Affinage

NELL1

Protein kinase C-binding protein NELL1 · UniProt Q92832

Length
810 aa
Mass
89.6 kDa
Annotated
2026-04-29
100 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NELL1 is a secreted homotrimeric glycoprotein that functions as a lineage-restricted osteoinductive factor, coupling skeletal cell differentiation with extracellular matrix organization and mineralization. Transcriptionally, NELL1 is a direct target of Runx2 via OSE2 promoter elements and is repressed by Osterix through Sp1 sites; NELL1 in turn signals through integrin α3β1/β1 receptors to activate ERK1/2 and JNK MAPK cascades, phosphorylate Runx2, and engage Wnt/β-catenin signaling, thereby promoting osteoblast differentiation while suppressing adipogenesis and osteoclastogenesis (PMID:17042739, PMID:21931789, PMID:18082140, PMID:22728432, PMID:26082355). Conditional loss of Nell-1 in neural crest cells causes craniofacial bone defects with diminished Wnt/β-catenin activity, while chondrocyte-specific deletion impairs endochondral ossification through reduced Ihh-PTHrP signaling, and haploinsufficiency produces age-related osteoporosis (PMID:31582804, PMID:30352124, PMID:26082355). In osteosarcoma, NELL1 remodels the extracellular matrisome via FAK signaling to promote tumor invasion and metastasis (PMID:35700263).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Establishing that NELL1 is a secreted homotrimeric glycoprotein with heparin-binding activity resolved its basic biochemical identity and demonstrated it could act extracellularly.

    Evidence COS-7 cell expression, gel filtration, heparin-affinity chromatography

    PMID:10548494

    Open questions at the time
    • Physiological binding partners unknown
    • Receptor not identified
    • In vivo function not determined
  2. 1999 Medium

    Discovery of NELL1 upregulation at prematurely fusing cranial sutures linked this secreted protein to intramembranous bone formation and craniosynostosis for the first time.

    Evidence Differential cDNA cloning and in situ hybridization/immunohistochemistry on human craniosynostosis specimens

    PMID:9893069

    Open questions at the time
    • Correlative expression data without causality
    • No loss-of-function evidence
  3. 2002 High

    Gain- and loss-of-function experiments established NELL1 as a direct regulator of osteoblast differentiation: overexpression caused craniosynostosis-like calvarial phenotypes in transgenic mice, while knockdown blocked osteoblast maturation.

    Evidence Transgenic mouse generation, adenoviral overexpression, and siRNA knockdown in calvarial osteoblast cultures

    PMID:12235118

    Open questions at the time
    • Signaling mechanism unknown
    • Receptor not identified
    • Effect outside calvaria not tested
  4. 2006 High

    An ENU-induced null mutation confirmed NELL1 is essential for both cranial and axial skeletal development, with loss reducing extracellular matrix genes critical for chondrogenesis and osteogenesis.

    Evidence ENU mutagenesis (Cys502Ter), positional cloning, transcriptomic profiling of mutant vs. wild-type mice

    PMID:16537572

    Open questions at the time
    • Cell-type-specific requirements not dissected
    • Downstream signaling not yet defined
  5. 2007 High

    Identification of Runx2 as a direct transcriptional activator of NELL1 via OSE2 elements placed NELL1 within the core osteogenic transcription factor hierarchy.

    Evidence Promoter-luciferase reporters, EMSA/supershift, ChIP, site-directed mutagenesis, rescue in Runx2-null calvarial cells

    PMID:17042739

    Open questions at the time
    • Whether other transcription factors modulate NELL1 expression not yet known
    • Osterix regulation not yet tested
  6. 2007 High

    NELL1 was shown to activate ERK1/2 and JNK MAPK pathways and phosphorylate Runx2 in osteoblasts, establishing its intracellular signaling cascade and distinguishing it from BMP-Smad signaling.

    Evidence Western blot for MAPK and Runx2 phosphorylation, Smad reporter assays, recombinant NELL1 treatment of osteoblastic cells

    PMID:17352654 PMID:18082140

    Open questions at the time
    • Upstream receptor mediating MAPK activation unknown
    • Kinase(s) directly phosphorylating Runx2 not identified
  7. 2011 High

    Genetic epistasis between Nell-1 and Runx2 in vivo — Nell-1 overexpression partially rescued Runx2 haploinsufficiency — confirmed that NELL1-mediated MAPK/Runx2 phosphorylation constitutes a functional feedforward loop in osteogenesis.

    Evidence Cross-breeding Nell-1 overexpression × Runx2+/- mice, calvarial phenotype rescue, siRNA and ENU-null cell signaling

    PMID:20939017

    Open questions at the time
    • Exact stoichiometry and kinetics of the Runx2-NELL1 feedforward loop not defined
  8. 2011 High

    Identification of integrin β1 as a cell-surface receptor for NELL1 and of Osterix as a transcriptional repressor via Sp1 sites defined both upstream regulation and receptor-level signal initiation.

    Evidence Co-IP/binding assays, integrin β1 siRNA abolishing cell adhesion; EMSA, ChIP, Sp1 mutagenesis, Osterix overexpression/knockdown

    PMID:21931789 PMID:22807400

    Open questions at the time
    • Specific integrin heterodimer not yet fully defined
    • Competition between Runx2 and Osterix at native chromatin not resolved
  9. 2011 High

    In chondrocytes, NELL1 was found to induce Nfatc2 as a primary response gene through Runx2, linking NELL1 to cartilage differentiation control beyond osteoblasts.

    Evidence Microarray in ATDC5 chondrocytes, dominant-negative Runx2, Nfatc2 siRNA, immunohistochemistry in Nell1-deficient mouse femurs

    PMID:21611965

    Open questions at the time
    • Whether Nfatc2 mediates all chondrocyte effects of NELL1 not tested
    • Role of Ihh signaling downstream not yet addressed
  10. 2012 High

    Integrin α3β1 was identified as the specific osteoblast receptor for NELL1, with C-terminal cysteine-rich domains mediating binding and FAK activation transducing the signal intracellularly.

    Evidence Recombinant deletion/cysteine-mutant NELL1 proteins, integrin α3 and β1 function-blocking antibodies, FAK phosphorylation assays

    PMID:22728432

    Open questions at the time
    • Whether additional co-receptors contribute not excluded
    • Crystal structure of NELL1–integrin complex lacking
  11. 2014 High

    Demonstrating that oligomerization is required for full cell-adhesion activity (monomeric mutant is impaired) established that the homotrimeric quaternary structure is functionally essential, not just structural.

    Evidence Coiled-coil cysteine-to-serine mutagenesis, cell adhesion assays comparing monomer vs. oligomer

    PMID:24563467

    Open questions at the time
    • Precise oligomeric stoichiometry at the receptor not defined
    • How oligomerization exposes integrin-binding epitopes not structurally resolved
  12. 2015 High

    NELL1 was shown to activate Wnt/β-catenin signaling via integrin β1, simultaneously promoting osteoblast differentiation and inhibiting osteoclast-mediated resorption; haploinsufficient mice developed age-related osteoporosis, establishing NELL1 as a dual-action skeletal maintenance factor.

    Evidence Integrin β1 binding assays, Wnt pathway analysis, Nell-1+/- mouse aging phenotype, gonadectomy model, systemic NELL-1 delivery, sheep spinal fusion

    PMID:26082355

    Open questions at the time
    • Whether NELL1 directly activates Wnt ligand/receptor or acts at the intracellular level not distinguished
    • Osteoclast cell-autonomous vs. paracrine mechanisms unclear
  13. 2015 High

    Mapping the heparin-binding site to the N-terminal TSPN domain via site-directed mutagenesis defined how NELL1 engages cell-surface proteoglycans, potentially concentrating it at the pericellular matrix.

    Evidence TSPN domain basic residue mutagenesis, heparin-binding and cell-surface proteoglycan interaction assays

    PMID:26627376

    Open questions at the time
    • Specific proteoglycan partners not identified
    • Functional consequence of proteoglycan binding on integrin signaling not tested
  14. 2018 High

    Conditional deletion of Nell-1 in chondrocytes caused dwarfism and premature osteoporosis via impaired Ihh-PTHrP signaling, establishing a cell-autonomous role in endochondral ossification separable from intramembranous bone effects.

    Evidence Nell-1flox/flox; Col2α1-Cre conditional KO, micro-CT, histomorphometry, Ihh rescue blocked by cyclopamine/GANT61

    PMID:30352124

    Open questions at the time
    • Direct biochemical link between NELL1 and Ihh pathway components not identified
    • Whether integrin signaling mediates Ihh activation not tested
  15. 2019 High

    Neural-crest-specific Nell-1 deletion caused frontonasal and mandibular defects with reduced Wnt/β-catenin activity, demonstrating that NELL1 is required cell-autonomously for craniofacial morphogenesis in neural-crest-derived skeletal progenitors.

    Evidence Nell-1flox/flox; Wnt1-Cre conditional KO, CNCC lineage tracing, active-β-catenin immunostaining, recombinant NELL1 rescue

    PMID:31582804

    Open questions at the time
    • Whether NELL1 acts through integrin–Wnt crosstalk in CNCCs specifically not tested
    • Downstream Wnt target genes mediating rescue not defined
  16. 2022 High

    In osteosarcoma, NELL1 was repurposed as a prometastatic factor that remodels the extracellular matrisome via FAK signaling, revealing a pathological context where NELL1's normal matrix-organizing function promotes tumor invasion.

    Evidence CRISPR-Cas9 NELL1 KO in OS cell lines, xenograft and conditional KO sarcoma mouse models, transcriptomics, phosphoproteomics, matricellular protein rescue

    PMID:35700263

    Open questions at the time
    • Whether NELL1 acts through integrin α3β1-FAK axis in sarcoma specifically not confirmed
    • Therapeutic targetability not assessed
  17. 2024 Medium

    NELL1 was found to modulate macrophage polarization toward M2 via JNK/MAPK signaling, extending its immunomodulatory functions beyond skeletal lineages.

    Evidence Rat periodontitis model with local NELL1 injection, LPS-stimulated RAW264.7 macrophages with JNK inhibitor SP600125

    PMID:38908089

    Open questions at the time
    • Whether NELL1 acts directly on macrophages via integrin receptors not tested
    • Relevance to systemic immune regulation unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the NELL1–integrin α3β1 interaction, the mechanism by which NELL1 activates Wnt/β-catenin signaling (direct vs. indirect), and the identity of the kinase(s) that phosphorylate Runx2 downstream of NELL1-MAPK activation.
  • No crystal or cryo-EM structure of NELL1 or NELL1–receptor complex
  • Wnt pathway activation mechanism (ligand-dependent vs. independent) unresolved
  • Direct Runx2 kinase downstream of NELL1 not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 2
Localization
GO:0005576 extracellular region 4 GO:0031012 extracellular matrix 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1474244 Extracellular matrix organization 2
Partners
ENO1ITGA3ITGB1RUNX2SP7

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 NELL1 and NELL2 proteins expressed in COS-7 cells are homotrimeric glycoproteins with heparin-binding activity; both are partially secreted into culture medium. They were originally cloned by yeast two-hybrid screening using the regulatory domain of PKCβI as bait, identifying them as PKCβI-binding proteins. Yeast two-hybrid screening, COS-7 cell expression, biochemical characterization (gel filtration, heparin-affinity chromatography) Biochemical and biophysical research communications High 10548494
1999 NELL-1 mRNA is up-regulated in premature fusing and fused coronal sutures in craniosynostosis patients, localized primarily in mesenchymal cells and osteoblasts at the osteogenic front, suggesting a role in cranial intramembranous bone formation. Differential cDNA cloning, in situ hybridization/immunohistochemistry, Northern blot of multiorgan tissues Journal of bone and mineral research Medium 9893069
2002 Overexpression of Nell-1 in transgenic mice induces craniosynostosis-like phenotypes restricted to calvarial bone, with increased osteoblast differentiation and reduced cell proliferation. In vitro, Nell-1 overexpression accelerates calvarial osteoblast differentiation and mineralization, and downregulation of Nell-1 inhibits osteoblast differentiation. Transgenic mouse generation, histology, in vitro calvarial osteoblast culture with adenoviral overexpression and siRNA knockdown The Journal of clinical investigation High 12235118
2003 Nell-1 overexpression induces apoptosis specifically in osteoblastic cells (not fibroblasts), associated with upregulation of Fas and Fas-L, and this apoptosis is observed in calvaria of Nell-1 transgenic mice. Adenoviral overexpression in osteoblasts and fibroblasts, apoptosis assays (TUNEL, flow cytometry), immunohistochemistry for Fas/Fas-L in transgenic mice Journal of bone and mineral research Medium 14672347
2006 Nell-1 deficiency (ENU-induced Cys502Ter truncation mutation) in mice causes skeletal defects in the cranium and vertebral column/ribcage, and is associated with reduced expression of extracellular matrix genes critical for chondrogenesis and osteogenesis (including genes associated with Ehlers-Danlos Syndrome). ENU mutagenesis, positional cloning, real-time quantitative RT-PCR of 219 genes in mutant vs. wild-type mice Human molecular genetics High 16537572
2006 Nell-1 overexpression during embryonic development induces acrania via massive apoptosis in calvarial osteoblasts and neural cells, associated with increased Fas and Fas-L production; chondrocyte overexpression leads to premature hypertrophy and increased apoptosis. Nell-1 transgenic mouse embryo analysis, immunohistochemistry for Fas/Fas-L, primary chondrocyte transduction with AdNell-1 Laboratory investigation Medium 16652108
2007 Runx2 directly binds to three OSE2 elements in the NELL-1 promoter and transactivates NELL-1 gene expression; forced Runx2 expression in rat osteoblasts upregulates Nell-1, and both Nell-1 and osteocalcin expression are rescued in Runx2-null calvarial cells by Runx2 transfection. Promoter-luciferase reporter assays, EMSA/supershift with Runx2 antibody, ChIP assay, site-directed mutagenesis of OSE2 sites, RT-PCR in Runx2-null cells Journal of bone and mineral research High 17042739
2007 NELL1 protein activates the MAPK signaling cascade (ERK, JNK), induces phosphorylation of Runx2, and promotes rapid intracellular accumulation of Tyr-phosphorylated proteins in osteoblastic cells, but does not activate the Smad signaling cascade (unlike BMP2). Western blot for MAPK phosphorylation, Runx2 phosphorylation assays, Smad reporter assays in osteoblastic cells treated with recombinant NELL1 FEBS letters High 18082140
2007 Nell-1 and BMP-2 synergistically enhance osteogenic differentiation of C2C12 myoblasts; Nell-1 stimulation on BMP-2-preconditioned myoblasts activates JNK MAPK but not p38 or ERK1/2. Nell-1 alone cannot induce osteogenic differentiation or ectopic bone formation in muscle, confirming osteochondral lineage specificity. Adenoviral overexpression in C2C12 myoblasts, alkaline phosphatase assay, osteopontin ELISA, MAPK western blot, nude mouse intramuscular injection model Journal of bone and mineral research High 17352654
2011 Nell-1 signaling activates ERK1/2 and JNK1 MAPK pathways in calvarial cells and enhances Runx2 phosphorylation and activity. Nell-1 is a critical downstream functional mediator of Runx2: Runx2-regulated Nell-1 promotes osteoblastic differentiation, and cross-mating Nell-1 overexpression mice with Runx2+/- mice partially rescues the cleidocranial dysplasia-like calvarial phenotype. Western blot for MAPK phosphorylation, genetic epistasis cross-breeding experiment, Nell-1 siRNA in calvarial cells, ENU-induced Nell-1-/- cells, Runx2 promoter-luciferase assays, in vitro mineralization in explants Journal of bone and mineral research High 20939017
2011 Nell-1 induces expression of Nfatc2 as a primary response gene (identified by microarray) in chondrocytes; this induction requires Runx2, and Nfatc2 induction mediates Nell-1's inhibitory effects on chondrocyte differentiation markers and cartilage nodule formation. Microarray screen, real-time PCR validation, dominant-negative Runx2 adenoviral transduction, siRNA knockdown of Nfatc2 in ATDC5 cells, immunohistochemistry in Nell1-deficient mouse femurs Journal of bone and mineral research High 21611965
2011 NELL-1 binds to extracellular Integrin β1, induces focal adhesion, and promotes cell adhesion; siRNA knockdown of Integrin β1 abolishes NELL-1-dependent cell attachment. Pre-coating with NELL-1 increases cell attachment and osteogenic differentiation on culture dishes and PLGA scaffolds. Cell adhesion assays, siRNA knockdown of Integrin β1, co-immunoprecipitation/binding assay, PLGA scaffold coating experiments Journal of cellular biochemistry High 22807400
2011 NELL-1 binds to APR3 (apoptosis related protein 3, a membrane proliferation suppressor) on the nuclear envelope of human osteoblasts; co-expression of NELL-1 and APR3 inhibits osteoblast proliferation via Cyclin D1 downregulation and enhances osteocalcin, BSP expression, and mineralization. Biopanning for NELL-1 binding proteins, co-localization by immunofluorescence, co-transfection, RNAi knockdown of APR3, western blot FEBS letters Medium 21723284
2011 Nell-1 inhibits adipogenic differentiation of 3T3-L1 preadipocytes and human adipose-derived stromal cells, and this anti-adipogenic effect is associated with upregulation of Hedgehog signaling markers (Ihh, Gli1, Ptc1). Oil red O staining, adipogenic gene expression (RT-PCR), adenoviral and recombinant protein delivery, Hedgehog pathway marker qPCR Biochemical and biophysical research communications Medium 21723263
2011 NELL-1 is a direct transcriptional target of Osterix, which represses NELL-1 expression by binding to Sp1 sites (-71 to -142 bp) in the NELL-1 promoter; Osterix competes with RNA Pol II binding but not with Runx2 at OSE2 sites. Osterix knockdown increases NELL-1 transcription and osteoblastic differentiation. Promoter-luciferase reporter assays, EMSA, ChIP assay (RNA Pol II and Osterix), site-directed mutagenesis of Sp1 sites, Osterix overexpression/siRNA knockdown in multiple cell lines and primary human osteoblasts PloS one High 21931789
2012 NELL1 promotes osteoblastic cell adhesion through at least three cell-binding domains in the C-terminal region; adhesion is strongly inhibited by function-blocking antibodies against integrin α3 and β1 subunits, identifying integrin α3β1 as an osteoblast receptor for NELL1. Focal adhesion kinase (FAK) activation is involved in NELL1 signaling. Recombinant deletion/cysteine-mutant NELL1 proteins, cell adhesion assays, integrin function-blocking antibodies, FAK phosphorylation western blot FEBS letters High 22728432
2012 NELL-1 increases pre-osteoblast matrix mineralization and inorganic phosphate (Pi) influx by activating both Pit-1 and Pit-2 sodium-dependent phosphate transporters (predominantly Pit-2), distinct from BMP-2 which activates only Pit-1. Neutralizing antibodies against Pit-1 and Pit-2 completely abrogate NELL-1-induced Pi influx. Malachite green Pi staining, Pit-1/Pit-2 expression (western blot, RT-PCR), forced upregulation of Pit-1/Pit-2, neutralizing antibody blockade in MC3T3-E1 pre-osteoblasts Biochemical and biophysical research communications Medium 22580275
2013 NELL-1 suppresses BMP2-induced inflammation by reducing NF-κB transcriptional activity and generation of reactive oxygen species (ROS) in vitro, and fully reverses BMP2-induced systemic (serum TNFα, IL-6) and local inflammation in a rat femoral bone onlay model. Rat femoral onlay model, histology/histomorphometry, real-time PCR, ELISA for TNFα/IL-6, NF-κB reporter assays, ROS measurement in NIH3T3 fibroblasts Tissue engineering. Part A Medium 23758588
2014 NELL1-mediated cell adhesion and spreading requires an oligomerization-induced conformational change in the C-terminal cysteine-rich region; a monomeric NELL1 mutant (cysteine-to-serine substitution in the coiled-coil domain) shows substantially reduced cell adhesion activity compared to wild-type oligomeric NELL1. Recombinant NELL1 deletion/cysteine mutant protein production, cell adhesion assays, reducing agent treatment experiments The Journal of biological chemistry High 24563467
2015 Recombinant NELL-1 binds to integrin β1 and induces Wnt/β-catenin signaling, resulting in increased osteoblast differentiation and inhibition of osteoclast-directed bone resorption. Nell-1-haploinsufficient mice undergo age-related osteoporosis with reduced OB:OC ratio. Integrin β1 binding assay, Wnt/β-catenin pathway analysis, haploinsufficient mouse model, gonadectomy-induced osteoporosis mouse model, systemic NELL-1 delivery, large animal (sheep) spinal model Nature communications High 26082355
2015 NELL1's N-terminal thrombospondin-1-like (TSPN) domain mediates binding to cell surface proteoglycans/heparin; site-directed mutagenesis of basic residues in the TSPN domain identified the major heparin-binding sites and confirmed their role in cell surface proteoglycan interaction. Site-directed mutagenesis, heparin-binding assays, structural modeling of TSPN domain, cell surface proteoglycan interaction assays FEBS letters High 26627376
2015 A short N-terminal truncated isoform of NELL-1 (NELL-1570, lacking the N-terminal 240 aa) is expressed postnatally, is secreted, induces MSC osteogenic differentiation similarly to full-length NELL-1810, and additionally stimulates MSC proliferation (unlike full-length NELL-1). In vivo, NELL-1570 induces calvarial defect regeneration with increased cell proliferation. RACE cloning, lentiviral expression vectors, recombinant protein production, cell proliferation assays in multiple MSC populations, in vivo calvarial defect model with histology Stem cells (Dayton, Ohio) Medium 25376942
2017 NELL-1 expression is induced by BMP9 in mesenchymal stem cells, and exogenous Nell1 potentiates BMP9-induced late-stage osteogenic differentiation while inhibiting BMP9-induced adipogenesis in vitro and in vivo. Silencing Nell1 in BMP9-stimulated MSCs results in immature chondroid-like matrix formation. Adenoviral overexpression and shRNA silencing in iMEF MSCs, early/late osteogenic marker staining and qPCR, ectopic bone formation in athymic mice Cellular physiology and biochemistry Medium 28214873
2017 NELL-1 systemically administered induces expansion of Sca-1+CD45-CD31- bone marrow mesenchymal progenitor cells (MPCs), and this effect requires intact Wnt/β-catenin signaling. Nell-1 haploinsufficiency reduces Sca-1+ MPC numbers in bone marrow associated with low bone mass. Systemic rhNELL-1 administration in mice, flow cytometry for Sca-1+CD45-CD31- bone marrow MPCs, Wnt/β-catenin inhibitor experiments, haploinsufficient mouse analysis, nonhuman primate spinal fusion model JCI insight High 28614787
2018 Conditional inactivation of Nell-1 in chondrocytes (Col2α1-Cre) impedes endochondral ossification, resulting in dwarfism and premature osteoporosis. Nell-1-deficient chondrocytes show reduced proliferation and differentiation associated with decreased Ihh-PTHrP signaling; exogenous Nell-1 rescues Ihh signaling but rescue is blocked by Ihh signaling inhibitors cyclopamine or GANT61. Conditional knockout (Nell-1flox/flox; Col2α1-Cre), in vivo micro-CT, dynamic histomorphometry, immunohistochemistry, primary chondrocyte culture with rescue and inhibitor experiments Journal of bone and mineral research High 30352124
2019 Conditional inactivation of Nell-1 in Wnt1-expressing cranial neural crest cells (Nell-1flox/flox; Wnt1-Cre) causes frontonasal and mandibular bone defects with reduced osteogenic and Wnt/β-catenin markers. Nell-1-deficient CNCCs show reduced cell proliferation and osteogenic differentiation with low active-β-catenin, rescued by exogenous Nell-1 protein. Conditional knockout generation, CNCC lineage tracing, immunostaining for osteocalcin and active-β-catenin, primary CNCC proliferation/differentiation assays with Nell-1 rescue Cell death and differentiation High 31582804
2018 Nell-1 enhances osteogenic differentiation of pre-osteoblasts on titanium surfaces via MAPK/ERK pathway activation; ERK inhibitor U0126 suppresses Nell-1-induced osteogenic markers (except ALP and Col-I). Nell-1 activates ERK and JNK but not P38 MAPK in MC3T3-E1 cells on Ti surfaces. Western blot for MAPK pathway, ERK inhibitor (U0126) treatment, ALP assay, ELISA for osteocalcin, RT-PCR for osteogenic markers Cellular physiology and biochemistry Medium 30359975
2018 A novel Nell-1 splice isoform lacking a calcium-binding EGF-like domain (Nell-1-ΔE) inhibits cell migration in vitro by interacting with enolase-1 (ENO-1) in extracellular spaces; this interaction was identified by co-immunoprecipitation and LC-MS/MS, and is specific to Nell-1-ΔE (not full-length Nell-1). Overexpression of ENO-1 combined with Nell-1-ΔE treatment confirms the ENO-1 dependence. Co-immunoprecipitation, LC-MS/MS proteomics, wound healing assay, ENO-1 overexpression, subcellular fractionation to confirm extracellular localization Journal of cellular biochemistry Medium 29388706
2022 NELL1 promotes osteosarcoma progression by modulating the extracellular matrix (matrisome); NELL1 genetic deletion reduces OS invasiveness and metastasis in xenograft and conditional knockout mouse sarcoma models. Transcriptomic and phosphoproteomic analyses show NELL1 loss skews matricellular protein expression and reduces FAK signaling; wild-type OS-enriched matricellular protein rescue restores invasiveness in NELL1-KO cells. CRISPR-Cas9 NELL1 deletion in OS cell lines, xenograft mouse model, p53/Rb-driven conditional KO sarcoma model, transcriptomics, phosphoproteomics, matricellular protein rescue assay Cancer research High 35700263
2019 Nell-1 is identified as having a specific receptor, contactin-associated protein-like 4 (Cntnap4), for osteogenesis (referenced in review context as an established finding). Nell-1 signals through MAPK and Wnt/β-catenin pathways in MSCs. In chondrogenesis, Nell-1 involves Nfatc1, Runx3, and Indian hedgehog (Ihh) signaling pathways. Review summarizing receptor identification and signaling pathway data from multiple primary studies Journal of dental research Low 31610747
2024 Nell-1 modulates M2/M1 macrophage polarization in periodontitis, shifting macrophages toward M2 phenotype via the JNK/MAPK signaling pathway; JNK inhibitor SP600125 reverses Nell-1's effect on macrophage polarization. Rat ligation-induced periodontitis model with local Nell-1 injection, LPS-stimulated RAW264.7 macrophage culture with Nell-1 and JNK inhibitor, flow cytometry, RT-PCR, western blot International immunopharmacology Medium 38908089

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney international 268 31901340
1999 Human NELL-1 expressed in unilateral coronal synostosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 145 9893069
2020 NELL1 is a target antigen in malignancy-associated membranous nephropathy. Kidney international 142 32828756
2002 Craniosynostosis in transgenic mice overexpressing Nell-1. The Journal of clinical investigation 129 12235118
1999 Biochemical characterization and expression analysis of neural thrombospondin-1-like proteins NELL1 and NELL2. Biochemical and biophysical research communications 117 10548494
1996 Cloning and characterization of two novel human cDNAs (NELL1 and NELL2) encoding proteins with six EGF-like repeats. Genomics 114 8975702
2007 Systematic association mapping identifies NELL1 as a novel IBD disease gene. PloS one 105 17684544
2010 The role of NELL-1, a growth factor associated with craniosynostosis, in promoting bone regeneration. Journal of dental research 104 20647499
2015 NELL-1 in the treatment of osteoporotic bone loss. Nature communications 97 26082355
2006 Nell1-deficient mice have reduced expression of extracellular matrix proteins causing cranial and vertebral defects. Human molecular genetics 97 16537572
2006 The osteoinductive properties of Nell-1 in a rat spinal fusion model. The spine journal : official journal of the North American Spine Society 87 17197333
2011 Nell-1, a key functional mediator of Runx2, partially rescues calvarial defects in Runx2(+/-) mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 79 20939017
2012 Additive effects of sonic hedgehog and Nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. Stem cells and development 76 22264144
2007 A study of the role of nell-1 gene modified goat bone marrow stromal cells in promoting new bone formation. Molecular therapy : the journal of the American Society of Gene Therapy 76 17653100
2007 Synergistic effects of Nell-1 and BMP-2 on the osteogenic differentiation of myoblasts. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 67 17352654
2007 Involvement of MAPK signaling molecules and Runx2 in the NELL1-induced osteoblastic differentiation. FEBS letters 67 18082140
2013 BMP2-induced inflammation can be suppressed by the osteoinductive growth factor NELL-1. Tissue engineering. Part A 66 23758588
2011 Nell-1 protein promotes bone formation in a sheep spinal fusion model. Tissue engineering. Part A 64 21128865
2007 Craniosynostosis-associated gene nell-1 is regulated by runx2. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 62 17042739
2011 Nell-1 enhances bone regeneration in a rat critical-sized femoral segmental defect model. Plastic and reconstructive surgery 55 21285762
2011 The Nell-1 growth factor stimulates bone formation by purified human perivascular cells. Tissue engineering. Part A 53 21615216
2011 A new function of Nell-1 protein in repressing adipogenic differentiation. Biochemical and biophysical research communications 52 21723263
2010 Delivery of lyophilized Nell-1 in a rat spinal fusion model. Tissue engineering. Part A 52 20528102
2003 Overexpression of Nell-1, a craniosynostosis-associated gene, induces apoptosis in osteoblasts during craniofacial development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 48 14672347
2017 NEL-Like Molecule-1 (Nell1) Is Regulated by Bone Morphogenetic Protein 9 (BMP9) and Potentiates BMP9-Induced Osteogenic Differentiation at the Expense of Adipogenesis in Mesenchymal Stem Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 46 28214873
2011 NELL-1 promotes cartilage regeneration in an in vivo rabbit model. Tissue engineering. Part A 42 21902605
2012 NELL-1 promotes cell adhesion and differentiation via Integrinβ1. Journal of cellular biochemistry 40 22807400
2010 Effect of Nell-1 delivery on chondrocyte proliferation and cartilaginous extracellular matrix deposition. Tissue engineering. Part A 39 20028218
2012 NELL-1 increases pre-osteoblast mineralization using both phosphate transporter Pit1 and Pit2. Biochemical and biophysical research communications 38 22580275
2010 The effect of NELL1 and bone morphogenetic protein-2 on calvarial bone regeneration. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons 38 20116699
2022 Runx2 and Nell-1 in dental follicle progenitor cells regulate bone remodeling and tooth eruption. Stem cell research & therapy 36 36175952
2019 Nell-1 Is a Key Functional Modulator in Osteochondrogenesis and Beyond. Journal of dental research 35 31610747
2013 Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans. The pharmacogenomics journal 35 23400010
2015 Expression and regulatory effects on cancer cell behavior of NELL1 and NELL2 in human renal cell carcinoma. Cancer science 34 25726761
2011 NELL-1 binds to APR3 affecting human osteoblast proliferation and differentiation. FEBS letters 34 21723284
2011 Nfatc2 is a primary response gene of Nell-1 regulating chondrogenesis in ATDC5 cells. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 33 21611965
2022 The Many Faces of NELL1 MN. Clinical kidney journal 31 36865014
2010 NELL1 promotes high-quality bone regeneration in rat femoral distraction osteogenesis model. Bone 31 20959151
2013 NELL-1 based demineralized bone graft promotes rat spine fusion as compared to commercially available BMP-2 product. Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association 30 23686083
2011 Combined effects of recombinant human BMP-2 and Nell-1 on bone regeneration in rapid distraction osteogenesis of rabbit tibia. Injury 30 21703614
2017 Neural EGF-like protein 1 (NELL-1): Signaling crosstalk in mesenchymal stem cells and applications in regenerative medicine. Genes & diseases 27 29276737
2011 Maxillary sinus floor elevation using BMP-2 and Nell-1 gene-modified bone marrow stromal cells and TCP in rabbits. Calcified tissue international 27 21584647
2006 Nell-1 induces acrania-like cranioskeletal deformities during mouse embryonic development. Laboratory investigation; a journal of technical methods and pathology 27 16652108
1999 The neuronal EGF-related genes NELL1 and NELL2 are expressed in hemopoietic cells and developmentally regulated in the B lineage. Gene 27 10231576
2016 Accelerated Chondrogenic Differentiation of Human Perivascular Stem Cells with NELL-1. Tissue engineering. Part A 26 26700847
2012 Calvarial cleidocraniodysplasia-like defects with ENU-induced Nell-1 deficiency. The Journal of craniofacial surgery 26 22337375
2017 NELL-1, HMGB1, and CCN2 Enhance Migration and Vasculogenesis, But Not Osteogenic Differentiation Compared to BMP2. Tissue engineering. Part A 25 28463604
2018 Tissue engineering using 3D printed nano-bioactive glass loaded with NELL1 gene for repairing alveolar bone defects. Regenerative biomaterials 24 30094060
2018 Nell-1 Enhances Osteogenic Differentiation of Pre-Osteoblasts on Titanium Surfaces via the MAPK-ERK Signaling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 24 30359975
2015 Proliferation and osteogenic differentiation of mesenchymal stem cells induced by a short isoform of NELL-1. Stem cells (Dayton, Ohio) 24 25376942
2012 The C-terminal region of NELL1 mediates osteoblastic cell adhesion through integrin α3β1. FEBS letters 24 22728432
2001 Brain specific human genes, NELL1 and NELL2, are predominantly expressed in neuroblastoma and other embryonal neuroepithelial tumors. Neurologia medico-chirurgica 24 11803583
2014 Effect of NELL1 gene overexpression in iPSC-MSCs seeded on calcium phosphate cement. Acta biomaterialia 23 25220281
2011 NELL-1, an osteoinductive factor, is a direct transcriptional target of Osterix. PloS one 22 21931789
2012 Lentiviral-mediated gene transfer into human adipose-derived stem cells: role of NELL1 versus BMP2 in osteogenesis and adipogenesis in vitro. Acta biochimica et biophysica Sinica 20 23017834
2012 Expression and localization of Nell-1 during murine molar development. Journal of molecular histology 20 23264108
2017 NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair. JCI insight 19 28614787
2021 Posttransplant nephrotic syndrome resulting from NELL1-positive membranous nephropathy. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 18 33866674
2018 DNA methylation of neural EGFL like 1 (NELL1) is associated with advanced disease and the metastatic state of renal cell cancer patients. Oncology reports 18 30272321
2017 Chitosan-stablized bovine serum albumin nanoparticles having ability to control the release of NELL-1 protein. International journal of biological macromolecules 18 29288032
2016 Vertebral Implantation of NELL-1 Enhances Bone Formation in an Osteoporotic Sheep Model. Tissue engineering. Part A 18 27113550
2015 Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration. Biomaterials 17 25913252
2022 NELL1 augments osteogenesis and inhibits inflammation of human periodontal ligament stem cells induced by BMP9. Journal of periodontology 16 34647317
2022 NELL1 Regulates the Matrisome to Promote Osteosarcoma Progression. Cancer research 16 35700263
2012 Efficient production and characterization of recombinant human NELL1 protein in human embryonic kidney 293-F cells. Molecular biotechnology 16 21814724
2014 Oligomerization-induced conformational change in the C-terminal region of Nel-like molecule 1 (NELL1) protein is necessary for the efficient mediation of murine MC3T3-E1 cell adhesion and spreading. The Journal of biological chemistry 15 24563467
2014 Bioactivity and circulation time of PEGylated NELL-1 in mice and the potential for osteoporosis therapy. Biomaterials 15 24818884
2021 Nell-1 attenuates lipopolysaccharide-induced inflammation in human dental pulp cells. Journal of molecular histology 14 33905072
2020 The synergistic effect of NELL1 and adipose-derived stem cells on promoting bone formation in osteogenesis imperfecta treatment. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 14 32454289
2019 Effect of NELL1 on lung cancer stem‑like cell differentiation. Oncology reports 13 30628703
2019 Nell-1 promotes the neural-like differentiation of dental pulp cells. Biochemical and biophysical research communications 13 30979495
2019 Synergistic Effect of NELL-1 and an Ultra-Low Dose of BMP-2 on Spinal Fusion. Tissue engineering. Part A 13 31337284
2019 Cumulative inactivation of Nell-1 in Wnt1 expressing cell lineages results in craniofacial skeletal hypoplasia and postnatal hydrocephalus. Cell death and differentiation 13 31582804
2023 Mercury-associated neural epidermal growth factor-like 1 protein (NELL-1) positive membranous nephropathy after use of skin lightening creams. Clinical toxicology (Philadelphia, Pa.) 12 37078902
2018 miR-27a protects human mitral valve interstitial cell from TNF-α-induced inflammatory injury via up-regulation of NELL-1. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 12 29694513
2017 NELL1, whose high expression correlates with negative outcomes, has different methylation patterns in alveolar and embryonal rhabdomyosarcoma. Oncotarget 12 28380437
2017 The Effects of Systemic Therapy of PEGylated NEL-Like Protein 1 (NELL-1) on Fracture Healing in Mice. The American journal of pathology 12 29294300
2018 Inactivation of Nell-1 in Chondrocytes Significantly Impedes Appendicular Skeletogenesis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 11 30352124
2018 Optimizing Osteogenic Differentiation of Ovine Adipose-Derived Stem Cells by Osteogenic Induction Medium and FGFb, BMP2, or NELL1 In Vitro. Stem cells international 11 30356449
2015 NELL-1 expression in benign and malignant bone tumors. Biochemical and biophysical research communications 11 25791475
2021 NELL-1 in Genome-Wide Association Studies across Human Diseases. The American journal of pathology 10 34890556
2020 Activation of Nell-1 in BMSC Sheet Promotes Implant Osseointegration Through Regulating Runx2/Osterix Axis. Frontiers in cell and developmental biology 10 33072736
2015 Mapping the heparin-binding site of the osteoinductive protein NELL1 by site-directed mutagenesis. FEBS letters 10 26627376
2015 MALDI-TOF Mass Array Analysis of Nell-1 Promoter Methylation Patterns in Human Gastric Cancer. BioMed research international 9 26090379
2016 Controlled release of NELL-1 protein from chitosan/hydroxyapatite-modified TCP particles. International journal of pharmaceutics 8 27349789
2016 Efficacy of Intraperitoneal Administration of PEGylated NELL-1 for Bone Formation. BioResearch open access 8 27354930
2015 NELL-1 expression in tumors of cartilage. Journal of orthopaedics 8 27047227
2022 Backtracking cryptic recurrence of esophageal cancer from membranous nephropathy: the detection of glomerular NELL-1 and IgG4. Clinical kidney journal 7 37007702
2021 NELL-1 Increased the Osteogenic Differentiation and mRNA Expression of Spheroids Composed of Stem Cells. Medicina (Kaunas, Lithuania) 7 34201046
2024 NELL1 membranous nephropathy: clinical associations provide mechanistic clues. Frontiers in nephrology 6 38596642
2021 Novel Molecule Nell-1 Promotes the Angiogenic Differentiation of Dental Pulp Stem Cells. Frontiers in physiology 6 34512380
2018 Association of DFNA5, SYK, and NELL1 variants along with HPV infection in oral cancer among the prolonged tobacco-chewers. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 6 30091681
2013 Human NELL1 protein augments constructive tissue remodeling with biologic scaffolds. Cells, tissues, organs 6 24335144
2024 Neural epidermal growth factor-like 1 protein (Nell-1) alleviates periodontal tissue destruction in periodontitis by regulating the ratio of M2/M1 macrophage phenotypes. International immunopharmacology 5 38908089
2023 Anti-PLA2R Antibody Development During NELL1-Associated Membranous Glomerulonephritis Treatment: A Case Report. Kidney medicine 5 37122392
2022 NELL1-Positive HIV-Associated Lupus-Like Membranous Nephropathy with Spontaneous Remission. Glomerular diseases 5 36817287
2012 NELL1 promotes bone regeneration in polyethylene particle-induced osteolysis. Tissue engineering. Part A 5 22404332
2009 An ectopic study of tissue-engineered bone with Nell-1 gene modified rat bone marrow stromal cells in nude mice. Chinese medical journal 5 19493425
2018 Nell-1-ΔE, a novel transcript of Nell-1, inhibits cell migration by interacting with enolase-1. Journal of cellular biochemistry 4 29388706
2016 [NELL-1: a novel highly efficient and specific growth factor]. Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences 4 27080300