Affinage

SPP1

Osteopontin · UniProt P10451

Round 2 corrected
Length
314 aa
Mass
35.4 kDa
Annotated
2026-04-28
130 papers in source corpus 48 papers cited in narrative 49 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SPP1 (osteopontin) is a secreted, intrinsically disordered phosphoglycoprotein that functions as a multivalent extracellular signaling molecule integrating cell adhesion, migration, immune regulation, and tissue remodeling by engaging αv-containing integrins (αvβ3, αvβ5, αvβ1) via its RGD motif and CD44 via a separate domain (PMID:7532190, PMID:8560266). Thrombin and MMP-3/MMP-7 cleavage generates fragments that expose a cryptic SVVYGLR motif binding α9β1 integrin, potentiating adhesion and migration (PMID:10593924, PMID:11375993); phosphorylation by the Golgi kinase FAM20C at S-x-E motifs governs receptor specificity, with the phosphorylated form stimulating macrophage IL-12 via integrins and the phosphorylation-independent form inhibiting IL-10 via CD44, thereby tuning type-1 immunity (PMID:10657301, PMID:22582013). SPP1 acts as a macrophage chemokine driving profibrotic SPP1⁺ macrophage differentiation via CXCL4, promotes cancer stemness and immune evasion through CD44- and integrin-dependent activation of PI3K/AKT, JAK2/STAT3, ERK, and NF-κB pathways, suppresses CD8⁺ T-cell activation as an immune checkpoint, and establishes an intercellular SPP1–CD61–GREM1–BMP regulatory loop that maintains mesenchymal cell fate in pancreatic cancer (PMID:36807143, PMID:30395540, PMID:30307407, PMID:40993391).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1990 High

    Cloning of human SPP1 cDNA and chromosomal mapping to 4q established the molecular identity of osteopontin, revealing splice variants and a conserved RGD cell-attachment motif that implied integrin-mediated adhesion.

    Evidence cDNA library screening, Northern blot, chromosomal mapping with human–rodent cell hybrids

    PMID:1974876

    Open questions at the time
    • No receptor binding demonstrated at this stage
    • Functional significance of splice variants unknown
  2. 1992 High

    Identification of uropontin as a direct calcium oxalate crystal growth inhibitor established a non-integrin biochemical function for SPP1 in kidney stone prevention.

    Evidence Immunoaffinity-purified uropontin in in vitro calcium oxalate crystal growth assay

    PMID:1729712

    Open questions at the time
    • In vivo relevance to nephrolithiasis not tested
    • Mechanism of crystal inhibition at atomic level unresolved
  3. 1995 High

    Demonstrating that OPN mediates adhesion through multiple αv integrins but directed migration specifically requires αvβ3 resolved which integrin heterodimer transduces the migratory signal.

    Evidence Boyden chamber migration assay with cells differing in αvβ3 expression and integrin-blocking antibodies

    PMID:7532190

    Open questions at the time
    • Downstream intracellular signaling from αvβ3 not characterized
    • In vivo migration role not established
  4. 1996 High

    Discovery that SPP1 is a protein ligand for CD44 that induces chemotaxis—but not homotypic aggregation—defined a second major receptor axis distinct from integrin engagement.

    Evidence Receptor-ligand binding assays and chemotaxis versus aggregation functional comparisons

    PMID:8560266

    Open questions at the time
    • CD44-binding domain not mapped
    • Relative contribution of CD44 vs integrin pathways in vivo unknown
  5. 1999 High

    Identification of the cryptic SVVYGLR motif exposed by thrombin cleavage as an α9β1-binding site explained how proteolytic processing generates new receptor specificities from a single SPP1 polypeptide.

    Evidence Site-directed mutagenesis of Tyr165, synthetic peptide blocking, adhesion assay with α9-transfected cells

    PMID:10593924

    Open questions at the time
    • In vivo relevance of thrombin-cleaved OPN fragments not established
    • Structural basis of α9β1 recognition unresolved
  6. 2000 High

    Knockout mouse studies revealed that SPP1 is a bifunctional immune regulator: phosphorylation-dependent integrin engagement stimulates IL-12, while phosphorylation-independent CD44 engagement suppresses IL-10, establishing SPP1 as a master switch for type-1 immunity.

    Evidence OPN-knockout mice challenged with viral and bacterial pathogens, cytokine measurement, receptor-pathway dissection

    PMID:10657301

    Open questions at the time
    • Identity of the kinase responsible for immunomodulatory phosphorylation not yet known (resolved in 2012)
    • Whether this dual-receptor mechanism operates in all tissue macrophages unclear
  7. 2001 High

    Parallel discoveries established SPP1 as an MMP substrate whose cleavage potentiates adhesion/migration, an intrinsically disordered protein enabling multivalent binding, and a critical regulator of TH1-mediated autoimmune demyelination.

    Evidence In vitro MMP-3/MMP-7 cleavage site mapping; NMR structural analysis confirming complete disorder; OPN-knockout EAE model with cytokine profiling

    PMID:11162539 PMID:11375993 PMID:11721059

    Open questions at the time
    • Relative contributions of individual MMP cleavage fragments in vivo not dissected
    • How disorder enables simultaneous multi-receptor engagement structurally undefined
  8. 2003 Medium

    Identification of SPP1 as the leading metastasis-associated gene in hepatocellular carcinoma, with anti-OPN antibody blocking invasion and pulmonary metastasis, established SPP1 as a pro-metastatic effector.

    Evidence cDNA microarray of HCC, antibody blockade in vitro invasion and nude mouse metastasis model

    PMID:12640447

    Open questions at the time
    • Receptor through which OPN drives HCC metastasis not identified
    • Antibody specificity concerns in single-study blockade
  9. 2012 High

    Discovery that FAM20C is the Golgi kinase phosphorylating SPP1 at S-x-E motifs resolved the long-standing question of which kinase controls SPP1's phosphorylation-dependent receptor specificity and immune functions.

    Evidence Biochemical kinase assay identifying FAM20C, genetic validation via Raine syndrome mutations

    PMID:22582013

    Open questions at the time
    • Whether all functionally relevant SPP1 phosphosites are FAM20C substrates unclear
    • Quantitative relationship between phosphorylation stoichiometry and integrin vs CD44 selectivity not defined
  10. 2014 High

    Demonstration that OPN in the perivascular niche activates CD44 signaling through γ-secretase-released CD44-ICD/CBP/p300/HIF-2α to promote glioma stem cell phenotypes revealed the intracellular signaling cascade downstream of SPP1–CD44.

    Evidence Cd44-knockout mouse glioma model, γ-secretase inhibition, CBP/p300 and HIF-2α functional assays

    PMID:24607407

    Open questions at the time
    • Whether this CD44-ICD cascade operates outside the glioma niche unknown
    • Direct SPP1 binding triggering γ-secretase cleavage not biochemically demonstrated
  11. 2017 High

    Mapping of SPP1 transcriptional regulation to GLI1 and OCT4 binding at the SPP1 locus, combined with CD44-binding-domain deletion rescue experiments, linked hedgehog/stemness pathways to SPP1 expression and confirmed CD44-binding is required for glioma sphere formation.

    Evidence ChIP assay for GLI1/OCT4, siRNA knockdown, rescue with WT vs CD44-binding-domain-deleted SPP1

    PMID:28030801

    Open questions at the time
    • Whether GLI1/OCT4 regulation is tissue-specific or general not tested
    • Structural basis of SPP1 CD44-binding domain not defined
  12. 2018 High

    Two concurrent studies established SPP1 as both a macrophage chemokine in glioblastoma (acting via αvβ5 to maintain M2 polarization) and an immune checkpoint suppressing CD8⁺ T-cell activation via CD44 (regulated by IRF8 at the Spp1 promoter), unifying SPP1's roles in tumor immune evasion.

    Evidence CRISPR/siRNA/shRNA knockdown, OPN-deficient mice, macrophage polarization assays; IRF8-knockout mice, ChIP for IRF8-Spp1 promoter, T-cell activation assays

    PMID:30307407 PMID:30395540

    Open questions at the time
    • Relative importance of integrin vs CD44 axis in immune suppression across tumor types not resolved
    • Whether IRF8-mediated Spp1 repression occurs in non-myeloid cells unknown
  13. 2020 Medium

    Multiple studies converged on SPP1 signaling through CD44 and integrins to activate PI3K/AKT, ERK, and Wnt/β-catenin pathways in diverse contexts including chondrocytes, endothelial progenitors, and gastric cancer, broadening the downstream effector landscape.

    Evidence Receptor-blocking antibodies, ERK/PI3K inhibitors, Wnt reporter assays, focal adhesion imaging across multiple cell types

    PMID:31990676 PMID:34367279 PMID:35005113 PMID:36034459

    Open questions at the time
    • Which downstream pathway is dominant in a given tissue context remains unclear
    • Direct biochemical link between SPP1-receptor binding and specific kinase activation not reconstituted
  14. 2022 Medium

    N-glycosylation at Asn79 was shown to be required for SPP1's osteoclast proliferative activity via NF-κB, while miR-433 was identified as a direct post-transcriptional regulator of SPP1 mRNA, expanding the known post-translational and post-transcriptional regulatory layers.

    Evidence N79Q site-directed mutagenesis with proliferation assay; dual luciferase reporter assay confirming miR-433 binding to SPP1 3′-UTR

    PMID:34306197 PMID:35451542

    Open questions at the time
    • Full glycosylation map and functional consequences of each site not established
    • In vivo relevance of miR-433 regulation of SPP1 not tested
  15. 2023 High

    CXCL4 was identified as the driver of profibrotic SPP1⁺ macrophage differentiation, with CXCL4-knockout abolishing this population and ameliorating fibrosis in heart and kidney injury, placing SPP1⁺ macrophages as a central cellular effector of organ fibrosis.

    Evidence Cxcl4-knockout mice in cardiac and renal injury models, single-nuclear RNA-seq, in vitro macrophage differentiation

    PMID:36807143

    Open questions at the time
    • Whether CXCL4 acts directly on macrophages or via intermediate cells not fully resolved
    • SPP1-independent functions of SPP1⁺ macrophages not dissected
  16. 2023 High

    Macrophage-derived SPP1 was shown to protect from NASH by inducing oncostatin-M and activating hepatocyte STAT3/ARG2 to enhance fatty acid oxidation, revealing a tissue-protective metabolic function distinct from SPP1's pro-fibrotic roles.

    Evidence Conditional Spp1 knockin and myeloid-specific knockout mice on high-fat diet, OSM/STAT3/ARG2 pathway dissection

    PMID:37028770

    Open questions at the time
    • Whether hepatoprotective vs profibrotic SPP1 functions are dose-dependent or context-specific not resolved
    • Receptor mediating SPP1-induced OSM production in macrophages not identified
  17. 2025 High

    Genetic epistasis in pancreatic cancer models revealed an intercellular SPP1–CD61–GREM1–BMP loop in which epithelial-derived SPP1 binds CD61 on mesenchymal cells to induce GREM1, which reciprocally sustains SPP1 expression and mesenchymal fate, with Spp1 inactivation abolishing metastasis.

    Evidence Spp1 and Grem1 single/double knockout PDAC mouse models, proteomic plasma analysis, heterozygosity rescue

    PMID:40993391

    Open questions at the time
    • Whether the SPP1-GREM1 loop operates in non-pancreatic cancers unknown
    • Direct structural basis of SPP1-CD61 binding not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of SPP1's multivalent receptor engagement as a disordered protein, how phosphorylation stoichiometry quantitatively tunes integrin vs CD44 selectivity in vivo, and what determines whether SPP1⁺ macrophages adopt profibrotic versus tissue-protective functions in different organs.
  • No high-resolution structure of SPP1 in complex with any receptor
  • Quantitative phosphorylation-receptor selectivity relationship undefined
  • Tissue-specific determinants of SPP1⁺ macrophage functional polarity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098631 cell adhesion mediator activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 5 GO:0031012 extracellular matrix 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 5 R-HSA-1643685 Disease 4 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1474244 Extracellular matrix organization 2 GO:0005794 Golgi apparatus 1
Partners
CD44FAM20CGREM1ITGA9ITGAVITGB1ITGB3ITGB5

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Osteopontin (SPP1/Eta-1) was identified as a direct protein ligand of CD44. This interaction induces cellular chemotaxis but not homotypic aggregation, distinguishing it from the CD44–hyaluronate interaction which promotes aggregation but not migration. Receptor-ligand binding assays, chemotaxis assays, homotypic aggregation assays Science High 8560266
1995 OPN mediates cell adhesion via multiple αv-containing integrins (αvβ3, αvβ5, αvβ1), but directed cell migration toward an OPN gradient specifically requires αvβ3. Cells lacking surface αvβ3 adhered to OPN at ~50% efficiency but could not migrate toward it. Boyden chamber migration assay, adhesion assay with cells differing in αvβ3 expression, integrin blocking antibodies The Journal of Clinical Investigation High 7532190
1999 Thrombin cleavage of OPN exposes a novel recognition sequence (SVVYGLR) in the N-terminal fragment that directly binds integrin α9β1, distinct from the RGD site. Site-directed mutagenesis of Tyr165 abolished α9β1-mediated adhesion. Site-directed mutagenesis, synthetic peptide blocking assays, cell adhesion assays with α9-transfected cells The Journal of Biological Chemistry High 10593924
2000 OPN/Eta-1 regulates macrophage IL-12 and IL-10 cytokine expression through two distinct receptor interactions: a phosphorylation-dependent interaction with integrin receptor stimulates IL-12 expression, while a phosphorylation-independent interaction with CD44 inhibits IL-10 expression. OPN-deficient mice show severely impaired type-1 immunity with diminished IL-12/IFN-γ and elevated IL-10. OPN-knockout mice (viral and bacterial infection models), cytokine measurement, phosphorylation-dependent vs. independent receptor interaction studies Science High 10657301
2001 OPN (osteopontin) is a novel substrate for MMP-3 (stromelysin-1) and MMP-7 (matrilysin). Three cleavage sites were identified for MMP-3 in human OPN (Gly166-Leu167, Ala201-Tyr202, Asp210-Leu211); MMP-7 cleaves at two of those sites. MMP cleavage of OPN potentiates its function as an adhesive and migratory stimulus through cell surface integrins. In vitro cleavage assay with purified MMPs, cleavage site mapping, cell adhesion and migration assays pre- and post-cleavage The Journal of Biological Chemistry High 11375993
2001 OPN regulates T helper cell-1 (TH1)-mediated demyelinating disease. OPN-deficient mice were resistant to progressive experimental autoimmune encephalomyelitis (EAE); myelin-reactive T cells in OPN−/− mice produced more IL-10 and less IFN-γ than in OPN+/+ mice. OPN-knockout mouse model of EAE, cytokine profiling of myelin-reactive T cells, microarray analysis of MS plaques Science High 11721059
2001 OPN and bone sialoprotein (BSP) are members of the SIBLING family on human chromosome 4, and both are completely unstructured in solution (flexible polypeptide backbones), enabling them to associate with multiple binding partners and bridge proteins into biologically active complexes, including bridging complement Factor H to integrins or CD44 to suppress the alternate complement pathway. 1D proton NMR, transverse relaxation time measurements, recombinant protein structural analysis Biochemical and Biophysical Research Communications High 11162539
2003 Osteopontin (SPP1) was identified as the lead metastasis-associated gene in HCC. An osteopontin-specific antibody effectively blocked HCC cell invasion in vitro and inhibited pulmonary metastasis of HCC cells in nude mice. cDNA microarray, antibody blockade of invasion in vitro, nude mouse pulmonary metastasis model Nature Medicine Medium 12640447
2012 OPN (osteopontin/SPP1) is phosphorylated within S-x-E motifs by FAM20C (Golgi casein kinase), a secreted atypical kinase that localizes to the Golgi and phosphorylates SIBLING family proteins including OPN. Mutations in FAM20C cause Raine syndrome. Kinase activity assay, identification of FAM20C as the responsible kinase, genetic linkage in Raine syndrome patients Science High 22582013
1992 Uropontin (OPN purified from urine) inhibits calcium oxalate crystal growth in vitro, demonstrating a direct functional role in regulating urinary stone formation as a crystal growth inhibitor. Monoclonal antibody immunoaffinity purification, in vitro calcium oxalate crystal growth assay Proceedings of the National Academy of Sciences High 1729712
1990 Human OPN/SPP1 cDNA was cloned; the gene is a single copy located on chromosome 4q near the centromere. Two mRNA variants were identified differing by a 14-amino-acid insertion at residue 58 (OPN1b vs OPN1a). The RGD cell attachment site is conserved between species. cDNA library screening, Northern blot, PCR amplification, chromosomal mapping with human-rodent cell hybrids, in situ hybridization Genomics High 1974876
2014 OPN in the glioma perivascular niche promotes cancer stem cell phenotypes and radiation resistance via CD44 signaling. The γ-secretase-regulated intracellular domain of CD44 mediates downstream effects via CBP/p300-dependent enhancement of HIF-2α activity. Cd44-deficient mice showed improved survival in a glioma model. Cd44-knockout mouse glioma model, survival analysis, γ-secretase inhibition, CBP/p300 functional assays, HIF-2α activity measurement Cell Stem Cell High 24607407
2018 OPN acts as an immune checkpoint to suppress CD8+ T cell activation. IRF8 represses OPN expression by binding the Spp1 promoter in myeloid cells; IRF8 deficiency elevates OPN, which signals through CD44 on T cells to suppress CTL activation and confer tumor immune tolerance. IRF8-knockout mice, chimeric bone marrow reconstitution, T cell-specific IRF8 deficiency, Spp1 promoter ChIP assay, T cell activation functional assays The Journal of Clinical Investigation High 30395540
2018 OPN is a potent chemokine for macrophages in glioblastoma, and integrin αvβ5 on glioblastoma-infiltrating macrophages is a major OPN receptor. OPN maintains M2 macrophage gene signature/phenotype. Both tumor-derived and host-derived OPN are required for glioma development. OPN blockade with 4-1BB-OPN bispecific aptamers extended median survival by 68% in mice. OPN siRNA/shRNA/CRISPR knockdown, OPN-deficient mice, macrophage migration assays, in vitro M2 polarization assays, therapeutic aptamer study The Journal of Clinical Investigation High 30307407
2021 OPN/SPP1 secreted by cancer-associated fibroblasts (CAFs) drives cancer stemness in pancreatic cancer through the SPP1–CD44 axis. SPP1 knockdown significantly reduced stemness characteristics. Overexpression of wild-type SPP1, but not an SPP1 lacking the CD44-binding domain, rescued sphere formation capacity, confirming CD44-binding is required. CAF conditioned media treatment, siRNA knockdown of SPP1, CD44-binding domain mutant rescue experiment, tumorsphere formation assay, 3D co-culture model Gastroenterology High 34418441
2016 AMPK activation promotes osteogenesis and inhibits adipogenesis through the AMPK-Gfi1-OPN (osteopontin) axis. AMPK activation downregulates the transcriptional repressor Gfi1 and causes it to dissociate from the OPN promoter, leading to OPN upregulation, which mediates the osteogenic and anti-adipogenic effects. AMPK overexpression via lentiviral vector, Gfi1 overexpression and dominant-negative constructs, ChIP-like promoter dissociation assay, ectopic bone formation model Cellular Signalling Medium 27283242
2017 SPP1 transcription in glioblastoma is driven by GLI1 binding to the SPP1 promoter and OCT4 binding to the first SPP1 intron. GLI1 knockdown reduced SPP1 mRNA and protein levels. SPP1-CD44 interaction is required for glioma sphere formation: SPP1 lacking the CD44-binding domain failed to rescue sphere formation in SPP1-depleted cells. ChIP assay (GLI1 and OCT4 binding to SPP1 locus), siRNA knockdown of SPP1/GLI1/CD44, rescue with wild-type vs CD44-binding-domain-deleted SPP1, sphere formation assays Oncotarget High 28030801
2017 SPP1 regulates nerve degeneration and regeneration after sciatic nerve injury through c-Fos, PKCα, and p-ERK/ERK pathways in Schwann cells. Spp1 silencing reduced Schwann cell proliferation and promoted migration, while Spp1 overexpression had opposite effects. siRNA knockdown and overexpression of Spp1 in Schwann cells, sciatic nerve injury model in rats, cytokine and pathway analysis (c-Fos, PKCα, ERK phosphorylation) BMC Neuroscience Medium 28270094
2018 SPP1 promotes ovarian cancer cell proliferation, migration, and invasion via the Integrin β1/FAK/AKT signaling pathway. Silencing SPP1 inhibited Integrin β1/FAK/p-AKT and suppressed tumor growth in vivo; ectopic SPP1 expression activated this pathway. siRNA knockdown and overexpression, Western blot for pathway components, Boyden chamber migration/invasion assays, nude mouse xenograft OncoTargets and Therapy Medium 29559792
2020 BRD4 (BET bromodomain protein) regulates SPP1 expression indirectly through NFKB2 (noncanonical NF-κB). BRD4 does not bind directly to the SPP1 promoter; instead, it regulates NFKB2, which then drives SPP1 transcription. BET inhibitors suppress melanoma progression via this noncanonical NF-κB/SPP1 pathway. ChIP assay (BRD4 binding to promoters), NFKB2 silencing, BET inhibitor treatment, SPP1 overexpression rescue experiment Theranostics Medium 33052224
2020 OPN inhibits autophagy in osteoarthritic chondrocytes through CD44 and αvβ3 integrin receptors via the ERK MAPK signaling pathway. Blocking CD44 or αvβ3 with antibodies prevented OPN-mediated suppression of LC3II and Beclin1. ERK inhibition abolished OPN's autophagy-suppressing activity. Recombinant OPN treatment, anti-CD44 and anti-αvβ3 blocking antibodies, ERK inhibitor, Western blot, mRFP-GFP-LC3 confocal imaging, transmission electron microscopy Frontiers in Endocrinology Medium 36034459
2020 OPN (osteopontin) activates PI3K signaling in osteoarthritic chondrocytes by binding to CD44 on the cell surface, causing downstream cascading effects that inhibit chondrocyte degeneration and reduce cartilage matrix loss. OPN binding was verified in vivo in mice. siOPN knockdown, rhOPN treatment, PI3K inhibitor (LS-C179404), in vivo mouse OA model Genes & Diseases Medium 35005113
2020 OPN binds αv integrin on endothelial progenitor cells (EPCs) to support adhesion and promote EPC incorporation into angiogenic vascular networks. siRNA knockdown of αv integrin reduced EPC binding to OPN and focal adhesion assembly. αv integrin was localized to focal adhesions at the basal surface of OPN-coated EPCs. siRNA knockdown of αv integrin, OPN-coated substrate adhesion assay, focal adhesion immunofluorescence microscopy, EPC incorporation into HUVEC networks Reproduction Medium 31990676
2022 EEF2K promotes melanoma progression by phosphorylating STAT3 at Tyr705, which binds to the SPP1 promoter and enhances SPP1 transcription. Re-expression of SPP1 partially reversed the inhibitory effect of EEF2K silencing, while SPP1 or STAT3 inhibition abolished EEF2K's tumorigenic effects. EEF2K silencing and overexpression, RNA-seq, ChIP assay (p-STAT3 binding to SPP1 promoter), SPP1 re-expression rescue Clinical and Translational Medicine Medium 35184394
2022 SPP1 promotes radiation resistance in esophageal carcinoma via the JAK2/STAT3 pathway. Radiation increases SPP1 expression, which in turn increases JAK2 and STAT3 phosphorylation. SPP1 knockdown combined with JAK2/STAT3 inhibition synergistically reduced tumor volume in vivo. SPP1 knockdown and overexpression, Western blot for JAK2/STAT3 phosphorylation, xenograft mouse model, pharmacological JAK2-STAT3 inhibition Cancer Medicine Medium 35593388
2022 miR-433 directly binds to the 3'-UTR of SPP1 mRNA to regulate SPP1 expression. Overexpression of miR-433 via agomiR-433 in osteoblast cells reduced SPP1 mRNA and protein levels. Dual luciferase reporter assay confirmed direct interaction between miR-433 and the SPP1 3'-UTR. Dual luciferase reporter assay, agomiR-433 transfection, RT-qPCR, Western blot Experimental and Therapeutic Medicine Medium 34306197
2022 OPN N-glycosylation at asparagine-79 promotes osteoclast proliferation and modulates osteoblast function through the NF-κB signaling pathway. Mutation of the N79 glycosylation site abolished OPN's ability to increase osteoblast proliferation. N-glycosylated OPN promotes nuclear translocation of NF-κB in both osteoclasts and osteoblasts. Site-directed mutagenesis (N79Q), CCK8 proliferation assay, Western blot for NF-κB signaling, mass spectrometry glycosylation site identification Oral Diseases Medium 35451542
2022 Macrophage-derived SPP1 promotes fibroblast conversion to an inflammatory phenotype with high Ccl2/Ccl7 expression in viral myocarditis, which increases monocyte chemotaxis to the heart. SPP1 inhibition reduced cardiac macrophage infiltration and improved cardiac function in CVB3-induced myocarditis mice. Single-cell RNA sequencing, indirect co-culture of macrophages with fibroblasts, SPP1 inhibition in vivo, CellPhoneDB ligand-receptor analysis Biology Direct Medium 40087693
2023 Macrophage-derived OPN (SPP1) protects from NASH by inducing oncostatin-M (OSM) production in macrophages; OSM activates STAT3 signaling in hepatocytes, which upregulates arginase-2 (ARG2), enhancing fatty acid oxidation to reduce steatosis. Conditional Spp1 knockin protected mice from NASH while Spp1 myeloid knockout worsened disease. Conditional Spp1 knockin and knockout mice (myeloid-specific), Western blot for OSM/STAT3/ARG2 pathway, fatty acid oxidation assays, high-fat diet NASH model Gastroenterology High 37028770
2023 SOCS3 in myeloid cells directly regulates SPP1 gene expression; SPP1 is a transcriptional target of STAT3. Loss of SOCS3 in myeloid cells leads to elevated STAT3 activity and increased SPP1 expression in microglia/macrophages, driving pathological retinal neovascularization. Pharmaceutical activation of SOCS3 or SPP1 blockade reduced pathological neovascularization. Myeloid-specific SOCS3 knockout mice, scRNA-seq, STAT3 transcriptional target validation, SPP1 neutralizing antibody in vivo Molecular Therapy Medium 38504518
2023 Microglia-derived SPP1 promotes retinal neovascularization by activating endothelial Akt/mTOR signaling via the Kit receptor. SPP1 expression in microglia is regulated by NF-κB and HIF-1α pathways. Spp1 neutralizing antibody attenuated pathological retinal neovascularization and improved visual function. OIR mouse model, scRNA-seq, conditioned medium from BV2 microglia, recombinant SPP1 treatment, SPP1 neutralizing antibody intravitreal injection, RNA-seq of bEnd.3 cells, Akt/mTOR phosphorylation assays Journal of Personalized Medicine Medium 36675807
2023 Vitamin C promotes neuroprotection of retinal ganglion cells by upregulating SPP1 in reactive astrocytes via the transcription factor E2F1. SPP1+ astrocytes in turn promote retinal ganglion cell survival in a mouse glaucoma model. Mouse glaucoma model, SPP1 expression analysis, E2F1 transcription factor identification, retinal ganglion cell survival assay Life Science Alliance Medium 37160307
2024 SPP1 secreted by hepatocellular carcinoma tumor cells interacts with the CD44 receptor on hepatic stellate cells (HSCs), activating the PI3K/AKT signaling pathway and promoting HSC differentiation into cancer-associated fibroblasts. CD44 receptor blockade abrogated this interaction; in vivo SPP1 silencing impaired HSC-to-CAF differentiation and reduced tumor volume and collagen deposition. Spatial transcriptomics, scRNA-seq, CD44 receptor blockade, in vivo SPP1 silencing, collagen deposition quantification Journal of Translational Medicine Medium 39267037
2025 SPP1 binds the CD61 (integrin β3/αvβ3 complex) receptor on mesenchymal PDAC cells to induce Bmp2 and Grem1 expression. GREM1 in turn inhibits BMP signaling, which is required for SPP1 expression in epithelial PDAC cells, forming an intercellular SPP1-GREM1 regulatory loop that maintains mesenchymal cell fate. Spp1 inactivation in mouse PDAC models delayed tumorigenesis and abolished metastasis. Spp1 knockout mouse PDAC models, proteomic plasma analysis, Grem1/Spp1 double knockout and heterozygous genetic epistasis experiments, receptor identification Nature High 40993391
2024 Histone H4 lysine 12 lactylation (H4K12la) promotes SPP1 transcription in reprogrammed microglia following spinal cord injury. DNA-pulldown experiments identified H4K12la as an upstream regulatory modification on Spp1. Recombinant SPP1 promoted neuronal maturation and enhanced mitochondrial function in axons, improving functional recovery after SCI. scRNA-seq, DNA-pulldown assay for H4K12la regulatory proteins, pseudotime analysis, recombinant SPP1 injection into injured spinal cord, functional recovery assessment CNS Neuroscience & Therapeutics Medium 39939834
2013 BAFF induces OPN (SPP1) expression specifically in splenic CD21−CD23+ B cells via an NF-κB-dependent signaling pathway. B cell-derived OPN then promotes anti-apoptotic Bcl2 expression in T cells, maintaining T cell survival in autoimmune EAE. TACI-IgG blockade of BAFF, NF-κB inhibition, OPN measurement in B cell subpopulations, T cell survival assays Molecular Immunology Medium 24084099
2022 SPP1 facilitates lung adenocarcinoma cell migration and invasion by upregulating COL11A1 expression. COL11A1 overexpression rescued the inhibitory effects of SPP1 knockdown on migration/invasion and reversed EMT marker changes, placing COL11A1 downstream of SPP1. siRNA knockdown of SPP1, COL11A1 overexpression rescue, wound healing and Matrigel invasion assays, Western blot for EMT markers, in vivo metastasis model Cancer Cell International Medium 36266702
2020 SPP1 regulates gastric adenocarcinoma radiosensitivity via Wnt/β-catenin signaling. SPP1 knockdown combined with irradiation increased DNA damage (H2AX phosphorylation), apoptosis, and G2/M phase arrest while reducing invasion. The Wnt/β-catenin inhibitor XAV939 enhanced these phenotypes, placing SPP1 upstream of Wnt/β-catenin in radioresistance. siSPP1 transfection, XAV939 Wnt inhibitor, TOP-flash reporter assay, flow cytometry cell cycle analysis, Western blot Journal of Oncology Medium 34367279
2023 Profibrotic SPP1+ macrophage differentiation is driven by CXCL4 (platelet factor 4). CXCL4 was identified as the top upregulated gene during Spp1 macrophage differentiation; Cxcl4 loss abrogated profibrotic Spp1 macrophage differentiation and ameliorated fibrosis after heart and kidney injury. Platelets (the main CXCL4 source in vivo) drive this differentiation. Spp1 macrophages orchestrate fibroblast activation via Spp1, Fn1, and Sema3 crosstalk. Cxcl4-knockout mice, organ injury models (heart and kidney), in vitro macrophage differentiation assays, single-nuclear RNA sequencing with ligand-receptor interaction analysis Cell Reports High 36807143
2024 Therapeutic silencing of Spp1 in atrial TREM2+ cardiac macrophages using an antibody-siRNA conjugate reduces atrial fibrosis and suppresses atrial fibrillation in mice. TREM2+ macrophages secrete OPN (encoded by Spp1), which drives fibrosis and AFib. Antibody-siRNA conjugate targeting TREM2+ macrophages, atrial fibrosis quantification, AFib induction in mouse model bioRxiv (PREPRINT)preprint Medium 39149373
1992 Clonal rat dental pulp cells (RDP4-1, RPC-C2A) synthesize and secrete osteopontin (SPP1/2ar) as a highly phosphorylated protein. OPN synthesis was markedly increased by TPA (phorbol ester), similar to osteoblastic cells, establishing OPN as a secreted phosphoprotein produced by dental pulp cells. Immunoprecipitation with anti-OPN antibody, thrombin susceptibility assay, metabolic labeling Biochemical and Biophysical Research Communications Medium 1472061
2013 Transgenic overexpression of OPN (Spp1) in mammary epithelium induces proliferation, exaggerated terminal end bud formation, increased lobulogenesis, and delayed gland involution. Ki-67 staining confirmed increased epithelial cell proliferation. OPN conveys a proliferative stimulus for mammary epithelial cells. MMTV-Opn transgenic mouse lines (3 founders), immunohistochemistry (Ki-67, OPN), ex vivo organoid lobulogenesis assay Genes & Cancer Medium 24069507
2017 A promoter polymorphism (rs28357094) in SPP1 modifies OPN expression in DMD myotubes, with the G allele associated with significantly higher OPN expression. Deflazacort treatment significantly increased OPN expression only in myotubes carrying the TG genotype, demonstrating that rs28357094 mediates differential glucocorticoid responsiveness of SPP1 transcription. Primary human DMD myoblasts/myotubes with defined rs28357094 genotypes, deflazacort treatment, immunoblot OPN quantification Human Molecular Genetics Medium 28595270
2010 The ATX-LPA axis upregulates OPN expression in hepatic cancer cells (SMMC7721) via PI3K/Akt signaling through LPA receptors. LPA receptor inhibitors and PI3K/Akt inhibitors reduced ATX-LPA-induced OPN upregulation, and OPN was required for ATX-LPA-induced cell migration. Western blot and RT-PCR for OPN expression, PI3K/Akt inhibitors, LPA receptor inhibitors, Transwell migration assay Anatomical Record Medium 21337710
2020 MR (mineralocorticoid receptor) acts as the upstream effector of OPN (SPP1) in hepatic stellate cells (LX-2), and OPN shares downstream HMGB1 with MR. The MR/OPN/HMGB1 axis drives NAFLD-associated liver fibrogenesis; MR antagonist eplerenone reduced this axis and fibrogenic markers. MR agonist/antagonist treatment of LX-2 cells, OPN siRNA knockdown, loss- and gain-of-function for MR and OPN, HMGB1 expression analysis Life Sciences Medium 33091447
2022 Macrophage Spp1 proliferation (SPP1hi macrophages) is markedly increased in IPF fibrotic lungs compared to normal lungs, and causal modelling supported a role for these SPP1hi macrophages in activating IPF myofibroblasts in fibrosis. Low-level local proliferation is present in normal lungs but is dramatically elevated in fibrotic lower lobes. Single-cell RNA sequencing of fresh lung explants (IPF vs. normal), co-localization analysis, causal modelling European Respiratory Journal Low 31221805
2022 Macrophage subpopulations marked by SPP1 expression communicate with fibroblasts via SPP1-CD44, SPP1-PTGER4, and SPP1-αvβ1 receptor pairs in colorectal cancer, mediating formation of an immune-excluded desmoplastic structure and limiting T cell infiltration. Single-cell RNA sequencing, spatial transcriptomics, immunofluorescent staining, ligand-receptor pair analysis across 14 independent CRC cohorts (2550 samples) Nature Communications Low 35365629
2025 H4K12 lactylation in reprogrammed microglia activates Spp1 transcription after spinal cord injury. Recombinant SPP1 promotes neuronal maturation and mitochondrial ATP production in axons via the SPP1 signaling pathway, improving functional recovery post-SCI. scRNA-seq, DNA-pulldown identifying H4K12la as regulatory mark on Spp1, recombinant SPP1 injection, functional behavioral recovery assay CNS Neuroscience & Therapeutics Medium 39939834
2024 SPP1+ macrophages in the SPP1-CD44 axis promote T-cell exhaustion in ovarian cancer. Blocking either SPP1 or CD44 reversed T-cell exhaustion, restored CD8+ T-cell functionality, and suppressed tumor growth in vivo. Molecular docking identified nilotinib as an SPP1 inhibitor that reduced PD-1 expression in macrophage-conditioned Jurkat cells. Functional T cell assays, SPP1/CD44 blocking, in vivo tumor suppression, molecular docking simulations, in vitro nilotinib treatment International Immunopharmacology Medium 40446696

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2000 Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science (New York, N.Y.) 936 10657301
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
1996 Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science (New York, N.Y.) 806 8560266
2001 The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science (New York, N.Y.) 737 11721059
2003 Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nature medicine 677 12640447
2022 Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer. Nature communications 675 35365629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
2019 Proliferating SPP1/MERTK-expressing macrophages in idiopathic pulmonary fibrosis. The European respiratory journal 609 31221805
2001 Flexible structures of SIBLING proteins, bone sialoprotein, and osteopontin. Biochemical and biophysical research communications 481 11162539
1995 The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of alpha v beta 3 in smooth muscle cell migration to osteopontin in vitro. The Journal of clinical investigation 473 7532190
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2023 CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers. Science (New York, N.Y.) 452 37535729
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2014 Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth. Cell stem cell 422 24607407
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2002 Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA 368 11926891
2012 Secreted kinase phosphorylates extracellular proteins that regulate biomineralization. Science (New York, N.Y.) 365 22582013
1992 Inhibition of calcium oxalate crystal growth in vitro by uropontin: another member of the aspartic acid-rich protein superfamily. Proceedings of the National Academy of Sciences of the United States of America 355 1729712
1990 cDNA cloning, mRNA distribution and heterogeneity, chromosomal location, and RFLP analysis of human osteopontin (OPN). Genomics 347 1974876
2015 Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1. PloS one 335 25658639
2001 Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin). The Journal of biological chemistry 334 11375993
2003 Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins. Connective tissue research 331 12952171
2018 Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. The Journal of clinical investigation 316 30307407
2004 The role of Osteopontin in tumor metastasis. The Journal of surgical research 302 15501463
2002 Real-time quantitative RT-PCR analysis of human bone marrow stromal cells during osteogenic differentiation in vitro. Journal of cellular biochemistry 292 11968014
2018 An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion. The Journal of clinical investigation 288 30395540
1999 The integrin alpha(9)beta(1) binds to a novel recognition sequence (SVVYGLR) in the thrombin-cleaved amino-terminal fragment of osteopontin. The Journal of biological chemistry 277 10593924
2023 Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner. Cell reports 218 36807143
2021 Pancreatic Tumor Microenvironment Factor Promotes Cancer Stemness via SPP1-CD44 Axis. Gastroenterology 201 34418441
2012 The COMPASS subunit Spp1 links histone methylation to initiation of meiotic recombination. Science (New York, N.Y.) 159 23160953
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 150 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
2021 Construction of TME and Identification of crosstalk between malignant cells and macrophages by SPP1 in hepatocellular carcinoma. Cancer immunology, immunotherapy : CII 112 34028567
2023 Macrophage-derived Osteopontin (SPP1) Protects From Nonalcoholic Steatohepatitis. Gastroenterology 110 37028770
2018 SPP1 promotes ovarian cancer progression via Integrin β1/FAK/AKT signaling pathway. OncoTargets and therapy 102 29559792
2020 BET inhibitor suppresses melanoma progression via the noncanonical NF-κB/SPP1 pathway. Theranostics 87 33052224
2002 An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus. Human mutation 77 11933203
2013 Headful DNA packaging: bacteriophage SPP1 as a model system. Virus research 72 23419885
2019 Direct electrical stimulation enhances osteogenesis by inducing Bmp2 and Spp1 expressions from macrophages and preosteoblasts. Biotechnology and bioengineering 69 31429922
2016 AMPK promotes osteogenesis and inhibits adipogenesis through AMPK-Gfi1-OPN axis. Cellular signalling 69 27283242
2023 Osteopontin (OPN)/SPP1: from its biochemistry to biological functions in the innate immune system and the central nervous system (CNS). International immunology 67 36525591
2015 OPN -Revisited. Journal of clinical and diagnostic research : JCDR 62 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 57 37706320
2003 Bacillus subtilis bacteriophage SPP1 DNA packaging motor requires terminase and portal proteins. The Journal of biological chemistry 57 12697751
2023 ANGPTL2+cancer-associated fibroblasts and SPP1+macrophages are metastasis accelerators of colorectal cancer. Frontiers in immunology 56 37691929
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) 47 39236316
2009 Regulation of H3K4 trimethylation via Cps40 (Spp1) of COMPASS is monoubiquitination independent: implication for a Phe/Tyr switch by the catalytic domain of Set1. Molecular and cellular biology 47 19398585
2022 SPP1 facilitates cell migration and invasion by targeting COL11A1 in lung adenocarcinoma. Cancer cell international 40 36266702
2017 The embryonic type of SPP1 transcriptional regulation is re-activated in glioblastoma. Oncotarget 40 28030801
2024 Spatial transcriptomics reveals tumor-derived SPP1 induces fibroblast chemotaxis and activation in the hepatocellular carcinoma microenvironment. Journal of translational medicine 39 39267037
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
2023 A comprehensive analysis of single-cell RNA transcriptome reveals unique SPP1+ chondrocytes in human osteoarthritis. Computers in biology and medicine 35 37141654
2022 EEF2K silencing inhibits tumour progression through repressing SPP1 and synergises with BET inhibitors in melanoma. Clinical and translational medicine 35 35184394
2002 Bacillus subtilis bacteriophage SPP1 hexameric DNA helicase, G40P, interacts with forked DNA. Nucleic acids research 35 12034814
1992 Clonal dental pulp cells (RDP4-1, RPC-C2A) synthesize and secrete osteopontin (SPP1, 2ar). Biochemical and biophysical research communications 34 1472061
2023 The critical role of osteopontin (OPN) in fibrotic diseases. Cytokine & growth factor reviews 32 37648616
2024 CTHRC1+ fibroblasts and SPP1+ macrophages synergistically contribute to pro-tumorigenic tumor microenvironment in pancreatic ductal adenocarcinoma. Scientific reports 31 39075108
2024 Identification of SPP1+ macrophages in promoting cancer stemness via vitronectin and CCL15 signals crosstalk in liver cancer. Cancer letters 29 39216547
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
2025 The Landscape of SPP1 + Macrophages Across Tissues and Diseases: A Comprehensive Review. Immunology 27 40395129
2024 Gpnmb and Spp1 mark a conserved macrophage injury response masking fibrosis-specific programming in the lung. JCI insight 27 39509324
2013 Spp1 at the crossroads of H3K4me3 regulation and meiotic recombination. Epigenetics 27 23511748
1982 SPP1-mediated plasmid transduction. Journal of virology 27 6292508
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 26 37727065
2012 Bacteriophage SPP1 DNA replication strategies promote viral and disable host replication in vitro. Nucleic acids research 26 23268446
2004 Osteopontin (Eta-1) is present in the rat basal ganglia. Brain research. Molecular brain research 25 15548430
2022 Macrophages Cytokine Spp1 Increases Growth of Prostate Intraepithelial Neoplasia to Promote Prostate Tumor Progression. International journal of molecular sciences 24 35457063
2013 Transgenic mammary epithelial osteopontin (spp1) expression induces proliferation and alveologenesis. Genes & cancer 24 24069507
2017 Effect of Spp1 on nerve degeneration and regeneration after rat sciatic nerve injury. BMC neuroscience 23 28270094
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 22 38504518
2022 Neuroinflammation-Related Proteins NOD2 and Spp1 Are Abnormally Upregulated in Amyotrophic Lateral Sclerosis. Neurology(R) neuroimmunology & neuroinflammation 22 36460480
2020 Integrins and OPN localize to adhesion complexes during placentation in sheep. Reproduction (Cambridge, England) 22 32668403
2024 Profibrotic Subsets of SPP1+ Macrophages and POSTN+ Fibroblasts Contribute to Fibrotic Scarring in Acne Keloidalis. The Journal of investigative dermatology 21 38218364
2021 SPP1 expression in the mouse uterus and placenta: implications for implantation†. Biology of reproduction 21 34165144
2018 Deletion of OPN in BSP knockout mice does not correct bone hypomineralization but results in high bone turnover. Bone 21 30529011
2022 SPP1 promotes radiation resistance through JAK2/STAT3 pathway in esophageal carcinoma. Cancer medicine 20 35593388
2015 Osteopontin (OPN) isoforms, diabetes, obesity, and cancer; what is one got to do with the other? A new role for OPN. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 20 25583441
2013 OPN gene polymorphisms influence the risk of knee OA and OPN levels in synovial fluid in a Chinese population. Arthritis research & therapy 20 23289928
2020 Significance of MR/OPN/HMGB1 axis in NAFLD-associated hepatic fibrogenesis. Life sciences 19 33091447
2025 SPP1 macrophages across diseases: A call for reclassification? FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 40047497
2016 Curcumin Veto the Effects of Osteopontin (OPN) Specific Inhibitor on Leukemic Stem Cell Colony Forming Potential via Promotion of OPN Overexpression. International journal of hematology-oncology and stem cell research 18 27489587
2013 BAFF maintains T-cell survival by inducing OPN expression in B cells. Molecular immunology 17 24084099
2025 Targeting SPP1+ macrophages via the SPP1-CD44 axis reveals a key mechanism of immune suppression and tumor progression in ovarian cancer. International immunopharmacology 16 40446696
2024 Targeted SPP1 Inhibition of Tumor-Associated Myeloid Cells Effectively Decreases Tumor Sizes. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 16 39639496
2024 SPP1 macrophages in colorectal cancer: Markers of malignancy and promising therapeutic targets. Genes & diseases 16 40092488
2023 SPP1/osteopontin: a driver of fibrosis and inflammation in degenerative ascending aortic aneurysm? Journal of molecular medicine (Berlin, Germany) 16 37698712
2003 Eta-1/osteopontin genetic polymorphism and primary biliary cirrhosis. Hepatology research : the official journal of the Japan Society of Hepatology 16 12809934
1972 Transcription after bacteriophage SPP1 infection in Bacillus subtilis. Journal of virology 16 4627475
2023 Microglia-Derived Spp1 Promotes Pathological Retinal Neovascularization via Activating Endothelial Kit/Akt/mTOR Signaling. Journal of personalized medicine 15 36675807
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
2020 OPN binds alpha V integrin to promote endothelial progenitor cell incorporation into vasculature. Reproduction (Cambridge, England) 15 31990676
2018 The Revisited Genome of Bacillus subtilis Bacteriophage SPP1. Viruses 15 30544981
2025 Single-cell multi-omics analysis identifies SPP1+ macrophages as key drivers of ferroptosis-mediated fibrosis in ligamentum flavum hypertrophy. Biomarker research 14 40001138
2025 SPP1 is required for maintaining mesenchymal cell fate in pancreatic cancer. Nature 14 40993391
2022 OPN inhibits autophagy through CD44, integrin and the MAPK pathway in osteoarthritic chondrocytes. Frontiers in endocrinology 14 36034459
2019 Comparison of the Opn-CreER and Ck19-CreER Drivers in Bile Ducts of Normal and Injured Mouse Livers. Cells 14 31027317
1978 Studies on transduction process by SPP1 phage. The Journal of general virology 14 106091
2023 Important oncogenic and immunogenic roles of SPP1 and CSF1 in hepatocellular carcinoma. Medical oncology (Northwood, London, England) 13 37097499
2003 Expression of osteopontin (OPN) mRNA in bovine ovarian follicles and corpora lutea. Reproduction in domestic animals = Zuchthygiene 13 12753549
2022 Role of osteopontin (OPN) in uterine spiral artery remodeling. Placenta 12 35780519
2021 SPP1 Regulates Radiotherapy Sensitivity of Gastric Adenocarcinoma via the Wnt/Beta-Catenin Pathway. Journal of oncology 12 34367279
2020 The β-catenin/TCF-4 pathway regulates the expression of OPN in human osteoarthritic chondrocytes. Journal of orthopaedic surgery and research 12 32819387
2017 Structural studies with BnSP-7 reveal an atypical oligomeric conformation compared to phospholipases A2-like toxins. Biochimie 12 28751219
2010 ATX-LPA axis induces expression of OPN in hepatic cancer cell SMMC7721. Anatomical record (Hoboken, N.J. : 2007) 12 21337710
1984 Homology between phages SPP1, 41c, 22a, rho 15 and SF6 of Bacillus subtilis. The Journal of general virology 12 6094718
2023 Vitamin C protects retinal ganglion cells via SPP1 in glaucoma and after optic nerve damage. Life science alliance 11 37160307
2023 Isoforskolin modulates AQP4-SPP1-PIK3C3 related pathway for chronic obstructive pulmonary disease via cAMP signaling. Chinese medicine 11 37817209
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
2016 Association between OPN genetic variations and nephrolithiasis risk. Biomedical reports 11 27602211
2025 Decoding SPP1 regulation: Genetic and nongenetic insights into its role in disease progression. Molecules and cells 10 40210132
2019 The non-synonymous mutation in bovine SPP1 gene influences carcass weight. Heliyon 10 31879711
2025 H4K12 Lactylation Activated-Spp1 in Reprogrammed Microglia Improves Functional Recovery After Spinal Cord Injury. CNS neuroscience & therapeutics 9 39939834
2025 Macrophage-derived SPP1 exacerbate myocardial injury by interacting with fibroblasts in viral myocarditis. Biology direct 9 40087693
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
2023 Entrectinib a Plausible Inhibitor for Osteopontin (SPP1) in Cervical Cancer-Integrated Bioinformatic Approach. Applied biochemistry and biotechnology 9 37086377
2022 OPN N-glycosylation promoted bone destruction. Oral diseases 9 35451542
2022 Formation, structure and stability of high internal phase Pickering emulsions stabilized by BSPI-C3G covalent complexes. Food chemistry: X 9 36203951
2021 Relationship between miRNA-433 and SPP1 in the presence of fracture and traumatic brain injury. Experimental and therapeutic medicine 9 34306197
2020 Melatonin has a stimulatory effect on osteoblasts by upregulating col-i and opn expression/secretion. Acta odontologica latinoamericana : AOL 9 32920615
2024 Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation. bioRxiv : the preprint server for biology 8 39149373