Affinage

GREM2

Gremlin-2 · UniProt Q9H772

Length
168 aa
Mass
19.3 kDa
Annotated
2026-04-28
31 papers in source corpus 19 papers cited in narrative 19 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GREM2 (also known as PRDC) is a secreted BMP antagonist of the DAN/cerberus family that functions as a key modulator of BMP/SMAD signaling across multiple developmental and homeostatic contexts. GREM2 directly binds BMP2, BMP4, and BMP7 through its cysteine-knot domain, suppressing canonical BMP-induced phospho-SMAD1/5/8 signaling, and its heparin/heparan sulfate–binding and BMP-binding epitopes are independent, with the GREM2–BMP2 complex exhibiting enhanced heparin affinity (PMID:22381466, PMID:28104757). Through BMP antagonism, GREM2 negatively regulates osteoblast differentiation and trabecular bone formation, inhibits visceral fat browning via BMPR2-dependent SMAD1/5/8 suppression, directs atrial cardiomyocyte specification and cardiac laterality, and is required for normal tooth morphogenesis (PMID:19073177, PMID:38839844, PMID:35349825, PMID:23223679, PMID:24686385). GREM2 expression is induced by Wnt/β-catenin signaling in a Tcf/LEF-independent manner and by STAT3, and in podocytes GREM2 overexpression shifts signaling toward phospho-SMAD2/3 to promote apoptosis (PMID:17222801, PMID:41322616, PMID:30831151).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 Medium

    The initial discovery of GREM2 (PRDC) established it as a novel secreted protein of the DAN family expressed in the developing nervous system, raising the question of its molecular function.

    Evidence Gene trap in mouse ES cells with lacZ reporter and cDNA structural analysis

    PMID:9639362

    Open questions at the time
    • No functional assay performed
    • Binding partners not identified
    • Relationship to BMP signaling unknown
  2. 2007 Medium

    Connecting GREM2 to upstream Wnt signaling established that β-catenin induces GREM2 expression, which then antagonizes BMP-4 — placing GREM2 as a Wnt-to-BMP signaling intermediary.

    Evidence Microarray, reporter assays, conditioned media, and β-catenin overexpression in cell lines

    PMID:17222801

    Open questions at the time
    • Tcf/LEF-independent mechanism of induction not molecularly defined
    • In vivo relevance of Wnt→GREM2→BMP axis not tested
  3. 2008 High

    Gain- and loss-of-function experiments in primary osteoblasts demonstrated that GREM2 suppresses BMP-2-induced SMAD1/5/8 phosphorylation and osteoblast differentiation, defining its cell-autonomous role in bone biology.

    Evidence Adenoviral overexpression and siRNA knockdown in primary osteoblasts with Western blot, ALP, and mineralization assays

    PMID:19073177

    Open questions at the time
    • In vivo skeletal phenotype of GREM2 loss not yet shown
    • Relative contributions of BMP2 vs BMP4 vs BMP7 antagonism in bone not dissected
  4. 2009 High

    In vivo gain/loss-of-function in chick demonstrated GREM2 modulates BMP signaling in pharyngeal pouches to regulate epibranchial placode neurogenesis, confirming its developmental BMP-antagonist role in a whole-organism context.

    Evidence Reciprocal gain- and loss-of-function in chick embryos with in situ hybridization

    PMID:19836367

    Open questions at the time
    • Mammalian relevance of pharyngeal arch function not confirmed
    • Receptor-level mechanism not defined
  5. 2012 High

    Biochemical reconstitution established that GREM2 directly binds BMP2, BMP4, and BMP7 (but not activin A), confirming ligand specificity, while zebrafish and mouse ES cell work revealed its role in cardiac laterality and atrial cardiomyocyte differentiation.

    Evidence Recombinant protein binding assays and cell-based reporter (PMID:22381466); zebrafish overexpression, live cardiac imaging, and mouse ES cell differentiation (PMID:23223679)

    PMID:22381466 PMID:23223679

    Open questions at the time
    • Structural basis of BMP-binding selectivity unknown
    • Whether cardiac role requires BMP antagonism specifically vs. other mechanisms not formally tested
  6. 2014 High

    Grem2-null mice revealed a requirement for GREM2 in tooth morphogenesis, providing the first mammalian knockout phenotype.

    Evidence Grem2-knockout mouse with histological and DEXA analysis

    PMID:24686385

    Open questions at the time
    • Full skeletal phenotype not deeply characterized in this study
    • Cardiac phenotype of knockout not reported
  7. 2017 High

    Mutagenesis dissected the GREM2 protein into functionally independent heparin/heparan sulfate–binding and BMP-binding epitopes, showing the GREM2–BMP2 complex has enhanced heparin affinity, suggesting extracellular matrix interactions regulate GREM2 bioavailability.

    Evidence Site-directed mutagenesis of lysine residues, heparin-binding quantification, cell-surface binding, and protein–protein interaction assays

    PMID:28104757

    Open questions at the time
    • In vivo significance of heparan sulfate interaction for GREM2 gradient/activity not tested
    • No structural model of GREM2–BMP complex available
  8. 2019 Medium

    GREM2 overexpression in podocytes was shown to shift SMAD signaling from SMAD1/5/8 toward SMAD2/3, promoting apoptosis — revealing a context-dependent pro-apoptotic output of BMP antagonism.

    Evidence Overexpression and siRNA in human podocytes, phospho-SMAD Western blots, apoptosis assays, Smad2/3 inhibitor epistasis

    PMID:30831151

    Open questions at the time
    • Mechanism by which GREM2 activates SMAD2/3 not defined (direct vs indirect)
    • In vivo renal phenotype not tested
  9. 2022 High

    Multiple genetic models established GREM2 as a physiological inhibitor of visceral fat browning via BMPR2-dependent SMAD1/5/8 antagonism, while separately its downregulation was shown to be protective in pulmonary arterial hypertension.

    Evidence Grem2 overexpression and knockout mice, preadipocyte-specific Bmpr2 KO (PMID:35349825); monocrotaline PAH rat model and human lung samples (PMID:35414785)

    PMID:35349825 PMID:35414785

    Open questions at the time
    • Whether GREM2 acts on brown vs white preadipocytes via identical mechanisms unclear
    • Human genetic validation of GREM2 in metabolic disease lacking
  10. 2024 High

    Grem2 haploinsufficiency in female mice increased trabecular bone mineral density and osteoblast differentiation markers upon BMP-2 stimulation, confirming GREM2 as a dose-sensitive negative regulator of bone formation.

    Evidence Grem2+/- and Grem2-/- mouse models, microCT, DEXA, primary osteoblast culture with BMP-2

    PMID:38839844

    Open questions at the time
    • Sex-specific mechanism not explained
    • Cortical bone unaffected — basis of compartment specificity unknown
  11. 2025 Medium

    STAT3 was identified as a direct transcriptional activator of GREM2, linking inflammatory signaling to GREM2 expression in thyroid cells.

    Evidence Dual-luciferase reporter assay and siRNA against STAT3 in LPS-stimulated thyroid cell model

    PMID:41322616

    Open questions at the time
    • Whether STAT3→GREM2 axis operates in other tissues not tested
    • Promoter elements mediating STAT3 binding not mapped at base-pair resolution

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of GREM2 alone and in complex with BMP ligands is lacking, and the mechanism by which GREM2 selectively antagonizes BMP2/4/7 but not activin A remains structurally undefined; additionally, the cardiac-specific in vivo consequences of GREM2 loss in mammals have not been reported.
  • No crystal or cryo-EM structure of GREM2 or GREM2–BMP complex
  • Mammalian cardiac knockout phenotype not reported
  • Relative in vivo contributions of heparan sulfate sequestration vs direct BMP binding not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1266738 Developmental Biology 4
Partners
BMP2BMP4BMP7BMPR2

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 GREM2 (PRDC) was identified as a novel secreted protein with limited similarity to DAN and cerberus, containing a signal peptide and expressed in commissural neurons of the developing spinal cord, suggesting a role in neural development. Gene trap in ES cells, lacZ reporter, cDNA structural analysis Development, growth & differentiation Medium 9639362
2004 GREM2 (CKTSF1B2/PRDC) was identified as a secreted BMP antagonist of the DAN family, defined by a conserved N-terminal signal peptide and DAN domain with nine cysteine residues, mapped to human chromosome 1q43. Bioinformatics/in silico sequence analysis and phylogenetic analysis Oncology reports Low 15254711
2006 In zebrafish, PRDC (GREM2 ortholog) is expressed as a secreted glycoprotein in developing eyes, pharyngeal arches, somites, and swim bladder, consistent with roles in eye development, pharyngeal arch remodeling, somitogenesis, and swim bladder organogenesis. In situ hybridization, developmental expression analysis in zebrafish Developmental dynamics Medium 16921498
2007 GREM2 (PRDC) expression is specifically induced by Wnt/β-catenin signaling in a Tcf/LEF-independent manner; the secreted PRDC protein then antagonizes BMP-4 signaling but does not inhibit Wnt signaling, placing GREM2 as a mediator that antagonizes BMP-4 downstream of Wnt. Microarray, reporter assays, conditioned media experiments, β-catenin overexpression Biochemical and biophysical research communications Medium 17222801
2008 GREM2 (PRDC) is expressed in pre-osteoblasts, suppresses BMP-2-induced phospho-Smad1/5/8, inhibits osteoblast differentiation markers and mineralization; siRNA knockdown of PRDC elevates alkaline phosphatase activity, phospho-Smad1/5/8, and promotes bone-like mineralized matrix deposition in vitro. Adenoviral overexpression, siRNA knockdown, Western blotting for phospho-Smad1/5/8, alkaline phosphatase assay, mineralization assay in primary osteoblasts Experimental cell research High 19073177
2009 In chick, PRDC (GREM2 ortholog) modulates BMP signaling in the pharyngeal pouches to regulate epibranchial placode neurogenesis: gain-of-PRDC function reduces Bmp4 and inhibits placode neurogenesis, while loss-of-PRDC function expands ectopic Bmp4 and placode neurogenesis. Gain- and loss-of-function experiments in chick embryos, in situ hybridization Developmental biology High 19836367
2012 Recombinant mouse PRDC (GREM2) was expressed, purified, and shown to directly bind BMP2, BMP4, and BMP7 (but not activin A), and to inhibit BMP2 and BMP4 in a cell-based luciferase reporter assay; circular dichroism confirmed folded protein with helical content. Recombinant protein expression/purification from E. coli, binding assays, cell-based luciferase reporter assay, circular dichroism Protein expression and purification High 22381466
2012 In zebrafish, GREM2 regulates cardiac laterality and atrial cardiomyocyte differentiation through BMP signaling; the Q76E variant has increased BMP-inhibitory activity; GREM2 overactivity causes slower cardiac contraction and induces atrial-specific genes (connexin-40, sarcolipin, atrial natriuretic peptide) in mouse ES cells. Zebrafish overexpression, live heart imaging, mouse ES cell differentiation, sequencing of AF probands Disease models & mechanisms High 23223679
2014 Grem2-null mice develop malformed mandibular and maxillary incisors, demonstrating that GREM2 is required for normal tooth morphogenesis in vivo. Grem2-knockout mouse model, histology, DEXA scanning Veterinary pathology High 24686385
2016 GREM1 and GREM2 modulate BMP2/4 signaling in human fetal ovarian somatic cells in a gene-specific manner, antagonizing the BMP-induced transcription of some target genes (including LGR5) but not others, fine-tuning BMP signal intensity during ovarian development. Primary human fetal ovarian somatic cell culture, recombinant GREM1/GREM2 treatment, qRT-PCR, immunoblotting Molecular human reproduction Medium 27385727
2016 Treatment of mouse embryonic stem cell embryoid bodies with Grem2 protein directs differentiation toward atrial cardiomyocytes with atrial-like molecular, histological, and electrophysiological characteristics. Mouse ES cell differentiation protocol, Myh6-DSRed reporter, molecular/histological/electrophysiological analyses Journal of visualized experiments : JoVE Medium 27023256
2017 Mutagenesis and heparin-binding measurements identified specific lysine residues on Grem2 that mediate heparin/heparan sulfate (HS) binding; these residues are not required for BMP antagonism; the Grem2 heparin/HS and BMP-binding epitopes are independent; the Grem2–BMP2 complex has higher heparin affinity than either protein alone. Site-directed mutagenesis, heparin-binding measurements, cell surface-binding analysis, in vitro protein–protein interaction assays The Biochemical journal High 28104757
2019 Grem2 overexpression in human podocytes increases phospho-Smad2/3 and decreases phospho-Smad1/5/8, promotes apoptosis (elevated Bax/Bcl2 ratio); Smad2/3 inhibition (SIS3) and BMP-7 (Smad1/5/8 agonist) attenuate Grem2-induced apoptosis, placing Grem2 upstream of Smad signaling in podocyte apoptosis. Plasmid transfection overexpression, siRNA knockdown, Western blotting for phospho-Smads, apoptosis assays, pharmacological inhibitors Biochimie Medium 30831151
2021 GREM2 increases LATS2 activity and YAP phosphorylation/degradation in liver cancer cells, suppressing migration and invasion; FOXA2 transcriptionally suppresses miR-103a-3p, which directly targets the GREM2 3'UTR, placing FOXA2→miR-103a-3p→GREM2→LATS2/YAP as a pathway controlling liver cancer cell motility. ChIP assay, luciferase reporter assay, Western blotting, migration/invasion assays, siRNA and overexpression experiments Cytotechnology Medium 34349344
2021 A GREM2 tooth-agenesis-associated variant (rs1414655) reduces GREM2 transcriptional activity and decreases MSX1 expression, and increases cell migration in dental stem cells (SHED), demonstrating functional consequences of this variant on tooth development gene networks. Plasmid transfection of reference and mutant alleles in SHED cells, luciferase reporter assay, qRT-PCR, cell migration assay Orthodontics & craniofacial research Medium 33369218
2022 Grem2 inhibits the browning program of visceral preadipocytes by antagonizing BMP4/7-SMAD1/5/8 signaling via BMPR2; Grem2 overexpression in mice reduces visceral fat browning, while Grem2 ablation enhances browning capacity and reduces visceral fat content; preadipocyte-specific Bmpr2 knockout abolishes the antagonistic effect of Grem2. Recombinant Grem2 protein, Grem2 overexpression and knockout mouse models, preadipocyte-specific Bmpr2 KO mice, Western blotting for SMAD1/5/8, adipocyte browning assays, ELISA EBioMedicine High 35349825
2022 PRDC (GREM2) decreases in hypertensive lungs; exogenous PRDC reverses BMP2/4-mediated inhibition of smooth muscle cell proliferation and migration and promotion of apoptosis in vitro, and PRDC supplementation worsens pulmonary arterial hypertension in vivo, indicating a compensatory protective role of PRDC downregulation in PAH. Human lung samples, monocrotaline rat PAH model, in vitro PASMC proliferation/migration/apoptosis assays, in vivo PRDC supplementation, hemodynamic measurements International journal of biological sciences Medium 35414785
2024 Partial Grem2 inactivation in female mice increases trabecular bone mineral density and trabecular thickness without changing cortical thickness; Grem2 deletion stimulates osteoblast differentiation (elevated Alp, Bglap, Sp7 mRNA after BMP-2 stimulation), confirming GREM2 as a negative regulator of osteoblast differentiation and trabecular bone formation acting via BMP-2 signaling. Grem2+/- and Grem2-/- mouse models, microCT, DEXA, primary osteoblast culture with BMP-2 stimulation, qRT-PCR Scientific reports High 38839844
2025 GREM2 is a downstream transcriptional target of STAT3; dual-luciferase assay and siRNA interference confirmed STAT3 drives GREM2 expression; in LPS-stimulated thyroid cells, dexamethasone inhibits STAT3 phosphorylation, reducing GREM2 expression and downstream proinflammatory cytokines (TNF-α, IL-1β, CCL2). Dual-luciferase assay, siRNA interference, phospho-STAT3 Western blotting, in vitro LPS-stimulated thyroid cell model ACS omega Medium 41322616

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Cancer-associated fibroblast-secreted exosomal miR-423-5p promotes chemotherapy resistance in prostate cancer by targeting GREM2 through the TGF-β signaling pathway. Experimental & molecular medicine 102 33144675
2023 SGLT2 inhibitor empagliflozin downregulates miRNA-34a-5p and targets GREM2 to inactivate hepatic stellate cells and ameliorate non-alcoholic fatty liver disease-associated fibrosis. Metabolism: clinical and experimental 91 37422021
1998 Sequence and expression of a novel mouse gene PRDC (protein related to DAN and cerberus) identified by a gene trap approach. Development, growth & differentiation 49 9639362
2004 Identification and characterization of human CKTSF1B2 and CKTSF1B3 genes in silico. Oncology reports 48 15254711
2008 Protein related to DAN and cerberus (PRDC) inhibits osteoblastic differentiation and its suppression promotes osteogenesis in vitro. Experimental cell research 47 19073177
2012 Functional modeling in zebrafish demonstrates that the atrial-fibrillation-associated gene GREM2 regulates cardiac laterality, cardiomyocyte differentiation and atrial rhythm. Disease models & mechanisms 44 23223679
2016 BMP signalling in human fetal ovary somatic cells is modulated in a gene-specific fashion by GREM1 and GREM2. Molecular human reproduction 28 27385727
2007 Wnt/beta-catenin signaling regulates expression of PRDC, an antagonist of the BMP-4 signaling pathway. Biochemical and biophysical research communications 27 17222801
2006 Expression of the protein related to Dan and Cerberus gene--prdc--During eye, pharyngeal arch, somite, and swim bladder development in zebrafish. Developmental dynamics : an official publication of the American Association of Anatomists 27 16921498
2021 LncRNA DNM3OS regulates GREM2 via miR-127-5p to suppress early chondrogenic differentiation of rat mesenchymal stem cells under hypoxic conditions. Cellular & molecular biology letters 26 34049478
2009 PRDC regulates placode neurogenesis in chick by modulating BMP signalling. Developmental biology 25 19836367
2014 Malformation of incisor teeth in Grem2⁻/⁻ mice. Veterinary pathology 24 24686385
2022 MiR-103a-3p Contributes to the Progression of Colorectal Cancer by Regulating GREM2 Expression. Yonsei medical journal 16 35619575
2019 Grem2 mediates podocyte apoptosis in high glucose milieu. Biochimie 16 30831151
2021 miR-122-5p targets GREM2 to protect against glucocorticoid-induced endothelial damage through the BMP signaling pathway. Molecular and cellular endocrinology 15 34973370
2018 Further evidence for the role of WNT10A, WNT10B and GREM2 as candidate genes for isolated tooth agenesis. Orthodontics & craniofacial research 13 30246922
2013 Genetic variants in GREM2 are associated with bone mineral density in a southern Chinese population. The Journal of clinical endocrinology and metabolism 13 23902946
2019 GREM2 maintains stem cell-like phenotypes in gastric cancer cells by regulating the JNK signaling pathway. Cell cycle (Georgetown, Tex.) 12 31345097
2017 GREM2 nucleotide variants and the risk of tooth agenesis. Oral diseases 12 28992378
2021 Inhibiting roles of FOXA2 in liver cancer cell migration and invasion by transcriptionally suppressing microRNA-103a-3p and activating the GREM2/LATS2/YAP axis. Cytotechnology 11 34349344
2017 Analysis and identification of the Grem2 heparin/heparan sulfate-binding motif. The Biochemical journal 11 28104757
2012 Expression and purification of recombinant protein related to DAN and cerberus (PRDC). Protein expression and purification 9 22381466
2022 GREM2 is associated with human central obesity and inhibits visceral preadipocyte browning. EBioMedicine 8 35349825
2021 Functional characterization of ATF1, GREM2 AND WNT10B variants associated with tooth agenesis. Orthodontics & craniofacial research 6 33369218
2022 Compensatory roles of Protein Related to DAN and Cerberus (PRDC) decrease in pulmonary arterial hypertension. International journal of biological sciences 5 35414785
2016 Differentiation of Atrial Cardiomyocytes from Pluripotent Stem Cells Using the BMP Antagonist Grem2. Journal of visualized experiments : JoVE 4 27023256
2024 6-Shogaol alleviates high-fat diet induced hepatic steatosis through miR-3066-5p/Grem2 pathway. Food chemistry 3 38941907
2025 Mesenchymal Stem Cells Mediated Suppression of GREM2 Inhibits Renal Epithelial-Mesenchymal Transition and Attenuates the Progression of Diabetic Kidney Disease. International journal of stem cells 2 39757007
2025 Overexpression of miR-671-3p alleviates postmenopausal osteoporosis by targeting GREM2 to activate BMP2/SMAD signaling pathway. Hereditas 2 40500779
2024 GREM2 inactivation increases trabecular bone mass in mice. Scientific reports 2 38839844
2025 Integrative Transcriptome and Machine Learning Analysis Uncovers Critical STAT3/GREM2 Signaling Mechanisms in Dexamethasone Treatment of Hashimoto's Thyroiditis. ACS omega 0 41322616