Affinage

SPP1

Sphingosine-1-phosphate phosphatase 1 · UniProt Q9BX95

Length
441 aa
Mass
49.1 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    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

    PMID:8560266

    Open questions at the time
    • Did not resolve integrin contribution
    • Downstream intracellular cascade not mapped
  2. 2000 High

    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

    PMID:10657301

    Open questions at the time
    • Specific integrin partner not pinned down
    • Phosphosite mapping incomplete
  3. 2003 High

    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

    PMID:12847283

    Open questions at the time
    • RGD-independent receptor not identified
    • In vivo source of OPN not defined
  4. 2010 Medium

    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

    PMID:21337710

    Open questions at the time
    • Transcription factor mediating induction not identified
    • Single cell line
  5. 2013 Medium

    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

    PMID:24084099 PMID:33052224

    Open questions at the time
    • Direct promoter elements not fully mapped
    • Single-lab findings
  6. 2015 Medium

    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

    PMID:26068949

    Open questions at the time
    • OPNc integrin-independent receptor unknown
    • Single lab
  7. 2020 Medium

    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

    PMID:33134374 PMID:35005113 PMID:36034459

    Open questions at the time
    • Receptor cross-talk quantitation incomplete
    • Single-lab series
  8. 2021 Medium

    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

    PMID:34028567 PMID:34418441

    Open questions at the time
    • PTGER4 axis not functionally validated
    • Single-lab findings
  9. 2021 Medium

    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

    PMID:33961903

    Open questions at the time
    • Receptor on fibroblasts not defined
    • Single mechanism
  10. 2022 Medium

    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

    PMID:35593388 PMID:36266702

    Open questions at the time
    • Receptor upstream of these cascades not specified in each system
    • Single-lab studies
  11. 2022 Medium

    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

    PMID:32819387 PMID:34306197 PMID:35106922 PMID:35451542

    Open questions at the time
    • Combined hierarchy of these inputs unknown
    • Single-lab findings
  12. 2023 High

    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

    PMID:36807143 PMID:37028770

    Open questions at the time
    • OSM and CXCL4 receptor mechanisms not fully integrated
    • Context-dependence of protective vs pathogenic roles unresolved
  13. 2024 Medium

    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

    PMID:36675807 PMID:37706320 PMID:38504518 PMID:39267037 PMID:39616302 PMID:39691723 PMID:40446696 PMID:40626359 PMID:41021043 PMID:41203813

    Open questions at the time
    • Causal hierarchy among multiple receptor axes within one cell context unresolved
    • Most findings from individual labs
  14. 2025 High

    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

    PMID:39939834 PMID:40993391

    Open questions at the time
    • Generality of CD61/BMP loop beyond PDAC unknown
    • H4K12la finding single-lab Medium-confidence

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unified structural or quantitative model of receptor selection
  • Context-dependent protective vs pathogenic roles not mechanistically reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 5 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 4 R-HSA-1474244 Extracellular matrix organization 3
Partners
CD44CD61ITGAVITGB3PTGER4

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 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. Receptor-ligand binding assay, chemotaxis assay, homotypic aggregation assay Science High 8560266
2000 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. OPN knockout mice, infection models (HSV-1, Listeria monocytogenes), cytokine measurement, phosphorylation-dependent binding assays Science High 10657301
2003 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. 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 of Immunology High 12847283
2013 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. ChIP assay, siRNA knockdown, BET inhibitor treatment, cell proliferation/migration/invasion assays, xenograft mouse model Theranostics Medium 33052224
2021 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. Conditioned media treatment, gene knockdown (siRNA), 3D co-culture, stemness assays (tumorsphere, ALDH, CD44 FACS), 3D sodium alginate bead co-culture Gastroenterology Medium 34418441
2023 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. Conditional myeloid Spp1 knockin and knockout mouse models, Western blot, STAT3 pathway analysis, FAO measurement, high-fat/fructose/cholesterol diet NASH model Gastroenterology High 37028770
2021 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). Receptor-ligand pair analysis from single-cell RNA-seq, in vitro macrophage polarization assay Cancer Immunology, Immunotherapy Medium 34028567
2022 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. SPP1 siRNA knockdown, COL11A1 overexpression rescue experiments, Western blot, in vitro and in vivo migration/invasion assays Cancer Cell International Medium 36266702
2023 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. In vitro and in vivo Cxcl4 loss-of-function, single nuclear RNA sequencing, ligand-receptor interaction analysis, heart and kidney injury models Cell Reports High 36807143
2021 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. Proteomic analysis of macrophage-derived exosomes, SPP1 knockdown in exosomes, fibrosis marker assays Toxicology and Applied Pharmacology Medium 33961903
2015 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. Stable transfection of OPN isoforms, RGD integrin inhibition, migration assay, adhesion assay, invasion assay in vitro and in vivo Oncotarget Medium 26068949
2020 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. 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 Frontiers in Endocrinology Medium 36034459
2020 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. OPN overexpression and siRNA depletion, GRGDSP integrin blocking peptide, integrin αvβ3 antibody blocking, Western blot, HA synthesis assay, in vivo mouse OA model Genes & Diseases Medium 35005113
2020 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. OPN overexpression and depletion, GRGDSP peptide blocking, integrin αvβ3 antibody, HAS expression, HA measurement BioMed Research International Medium 33134374
2022 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. SPP1 knockdown and overexpression, Western blot (JAK2/STAT3 phosphorylation), colony formation, flow cytometry, xenograft mouse model, pharmacological JAK2-STAT3 inhibitor Cancer Medicine Medium 35593388
2024 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. SPP1 knockdown, Western blot (p-FAK, p-ERK), GSEA, cell adhesion and spreading assays, FAK inhibitor Y15, in vitro proliferation/migration/invasion assays Journal of Gastrointestinal Oncology Medium 38989403
2013 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. TACI-IgG BAFF blockade in EAE model, in vitro B cell stimulation, NF-κB pathway analysis, T cell apoptosis assay, Bcl2 expression measurement Molecular Immunology Medium 24084099
2024 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. Spatial transcriptomics, scRNA-seq, CD44 receptor blockade, in vivo SPP1 silencing, PI3K/AKT pathway analysis, collagen deposition measurement Journal of Translational Medicine Medium 39267037
2024 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. In vitro conditioned medium experiments, CD44 and integrin blocking, scRNA-seq, spatial transcriptomics, multiplex immunofluorescence Arteriosclerosis, Thrombosis, and Vascular Biology Medium 37706320
2025 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. Spp1 knockout mouse PDAC models, Grem1 conditional heterozygosity genetic epistasis, proteomic analysis of patient plasma, in vivo tumorigenesis assays Nature High 40993391
2024 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. Functional T-cell exhaustion assays, SPP1 and CD44 blocking antibodies, in vivo tumor growth assay, scRNA-seq analysis, molecular docking International Immunopharmacology Medium 40446696
2023 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. 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 of Personalized Medicine Medium 36675807
2024 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. scRNA-seq, SOCS3 conditional knockout mice, STAT3 pathway analysis, SPP1 blocking, angiogenesis mouse models Molecular Therapy Medium 38504518
2022 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. Dual luciferase reporter assay, agomiR-433 overexpression in hFOB1.19 cells, RT-qPCR, Western blot Experimental and Therapeutic Medicine Medium 34306197
2022 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. 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 Oral Diseases Medium 35451542
2022 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. TCF4 shRNA knockdown, DKK1 inhibitor treatment, RT-PCR, Western blot in human chondrocytes Journal of Orthopaedic Surgery and Research Medium 32819387
2025 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. DNA-pulldown assay, scRNA-seq, pseudotime analysis, recombinant SPP1 injection in vivo, mitochondrial function assays, behavioral functional recovery assays CNS Neuroscience & Therapeutics Medium 39939834
2010 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. Western blot, RT-qPCR, PI3K/Akt inhibitors, LPA receptor inhibitors, Transwell migration assay Anatomical Record Medium 21337710
2024 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. 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 Frontiers in Immunology / Cancer Immunology Immunotherapy Medium 39691723 41021043
2024 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). B4GALNT1 and HES4 manipulation, Western blot (p38/JNK/HES4 phosphorylation), transcriptional activity assay, SPP1 secretion measurement, immune cell composition analysis in mouse model Molecular Biomedicine Medium 39616302
2025 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. Macrophage-specific Spp1 conditional knockout (cKO), single-cell transcriptional profiling, cell sorting, in vitro adipogenesis assay, diaphragm function measurement JCI Insight Medium 40626359
2024 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. Mouse models of colorectal cancer, patient-derived data, genetic epistasis (TGF-β pathway manipulation), T cell recruitment assays, collagen deposition measurement Nature Genetics Medium 41203813
2025 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. 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 Biology Direct Medium 40087693
2024 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. Antibody-siRNA conjugate for macrophage-specific Spp1 silencing in vivo, atrial fibrosis measurement, atrial fibrillation induction assay bioRxivpreprint Medium 39149373
2025 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. 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 for Immunotherapy of Cancer Medium 41120125
2022 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. 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 of Biomedical Materials Research Part B Medium 35106922

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science (New York, N.Y.) 938 10657301
1996 Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science (New York, N.Y.) 808 8560266
2022 Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer. Nature communications 716 35365629
2019 Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. The European respiratory journal 630 31221805
2023 CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers. Science (New York, N.Y.) 491 37535729
2023 Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner. Cell reports 231 36807143
2021 Pancreatic Tumor Microenvironment Factor Promotes Cancer Stemness via SPP1-CD44 Axis. Gastroenterology 204 34418441
2023 Colorectal Cancer Metastases in the Liver Establish Immunosuppressive Spatial Networking between Tumor-Associated SPP1+ Macrophages and Fibroblasts. Clinical cancer research : an official journal of the American Association for Cancer Research 157 36239989
2000 Structural and functional characterization of BnSP-7, a Lys49 myotoxic phospholipase A(2) homologue from Bothrops neuwiedi pauloensis venom. Archives of biochemistry and biophysics 133 10860537
2023 Macrophage-derived Osteopontin (SPP1) Protects From Nonalcoholic Steatohepatitis. Gastroenterology 121 37028770
2021 Construction of TME and Identification of crosstalk between malignant cells and macrophages by SPP1 in hepatocellular carcinoma. Cancer immunology, immunotherapy : CII 114 34028567
2003 Osteopontin (Eta-1) and fibroblast growth factor-2 cross-talk in angiogenesis. Journal of immunology (Baltimore, Md. : 1950) 102 12847283
2020 BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway. Theranostics 90 33052224
2023 Osteopontin (OPN)/SPP1: from its biochemistry to biological functions in the innate immune system and the central nervous system (CNS). International immunology 74 36525591
2013 Headful DNA packaging: bacteriophage SPP1 as a model system. Virus research 73 23419885
2003 Crystal structures of BnSP-7 and BnSP-6, two Lys49-phospholipases A(2): quaternary structure and inhibition mechanism insights. Biochemical and biophysical research communications 65 14623331
2015 OPN -Revisited. Journal of clinical and diagnostic research : JCDR 63 26266236
2023 Single-Cell RNA Sequencing of Coronary Perivascular Adipose Tissue From End-Stage Heart Failure Patients Identifies SPP1+ Macrophage Subpopulation as a Target for Alleviating Fibrosis. Arteriosclerosis, thrombosis, and vascular biology 61 37706320
2015 Osteopontin (OPN/SPP1) isoforms collectively enhance tumor cell invasion and dissemination in esophageal adenocarcinoma. Oncotarget 61 26068949
2023 ANGPTL2+cancer-associated fibroblasts and SPP1+macrophages are metastasis accelerators of colorectal cancer. Frontiers in immunology 59 37691929
2003 Bacillus subtilis bacteriophage SPP1 DNA packaging motor requires terminase and portal proteins. The Journal of biological chemistry 57 12697751
2024 SPP1+ TAM Regulates the Metastatic Colonization of CXCR4+ Metastasis-Associated Tumor Cells by Remodeling the Lymph Node Microenvironment. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 53 39236316
2023 SPP1+ TAM subpopulations in tumor microenvironment promote intravasation and metastasis of head and neck squamous cell carcinoma. Cancer gene therapy 48 38052857
2022 SPP1 facilitates cell migration and invasion by targeting COL11A1 in lung adenocarcinoma. Cancer cell international 47 36266702
2024 Spatial transcriptomics reveals tumor-derived SPP1 induces fibroblast chemotaxis and activation in the hepatocellular carcinoma microenvironment. Journal of translational medicine 43 39267037
2025 The Landscape of SPP1 + Macrophages Across Tissues and Diseases: A Comprehensive Review. Immunology 37 40395129
2024 Identification of SPP1+ macrophages in promoting cancer stemness via vitronectin and CCL15 signals crosstalk in liver cancer. Cancer letters 37 39216547
2023 A comprehensive analysis of single-cell RNA transcriptome reveals unique SPP1+ chondrocytes in human osteoarthritis. Computers in biology and medicine 36 37141654
2015 Human breast cancer cell death induced by BnSP-6, a Lys-49 PLA₂ homologue from Bothrops pauloensis venom. International journal of biological macromolecules 36 26519876
2010 The implication of osteopontin (OPN) expression and genetic polymorphisms of OPN promoter in oral carcinogenesis. Oral oncology 36 20219412
2023 The critical role of osteopontin (OPN) in fibrotic diseases. Cytokine & growth factor reviews 34 37648616
2021 SPP1 derived from silica-exposed macrophage exosomes triggers fibroblast transdifferentiation. Toxicology and applied pharmacology 34 33961903
2024 Gpnmb and Spp1 mark a conserved macrophage injury response masking fibrosis-specific programming in the lung. JCI insight 32 39509324
2023 Associations of cortical SPP1 and ITGAX with cognition and common neuropathologies in older adults. Alzheimer's & dementia : the journal of the Alzheimer's Association 29 37727065
1998 Coordinate expression of OPN and associated receptors during monocyte/macrophage differentiation of HL-60 cells. Journal of cellular physiology 29 9525482
2020 Osteopontin inhibits osteoarthritis progression via the OPN/CD44/PI3K signal axis. Genes & diseases 28 35005113
2017 SPP1 genotype and glucocorticoid treatment modify osteopontin expression in Duchenne muscular dystrophy cells. Human molecular genetics 28 28595270
2013 Spp1 at the crossroads of H3K4me3 regulation and meiotic recombination. Epigenetics 28 23511748
1982 SPP1-mediated plasmid transduction. Journal of virology 27 6292508
2012 Bacteriophage SPP1 DNA replication strategies promote viral and disable host replication in vitro. Nucleic acids research 26 23268446
2025 SPP1 macrophages across diseases: A call for reclassification? FASEB journal : official publication of the Federation of American Societies for Experimental Biology 25 40047497
2024 Profibrotic Subsets of SPP1+ Macrophages and POSTN+ Fibroblasts Contribute to Fibrotic Scarring in Acne Keloidalis. The Journal of investigative dermatology 25 38218364
2024 SOCS3 regulates pathological retinal angiogenesis through modulating SPP1 expression in microglia and macrophages. Molecular therapy : the journal of the American Society of Gene Therapy 24 38504518
2022 SPP1 promotes radiation resistance through JAK2/STAT3 pathway in esophageal carcinoma. Cancer medicine 24 35593388
2022 Neuroinflammation-Related Proteins NOD2 and Spp1 Are Abnormally Upregulated in Amyotrophic Lateral Sclerosis. Neurology(R) neuroimmunology & neuroinflammation 24 36460480
2025 Targeting SPP1+ macrophages via the SPP1-CD44 axis reveals a key mechanism of immune suppression and tumor progression in ovarian cancer. International immunopharmacology 23 40446696
2021 SPP1 expression in the mouse uterus and placenta: implications for implantation†. Biology of reproduction 23 34165144
2024 SPP1+ macrophages in HR+ breast cancer are associated with tumor-infiltrating lymphocytes. NPJ breast cancer 22 39349495
2025 SPP1 is required for maintaining mesenchymal cell fate in pancreatic cancer. Nature 20 40993391
2024 Targeted SPP1 Inhibition of Tumor-Associated Myeloid Cells Effectively Decreases Tumor Sizes. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 39639496
2023 SPP1/osteopontin: a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm? Journal of molecular medicine (Berlin, Germany) 18 37698712
2025 Single-cell multi-omics analysis identifies SPP1+ macrophages as key drivers of ferroptosis-mediated fibrosis in ligamentum flavum hypertrophy. Biomarker research 17 40001138
2025 Decoding SPP1 regulation: Genetic and nongenetic insights into its role in disease progression. Molecules and cells 17 40210132
2024 SPP1 macrophages in colorectal cancer: Markers of malignancy and promising therapeutic targets. Genes & diseases 17 40092488
2023 Microglia-Derived Spp1 Promotes Pathological Retinal Neovascularization via Activating Endothelial Kit/Akt/mTOR Signaling. Journal of personalized medicine 17 36675807
2022 OPN inhibits autophagy through CD44, integrin and the MAPK pathway in osteoarthritic chondrocytes. Frontiers in endocrinology 17 36034459
2013 BAFF maintains T-cell survival by inducing OPN expression in B cells. Molecular immunology 17 24084099
2025 Single-cell and spatial transcriptomics profile the interaction of SPP1 macrophages and FAP fibroblasts in non-small cell lung cancer. Translational lung cancer research 15 40799444
2024 SPP1+ macrophages and FAP+ fibroblasts promote the progression of pMMR gastric cancer. Scientific reports 15 39482333
2022 The Brucella Effector BspI Suppresses Inflammation via Inhibition of IRE1 Kinase Activity during Brucella Infection. Journal of immunology (Baltimore, Md. : 1950) 15 35840160
2021 Antiangiogenic effects of phospholipase A2 Lys49 BnSP-7 from Bothrops pauloensis snake venom on endothelial cells: An in vitro and ex vivo approach. Toxicology in vitro : an international journal published in association with BIBRA 15 33486049
2023 Important oncogenic and immunogenic roles of SPP1 and CSF1 in hepatocellular carcinoma. Medical oncology (Northwood, London, England) 14 37097499
2022 Role of osteopontin (OPN) in uterine spiral artery remodeling. Placenta 14 35780519
2022 Magnesium promotes osteogenesis via increasing OPN expression and activating CaM/CaMKIV/CREB1 pathway. Journal of biomedical materials research. Part B, Applied biomaterials 13 35106922
2020 The β-catenin/TCF-4 pathway regulates the expression of OPN in human osteoarthritic chondrocytes. Journal of orthopaedic surgery and research 13 32819387
2024 SPP1 expression indicates outcome of immunotherapy plus tyrosine kinase inhibition in advanced renal cell carcinoma. Human vaccines & immunotherapeutics 12 38738709
2023 Isoforskolin modulates AQP4-SPP1-PIK3C3 related pathway for chronic obstructive pulmonary disease via cAMP signaling. Chinese medicine 12 37817209
2021 Relationship between miRNA-433 and SPP1 in the presence of fracture and traumatic brain injury. Experimental and therapeutic medicine 12 34306197
2010 ATX-LPA axis induces expression of OPN in hepatic cancer cell SMMC7721. Anatomical record (Hoboken, N.J. : 2007) 12 21337710
2025 Macrophage-derived SPP1 exacerbate myocardial injury by interacting with fibroblasts in viral myocarditis. Biology direct 11 40087693
2024 Microglial- neuronal crosstalk in chronic viral infection through mTOR, SPP1/OPN and inflammasome pathway signaling. Frontiers in immunology 11 38646526
2020 Mechanistic Insight on the Interaction between OPN and Integrin ανβ3 in Osteoarthritis. BioMed research international 11 33134374
2019 Osteopontin Gene Polymorphism and Urinary OPN Excretion in Patients with Immunoglobulin A Nephropathy. Cells 11 31159229
2025 H4K12 Lactylation Activated-Spp1 in Reprogrammed Microglia Improves Functional Recovery After Spinal Cord Injury. CNS neuroscience & therapeutics 10 39939834
2025 Intercellular communication between FAP+ fibroblasts and SPP1+ macrophages in prostate cancer via multi-omics. Frontiers in immunology 10 40438108
2025 Multi-omics analyses reveal interactions between GREM1+ fibroblasts and SPP1+ macrophages in gastric cancer. NPJ precision oncology 10 40473882
2025 Macrophage-derived Spp1 promotes intramuscular fat in dystrophic muscle. JCI insight 10 40626359
2022 OPN N-glycosylation promoted bone destruction. Oral diseases 10 35451542
2022 Formation, structure and stability of high internal phase Pickering emulsions stabilized by BSPI-C3G covalent complexes. Food chemistry: X 10 36203951
2019 The non-synonymous mutation in bovine SPP1 gene influences carcass weight. Heliyon 10 31879711
2025 Semaglultide targets Spp1+ microglia/macrophage to attenuate neuroinflammation following perioperative stroke. Journal of neuroinflammation 9 40426210
2025 Identification of a stromal immunosuppressive barrier orchestrated by SPP1+/C1QC+ macrophages and CD8+ exhausted T cells driving gastric cancer immunotherapy resistance. Frontiers in immunology 9 40740771
2024 Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation. bioRxiv : the preprint server for biology 9 39149373
2024 Single-cell RNA sequencing reveals the CRTAC1+ population actively contributes to the pathogenesis of spinal ligament degeneration by SPP1+ macrophage. Aging cell 9 39158018
2020 Melatonin has a stimulatory effect on osteoblasts by upregulating col-i and opn expression/secretion. Acta odontologica latinoamericana : AOL 9 32920615
2025 Single cell analysis reveals that SPP1+ macrophages enhance tumor progression by triggering fibroblast extracellular vesicles. Translational oncology 8 40086324
2025 Single-cell transcriptomic analyses provide insights into SPP1+ TAM-mediated immune suppression and CD8+ T cell dysfunction in lung cancer. Cancer immunology, immunotherapy : CII 8 41021043
2025 SPP1high macrophage-induced T-cell stress promotes colon cancer liver metastasis through SPP1/CD44/PI3K/AKT signaling. Journal for immunotherapy of cancer 8 41120125
2025 TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages. Nature genetics 8 41203813
2024 SPP1 promotes tumor progression in esophageal carcinoma by activating focal adhesion pathway. Journal of gastrointestinal oncology 8 38989403
2024 The Role of Osteopontin (OPN) in Regulating Microglia Phagocytosis in Nervous System Diseases. Journal of integrative neuroscience 8 39344228
2024 Identification of SPP1 + macrophages as an immune suppressor in hepatocellular carcinoma using single-cell and bulk transcriptomics. Frontiers in immunology 8 39691723
2021 SPP1 and FN1 are significant gene biomarkers of tongue squamous cell carcinoma. Oncology letters 8 34457068
2025 Deciphering SPP1-related macrophage signaling in the pathogenesis of intervertebral disc degeneration. Cell biology and toxicology 7 39825191
2025 Human hypofunctional NCF1 variants promote pulmonary fibrosis in the bleomycin-induced mouse model and patients with systemic sclerosis via expansion of SPP1+ monocytes-derived macrophages. Annals of the rheumatic diseases 7 39919902
2025 Relationship between SPP1 (Osteopontin) and extracellular matrix dynamics: a comprehensive review. Frontiers in medicine 7 41293726
2024 Uncovering SPP1+ Macrophage, Neutrophils and Their Related Diagnostic Biomarkers in Intracranial Aneurysm and Subarachnoid Hemorrhage. Journal of inflammation research 7 39539729
2024 Glycosyltransferase B4GALNT1 promotes immunosuppression in hepatocellular carcinoma via the HES4-SPP1-TAM/Th2 axis. Molecular biomedicine 7 39616302
2023 Identification of LBH and SPP1 involved in hepatic stellate cell activation during liver fibrogenesis. Human cell 7 36917392
2023 Role of SPP1 in the diagnosis of gastrointestinal cancer. Oncology letters 7 37614657

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