, replicated across multiple genetic combinations\",\n      \"pmids\": [\"40993391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPP1 secreted by SPP1+ macrophages drives T-cell exhaustion via the SPP1-CD44 axis. Blocking either SPP1 or CD44 reverses T-cell exhaustion and restores CD8+ T-cell functionality, suppressing tumor growth in vivo in ovarian cancer models.\",\n      \"method\": \"Functional T-cell exhaustion assays, SPP1 and CD44 blocking antibodies, in vivo tumor growth assay, scRNA-seq analysis, molecular docking\",\n      \"journal\": \"International Immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blocking in vitro and in vivo with defined T-cell exhaustion phenotype readout, single lab\",\n      \"pmids\": [\"40446696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Microglia-derived Spp1 promotes pathological retinal neovascularization by activating endothelial Kit/Akt/mTOR signaling. Spp1 expression in microglia is regulated by NF-κB and HIF-1α pathways. Spp1 neutralizing antibody reduces endothelial proliferation and migration in vitro and attenuates pathological retinal neovascularization and improves visual function in vivo.\",\n      \"method\": \"scRNA-seq, BV2 conditioned medium assays with/without Spp1 neutralization, recombinant Spp1 treatment, RNA sequencing of endothelial cells, intravitreal injection of neutralizing antibody, in vitro (BV2, bEnd.3) and in vivo OIR mouse model\",\n      \"journal\": \"Journal of Personalized Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neutralizing antibody in vitro and in vivo, RNA-seq defining Kit/Akt/mTOR pathway, NF-κB/HIF-1α regulation confirmed in vitro, single lab\",\n      \"pmids\": [\"36675807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SOCS3 in myeloid cells directly regulates Spp1 as a transcriptional target of STAT3. Loss of myeloid SOCS3 leads to increased STAT3 activation and elevated Spp1 expression in microglia/macrophages, promoting pathological retinal neovascularization. Pharmaceutical SOCS3 activation or SPP1 blocking reduces pathological neovascularization.\",\n      \"method\": \"scRNA-seq, SOCS3 conditional knockout mice, STAT3 pathway analysis, SPP1 blocking, angiogenesis mouse models\",\n      \"journal\": \"Molecular Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional loss-of-function with defined SOCS3/STAT3/SPP1 transcriptional axis confirmed in vivo, single lab\",\n      \"pmids\": [\"38504518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-433 directly binds to the 3'-UTR of SPP1 mRNA to suppress SPP1 expression. Overexpression of miR-433 in human osteoblast cells (hFOB1.19) decreases SPP1 mRNA and protein levels. In patients with tibial fracture combined with TBI, reduced miR-433 correlates with elevated SPP1.\",\n      \"method\": \"Dual luciferase reporter assay, agomiR-433 overexpression in hFOB1.19 cells, RT-qPCR, Western blot\",\n      \"journal\": \"Experimental and Therapeutic Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual luciferase reporter assay establishes direct miR-433/SPP1 3'-UTR interaction, confirmed by functional overexpression, single lab\",\n      \"pmids\": [\"34306197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OPN N-glycosylation at asparagine-79 promotes osteoclast proliferation and modulates OPN function. N-glycosylation of OPN activates the NF-κB signaling pathway and promotes nuclear translocation of NF-κB in both osteoclasts and osteoblasts. Mutation of N79 prevents OPN from increasing osteoblast proliferation but retains effects on osteoclasts.\",\n      \"method\": \"Site-directed mutagenesis (N79Q), plasmid transfection into osteoblasts and osteoclasts, mass spectrometry for glycosylation site identification, CCK-8 proliferation assay, Western blot, NF-κB nuclear translocation assay\",\n      \"journal\": \"Oral Diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis of post-translational modification site combined with cellular functional assays, single lab\",\n      \"pmids\": [\"35451542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The β-catenin/TCF-4 pathway regulates OPN expression in human chondrocytes. TCF4 shRNA knockdown downregulates OPN expression; treatment with the Wnt/β-catenin inhibitor DKK1 decreases both β-catenin and OPN mRNA and protein in OA chondrocytes.\",\n      \"method\": \"TCF4 shRNA knockdown, DKK1 inhibitor treatment, RT-PCR, Western blot in human chondrocytes\",\n      \"journal\": \"Journal of Orthopaedic Surgery and Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (shRNA) and pharmacological inhibition establishing β-catenin/TCF4→OPN transcriptional regulation, single lab\",\n      \"pmids\": [\"32819387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H4K12 lactylation (H4K12la) promotes transcription of Spp1 in reprogrammed microglia after spinal cord injury. DNA-pulldown experiments identified H4K12la as an upstream epigenetic regulator of Spp1. Recombinant SPP1 (rSPP1) promotes neuronal maturation, enhances mitochondrial function in axons, and improves functional recovery after SCI.\",\n      \"method\": \"DNA-pulldown assay, scRNA-seq, pseudotime analysis, recombinant SPP1 injection in vivo, mitochondrial function assays, behavioral functional recovery assays\",\n      \"journal\": \"CNS Neuroscience & Therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DNA-pulldown identifies H4K12la as SPP1 transcriptional regulator; rSPP1 gain-of-function in vivo with defined neuronal and mitochondrial readouts; single lab\",\n      \"pmids\": [\"39939834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The ATX-LPA axis induces OPN expression in hepatic cancer cells (SMMC7721) via activation of the PI3K/Akt pathway through LPA receptors. OPN is required for cell migration induced by the ATX-LPA axis; LPA receptor or PI3K/Akt inhibitors block ATX/LPC-induced OPN expression.\",\n      \"method\": \"Western blot, RT-qPCR, PI3K/Akt inhibitors, LPA receptor inhibitors, Transwell migration assay\",\n      \"journal\": \"Anatomical Record\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway inhibition establishing LPA receptor→PI3K/Akt→OPN induction axis with functional migration readout, single lab\",\n      \"pmids\": [\"21337710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPP1 secreted by SPP1+ macrophages inhibits CD8+ T cell proliferation. Targeting SPP1 in tumor-associated macrophages shifts their phenotype toward a favorable (less immunosuppressive) state in hepatocellular carcinoma. In vitro, SPP1 overexpression in macrophages upregulates CD73, IL-10, and TGF-β, impairing CD8+ T cell function via A2AR signaling; anti-SPP1 or anti-A2AR treatment restores CD8+ T cell activity.\",\n      \"method\": \"scRNA-seq, bulk RNA-seq, in vitro co-culture of SPP1-overexpressing macrophages and CD8+ T cells, flow cytometry, Western blot, anti-SPP1 and anti-A2AR neutralization, CD8+ T cell proliferation and cytokine assays\",\n      \"journal\": \"Frontiers in Immunology / Cancer Immunology Immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro co-culture with SPP1 overexpression and receptor neutralization establishing SPP1→A2AR→CD8+ T cell suppression axis, single lab\",\n      \"pmids\": [\"39691723\", \"41021043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Glycosyltransferase B4GALNT1 upregulates SPP1 synthesis and secretion in HCC tumor cells by increasing phosphorylation of HES4 via p38/JNK signaling, thereby increasing HES4 transcriptional activity which drives SPP1 expression and reshapes the immunosuppressive microenvironment (TAMs, Th2 cells).\",\n      \"method\": \"B4GALNT1 and HES4 manipulation, Western blot (p38/JNK/HES4 phosphorylation), transcriptional activity assay, SPP1 secretion measurement, immune cell composition analysis in mouse model\",\n      \"journal\": \"Molecular Biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined B4GALNT1→p38/JNK→HES4→SPP1 signaling cascade, single lab\",\n      \"pmids\": [\"39616302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Macrophage-derived Spp1 promotes accumulation of adipogenic stromal cells (PDGFRα+ Lifr+ and Procr+ populations) in dystrophic (mdx) muscles, leading to intramuscular fat accumulation. Macrophage-specific Spp1 conditional knockout reduces these adipogenic progenitor populations, decreases intramuscular diaphragmatic fat, and improves diaphragm function.\",\n      \"method\": \"Macrophage-specific Spp1 conditional knockout (cKO), single-cell transcriptional profiling, cell sorting, in vitro adipogenesis assay, diaphragm function measurement\",\n      \"journal\": \"JCI Insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional knockout with scRNA-seq defining target cell populations and in vitro adipogenesis confirmation, single lab\",\n      \"pmids\": [\"40626359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TGF-β instructs tumor-associated macrophages to induce SPP1 expression. SPP1, in turn, promotes collagen deposition and accumulation of tumor-associated macrophages and fibroblasts, creating an immunosuppressive barrier that blocks clonal expansion of newly arrived T cells, thereby driving immune checkpoint blockade resistance in colorectal cancer liver metastases.\",\n      \"method\": \"Mouse models of colorectal cancer, patient-derived data, genetic epistasis (TGF-β pathway manipulation), T cell recruitment assays, collagen deposition measurement\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models establishing TGF-β→SPP1 induction and SPP1→collagen/immune suppression with defined cellular and functional readouts, single lab\",\n      \"pmids\": [\"41203813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Spp1+ macrophages in viral myocarditis promote fibroblast conversion to an inflammatory phenotype with high Ccl2/Ccl7 expression, which in turn increases monocyte chemotaxis to the heart. Inhibition of SPP1 reduces cardiac macrophage infiltration, attenuates myocardial inflammation, and improves cardiac function in CVB3-induced VMC mice.\",\n      \"method\": \"scRNA-seq, indirect co-culture of macrophages and cardiac fibroblasts in vitro, CellPhoneDB ligand-receptor analysis, macrophage depletion, SPP1 inhibition in vivo, cardiac function measurement\",\n      \"journal\": \"Biology Direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro co-culture establishing SPP1→fibroblast Ccl2/Ccl7 induction plus in vivo SPP1 inhibition with cardiac functional readout, single lab\",\n      \"pmids\": [\"40087693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Therapeutic silencing of Spp1 in TREM2+ cardiac macrophages using an antibody-siRNA conjugate reduces atrial fibrosis and suppresses atrial fibrillation in mice, demonstrating that macrophage-secreted osteopontin (encoded by Spp1) drives atrial fibrosis and arrhythmia.\",\n      \"method\": \"Antibody-siRNA conjugate for macrophage-specific Spp1 silencing in vivo, atrial fibrosis measurement, atrial fibrillation induction assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific in vivo loss-of-function with defined fibrosis and electrophysiological readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"39149373\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPP1 macrophage-derived SPP1 mediates immune suppression in colon cancer liver metastasis via the SPP1/CD44/PI3K/AKT signaling pathway, inducing T-cell stress (HSPA1A/HSPA1Bhigh T cells). Combination treatment with anti-SPP1 and anti-PD-1 antibodies inhibits liver metastasis growth and restores T-cell infiltration and function.\",\n      \"method\": \"scRNA-seq, in vitro co-culture of Macro_SPP1high cells with T cells, CD44 blocking, PI3K/AKT pathway analysis, anti-SPP1/anti-PD-1 combination therapy in vivo\",\n      \"journal\": \"Journal for Immunotherapy of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic dissection with CD44 blocking and defined PI3K/AKT pathway, in vivo combination therapy validation, single lab\",\n      \"pmids\": [\"41120125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Magnesium ions promote OPN expression in osteoblastic cells through the CaM/CaMKIV/CREB1 signaling pathway. Phosphorylated CREB1 directly binds the OPN promoter to upregulate OPN transcription. Knockdown of CaMKIV or CREB1 reduces Mg2+-induced OPN expression and mineralization.\",\n      \"method\": \"Dual-luciferase reporter assay (p-CREB1 binding to OPN promoter), shCaMKIV and shCREB1 knockdown, KN93 CaMKIV inhibitor, Western blot, in vivo Mg screw implantation\",\n      \"journal\": \"Journal of Biomedical Materials Research Part B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — luciferase reporter assay for direct transcription factor binding to OPN promoter, shRNA knockdown, pharmacological inhibitor, in vivo validation, single lab\",\n      \"pmids\": [\"35106922\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPP1 (osteopontin/OPN) is a secreted, multifunctional phosphoglycoprotein that signals through cell-surface receptors—primarily CD44 and integrins (αvβ3, RGD-binding)—to regulate immunity, cell migration, adhesion, fibrosis, and cancer progression; its phosphorylation state determines receptor selectivity (phosphorylation-dependent integrin engagement stimulates IL-12, phosphorylation-independent CD44 binding suppresses IL-10), and its expression is controlled transcriptionally by NF-κB/NFKB2, β-catenin/TCF-4, STAT3, and CREB1 (via CaM/CaMKIV), post-translationally by N-glycosylation at N79 and H4K12 lactylation, and post-transcriptionally by miR-433, while acting downstream of FGF2, ATX-LPA/PI3K-Akt, CXCL4 (from platelets), and TGF-β to drive angiogenesis, macrophage polarization, T-cell exhaustion, fibroblast activation, and cancer cell invasion via COL11A1 upregulation and FAK/ERK or PI3K/AKT/JAK2-STAT3 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPP1 (osteopontin/OPN) is a secreted phosphoglycoprotein that acts as an extracellular signaling ligand to coordinate immunity, fibrosis, tissue remodeling, and cancer progression through engagement of cell-surface receptors [#0, #1]. Receptor selectivity is dictated by its phosphorylation and isoform state: a phosphorylation-dependent interaction between the N-terminal region of OPN and its integrin receptor stimulates IL-12 in macrophages, whereas a phosphorylation-independent interaction with CD44 suppresses IL-10, together promoting type-1 immunity [#1], and binding to CD44 versus hyaluronate elicits distinct cellular responses such as chemotaxis [#0]. Splice isoforms further diversify output, with OPNb signaling through RGD-dependent integrins while OPNc acts integrin-independently [#10]. Across diverse tissues, OPN signals through CD44 and αvβ3/CD61 integrins to drive PI3K/AKT, FAK/ERK, JAK2-STAT3, and ERK MAPK cascades, controlling chondrocyte autophagy and hyaluronan synthesis [#11, #12, #13], cancer cell migration and invasion via COL11A1 induction [#7], radioresistance through JAK2-STAT3 [#14], and adhesion-dependent progression via FAK/ERK [#15]. A recurrent theme is OPN produced by SPP1+ macrophages acting on stromal and immune cells: it converts hepatic stellate cells and fibroadipogenic progenitors into activated fibroblasts via CD44/integrin-PI3K/AKT [#17, #18], drives profibrotic crosstalk in heart, kidney, and muscle downstream of platelet CXCL4 [#8, #30], polarizes tumor-associated macrophages to an M2 state [#6], and enforces CD8+ T-cell exhaustion and immune-checkpoint resistance through the SPP1-CD44 axis and A2AR signaling [#20, #28, #34]. In pancreatic cancer, SPP1 binding to CD61 sustains a mesenchymal, metastatic cell state through a BMP2/GREM1 intercellular regulatory loop [#19]. SPP1 expression is controlled transcriptionally by non-canonical NF-κB/NFKB2, β-catenin/TCF-4, STAT3 (via SOCS3 and B4GALNT1/HES4), and CaM/CaMKIV/CREB1 [#3, #25, #22, #29, #35], post-transcriptionally by miR-433 [#23], and by the epigenetic and post-translational modifications H4K12 lactylation and N79 N-glycosylation [#26, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing that OPN is a functional ligand of CD44 defined a receptor-based mechanism for its biological activity and showed that different CD44 ligands route distinct responses.\",\n      \"evidence\": \"Receptor-ligand binding, chemotaxis, and homotypic aggregation assays\",\n      \"pmids\": [\"8560266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve integrin contribution\", \"Downstream intracellular cascade not mapped\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Knockout and infection models revealed that OPN promotes type-1 immunity through two molecularly separable arms, defining phosphorylation state as the switch for receptor choice.\",\n      \"evidence\": \"OPN knockout mice in HSV-1/Listeria infection with phosphorylation-dependent binding assays and cytokine readouts\",\n      \"pmids\": [\"10657301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific integrin partner not pinned down\", \"Phosphosite mapping incomplete\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placing OPN downstream of FGF2 in endothelium and showing RGD-independent angiogenesis broadened OPN's role beyond integrin engagement to monocyte recruitment.\",\n      \"evidence\": \"FGF2 induction, RGD-deletion mutant, CAM and Matrigel angiogenesis assays, monocyte cytokine induction\",\n      \"pmids\": [\"12847283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RGD-independent receptor not identified\", \"In vivo source of OPN not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking the ATX-LPA axis to OPN induction via PI3K/Akt identified an upstream lipid-signaling route controlling OPN-dependent migration.\",\n      \"evidence\": \"Pharmacological LPA receptor and PI3K/Akt inhibition with Transwell migration in hepatic cancer cells\",\n      \"pmids\": [\"21337710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor mediating induction not identified\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two studies defined upstream transcriptional control of SPP1, through non-canonical NF-κB/NFKB2 in melanoma and through BAFF/NF-κB in B cells feeding T-cell survival.\",\n      \"evidence\": \"ChIP, siRNA/BET inhibition with xenografts; BAFF blockade and B-cell stimulation with Bcl2 readout\",\n      \"pmids\": [\"33052224\", \"24084099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter elements not fully mapped\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Isoform-resolved analysis showed OPNb and OPNc use integrin-dependent versus integrin-independent mechanisms, explaining functional heterogeneity of OPN outputs.\",\n      \"evidence\": \"Stable isoform transfection with RGD integrin inhibition in esophageal adenocarcinoma\",\n      \"pmids\": [\"26068949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"OPNc integrin-independent receptor unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Chondrocyte studies established that OPN signals through both CD44 and αvβ3 to control autophagy (ERK MAPK) and hyaluronan synthesis (PI3K/HAS), connecting receptor usage to specific intracellular cascades.\",\n      \"evidence\": \"Recombinant OPN, anti-CD44/anti-αvβ3 and RGD-peptide blocking, ERK inhibition, autophagy and HA assays in vitro and in vivo\",\n      \"pmids\": [\"36034459\", \"35005113\", \"33134374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor cross-talk quantitation incomplete\", \"Single-lab series\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tumor-microenvironment studies showed SPP1 from CAFs and tumor cells engages CD44 (and PTGER4) to drive stemness and M2 macrophage polarization, framing SPP1 as a stromal-immune crosstalk node.\",\n      \"evidence\": \"Conditioned media, siRNA knockdown, 3D co-culture, stemness assays, scRNA-seq receptor-ligand analysis with polarization assays\",\n      \"pmids\": [\"34418441\", \"34028567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PTGER4 axis not functionally validated\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Exosomal delivery of SPP1 from silica-exposed macrophages was shown to drive fibroblast-to-myofibroblast transdifferentiation, identifying a paracrine vehicle for OPN-mediated fibrosis.\",\n      \"evidence\": \"Exosome proteomics with SPP1 knockdown and fibrosis marker assays\",\n      \"pmids\": [\"33961903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor on fibroblasts not defined\", \"Single mechanism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mechanistic dissection in cancer defined SPP1 downstream effectors and signaling, including COL11A1 induction for invasion and JAK2-STAT3 for radioresistance.\",\n      \"evidence\": \"SPP1 knockdown with COL11A1 rescue; JAK2/STAT3 phosphorylation with pharmacological inhibition and xenografts\",\n      \"pmids\": [\"36266702\", \"35593388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor upstream of these cascades not specified in each system\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple regulators of SPP1 expression were defined, spanning transcriptional (β-catenin/TCF-4, CaM/CaMKIV/CREB1), post-transcriptional (miR-433), and post-translational (N79 glycosylation) control.\",\n      \"evidence\": \"shRNA/inhibitor, luciferase reporters for CREB1 and miR-433/3'UTR, N79Q mutagenesis with proliferation and NF-κB readouts\",\n      \"pmids\": [\"32819387\", \"35106922\", \"34306197\", \"35451542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Combined hierarchy of these inputs unknown\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo work showed that SPP1+ macrophage identity and profibrotic action are driven by platelet CXCL4 and that macrophage OPN can also be protective, inducing an OSM-STAT3-ARG2 axis that limits NASH steatosis.\",\n      \"evidence\": \"Cxcl4 loss-of-function with snRNA-seq in heart/kidney injury; conditional myeloid Spp1 knockin/knockout in NASH with FAO readouts\",\n      \"pmids\": [\"36807143\", \"37028770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"OSM and CXCL4 receptor mechanisms not fully integrated\", \"Context-dependence of protective vs pathogenic roles unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A convergent body of work established SPP1+ macrophage-derived OPN as a driver of immune suppression and fibrosis across organs, acting through CD44/integrin-PI3K/AKT and A2AR to suppress CD8+ T cells and via TGF-β-induced collagen barriers to confer checkpoint resistance.\",\n      \"evidence\": \"scRNA/spatial transcriptomics, receptor blockade, co-culture, conditional knockouts, and anti-SPP1/anti-PD-1 or anti-A2AR combination therapy in tumor, retina, PVAT, and muscle models\",\n      \"pmids\": [\"39267037\", \"37706320\", \"40446696\", \"39691723\", \"41021043\", \"36675807\", \"38504518\", \"39616302\", \"41203813\", \"40626359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal hierarchy among multiple receptor axes within one cell context unresolved\", \"Most findings from individual labs\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic epistasis in pancreatic cancer defined SPP1 binding to CD61 as required for maintaining mesenchymal, metastatic cell fate through a BMP2/GREM1 intercellular loop, and identified H4K12 lactylation as an epigenetic driver of Spp1 in neural repair.\",\n      \"evidence\": \"Spp1 knockout PDAC models with Grem1 conditional heterozygosity double-mutant epistasis; DNA-pulldown and recombinant SPP1 in spinal cord injury\",\n      \"pmids\": [\"40993391\", \"39939834\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of CD61/BMP loop beyond PDAC unknown\", \"H4K12la finding single-lab Medium-confidence\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OPN phosphorylation, glycosylation, isoform identity, and receptor availability are integrated within a single cell to select among CD44, αvβ3/CD61, and downstream PI3K/AKT, FAK/ERK, or JAK2-STAT3 outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural or quantitative model of receptor selection\", \"Context-dependent protective vs pathogenic roles not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 10, 19]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 4, 8, 9, 17]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 20, 28, 31, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 14, 15, 17, 21]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [8, 17, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 7, 14, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD44\", \"ITGAV\", \"ITGB3\", \"CD61\", \"PTGER4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}