Affinage

BMP6

Bone morphogenetic protein 6 · UniProt P22004

Length
513 aa
Mass
57.2 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BMP6 is a secreted TGF-β superfamily ligand that serves as the principal endogenous regulator of systemic iron homeostasis and contributes to osteoblast differentiation, angiogenesis, and context-dependent transcriptional programs in multiple tissues. In the liver, BMP6 is produced primarily by sinusoidal endothelial cells in response to iron-induced oxidative stress sensed through NTBI uptake and Nrf2 activation; it signals in a paracrine manner through the hemojuvelin co-receptor and BMPR complex on hepatocytes to phosphorylate SMAD1/5/8 and drive hepcidin transcription, thereby limiting dietary iron absorption and macrophage iron release (PMID:19252486, PMID:19252488, PMID:31276102, PMID:36351237). This pathway is modulated by erythroferrone (which traps BMP6 to suppress hepcidin during stress erythropoiesis), by HFE (which facilitates BMP6-SMAD signal transduction), and by matriptase-2/TMPRSS6 (which acts as a negative-feedback regulator induced by BMP6 via Id1) (PMID:30097509, PMID:20682319, PMID:21374653). Beyond iron regulation, BMP6 drives endochondral ossification cooperatively with BMP2 and BMP5, promotes endothelial migration via Myo10/ALK6 and VEGFR2/TAZ-dependent angiogenesis, modulates E-cadherin and MMP expression in cancer cells through SMAD and MAPK pathways, and inhibits B-cell proliferation via SMAD1/5/8-Id1 signaling (PMID:8089189, PMID:9664685, PMID:16109715, PMID:18158328, PMID:15877825, PMID:17997862).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1994 High

    Establishing that BMP6 is a secreted, proteolytically processed ligand capable of inducing endochondral bone formation answered the fundamental question of whether BMP6 functions as an osteoinductive morphogen.

    Evidence Implantation of BMP6-expressing CHO cells in nude mice with histological and neutralizing-antibody confirmation

    PMID:8089189

    Open questions at the time
    • Receptor identity for BMP6 osteoinductive signaling not defined
    • In vivo processing site not mapped
  2. 1998 High

    Generation of Bmp6-null mice revealed that BMP6 has a specific but partially redundant role in sternal ossification, with BMP5 compensating; this established the first loss-of-function phenotype and set the stage for identifying non-skeletal functions.

    Evidence Bmp6 knockout and Bmp5/Bmp6 double-mutant skeletal analysis

    PMID:9664685

    Open questions at the time
    • Iron homeostasis phenotype not yet examined in these mice
    • Molecular compensation mechanisms with BMP2/5/7 not dissected
  3. 2001 High

    Double knockout of Bmp6 and Bmp7 revealed a non-redundant requirement for BMP6 in cardiac outflow tract cushion formation, broadening its developmental role beyond skeletal tissues.

    Evidence Bmp6/Bmp7 double-knockout mice with histological analysis of cardiac development

    PMID:11437450

    Open questions at the time
    • Downstream targets in cardiac cushion mesenchyme not identified
    • Whether BMP6 acts on endocardium vs mesenchyme not resolved
  4. 2005 High

    Compound Bmp2+/−;Bmp6−/− mice demonstrated cooperative regulation of trabecular bone formation and endochondral fracture repair, distinguishing BMP6's role from intramembranous ossification.

    Evidence Compound knockout mice with micro-CT, histomorphometry, and fracture model

    PMID:16109715

    Open questions at the time
    • Receptor complex mediating cooperative BMP2/BMP6 signaling in bone not defined
  5. 2007 High

    The crystal structure of BMP6 defined its type I and type II receptor-binding interfaces, providing the first structural framework for understanding its signaling specificity.

    Evidence X-ray crystallography with SPR binding kinetics and Smad-based luciferase reporter validation

    PMID:17924656

    Open questions at the time
    • Structure of BMP6 in complex with its receptors not determined
    • Basis for selectivity over BMP7 at type I receptor level not fully resolved
  6. 2007 High

    Identification of Myo10 as a BMP6-induced effector in endothelial cells that amplifies BMP6/ALK6 signaling at filopodia revealed a positive-feedback mechanism linking BMP6 to directional cell migration and angiogenesis.

    Evidence Microarray, siRNA knockdown, live imaging, and co-localization of ALK6 with Myo10 in filopodia

    PMID:18158328

    Open questions at the time
    • Whether Myo10-dependent amplification is specific to endothelial cells or generalizable not tested
  7. 2007 Medium

    BMP6 was shown to promote E-cadherin expression and suppress miR-21 transcription in breast cancer cells via deltaEF1 displacement from target promoters, establishing a direct transcriptional mechanism for BMP6's anti-invasive activity.

    Evidence ChIP, luciferase reporters, and siRNA knockdown of deltaEF1 in breast cancer cell lines

    PMID:17997862 PMID:19308091

    Open questions at the time
    • In vivo relevance of BMP6-deltaEF1 axis in tumor suppression not demonstrated
    • Whether SMAD signaling mediates deltaEF1 regulation not fully dissected
  8. 2009 High

    Two independent studies demonstrated that Bmp6-null mice develop severe iron overload with reduced hepcidin and impaired hepatic SMAD1/5/8 phosphorylation, establishing BMP6 as the non-redundant endogenous activator of hepcidin — a paradigm-shifting discovery linking a BMP ligand to systemic iron regulation.

    Evidence Bmp6 knockout mice, neutralizing anti-BMP6 antibody, HJV.Fc co-immunoprecipitation, phospho-SMAD Western blot

    PMID:19252486 PMID:19252488

    Open questions at the time
    • Cell type producing BMP6 in the liver not yet identified
    • How iron loading increases BMP6 expression not resolved
  9. 2009 High

    Hfe-deficient mice showed elevated BMP6 but impaired downstream SMAD phosphorylation, placing HFE as a facilitator of BMP6 signal transduction rather than BMP6 production.

    Evidence Hfe knockout mice in multiple genetic backgrounds with phospho-SMAD1/5/8 and Id1 measurement

    PMID:19622835

    Open questions at the time
    • Physical mechanism by which HFE facilitates BMP6/SMAD transduction not identified
  10. 2010 High

    Genetic epistasis showed that Bmp6 co-deletion corrects the elevated hepcidin and anemia of Tmprss6-null mice, positioning matriptase-2 as a negative regulator acting specifically on the BMP6/HJV/hepcidin axis.

    Evidence Tmprss6−/−;Bmp6−/− double-knockout mice with hematological and hepcidin analysis

    PMID:20940420

    Open questions at the time
    • Whether TMPRSS6 cleaves HJV directly at the cell surface in physiological context not resolved in this study
  11. 2011 High

    BMP6 was found to induce its own negative regulator TMPRSS6 via the SMAD/Id1 pathway, revealing an autoregulatory feedback loop in hepcidin control.

    Evidence In vitro BMP6 treatment with Id1 knockdown and in vivo BMP6 injection

    PMID:21374653

    Open questions at the time
    • Kinetic modeling of the feedback loop in iron homeostasis not performed
  12. 2017 High

    Endothelial-specific Bmp2 knockout and Bmp6/Hjv double knockout studies demonstrated that BMP2 and BMP6 are both endothelial-derived hepcidin regulators with partially overlapping but non-identical functions, and that BMP6 retains some HJV-independent signaling capacity.

    Evidence Conditional endothelial Bmp2 KO; Hjv/Bmp6 double KO; neutralizing antibody; LPS challenge

    PMID:28815688 PMID:29021231

    Open questions at the time
    • Relative contributions of BMP2 vs BMP6 under different iron-loading conditions not quantitatively defined
  13. 2018 High

    Erythroferrone was identified as a physiological ligand trap that selectively sequesters BMP5/6/7 (not BMP2/4/9) to suppress hepcidin during stress erythropoiesis, explaining the erythroid regulation of iron supply.

    Evidence Cell-free HTRF binding assays, SMAD phosphorylation and hepcidin reporter in hepatocytes, neutralizing antibody

    PMID:30097509

    Open questions at the time
    • Structural basis of ERFE selectivity for BMP6 over BMP2 not determined
    • In vivo stoichiometry of ERFE-BMP6 trapping not measured
  14. 2018 Medium

    BMP6 was shown to signal through ALK2, ALK3, ALK6, and ActRIIA receptors in pancreatic and hepatic cells to suppress gluconeogenesis via PEPCK downregulation, expanding BMP6's metabolic role beyond iron.

    Evidence Receptor-specific Fc fusion inhibitors, ChIP, glucose output assay, ob/ob mouse treatment

    PMID:30539233

    Open questions at the time
    • Whether glucose-regulatory effects are physiologically relevant beyond ob/ob model not tested
    • Relative receptor usage across tissues not systematically compared
  15. 2019 High

    Nrf2 was identified as the transcription factor that senses iron-induced mitochondrial oxidative stress and directly drives Bmp6 transcription in liver sinusoidal endothelial cells, closing the circuit between iron sensing and BMP6 production.

    Evidence Nrf2 knockout mice, pharmacological Nrf2 activation, ChIP for Nrf2 on Bmp6 promoter, iron loading

    PMID:31276102

    Open questions at the time
    • Whether Nrf2 is the sole transcription factor driving iron-induced Bmp6 not excluded
    • Epigenetic regulation of Bmp6 not explored
  16. 2023 High

    Single-cell transcriptomics and conditional knockout confirmed that LSECs sense NTBI to activate Bmp6 via oxidative stress/Nrf2, refining the cellular iron-sensing mechanism to a specific cell type and iron species.

    Evidence Endothelial Tfr1 conditional KO, single-cell RNA-seq, NTBI-Bmp6 correlation analysis

    PMID:36351237

    Open questions at the time
    • Identity of the NTBI transporter on LSECs not determined
    • Whether other non-parenchymal cells contribute Bmp6 in pathological states remains open

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of BMP6 selectivity for HJV over other co-receptors, the identity of the LSEC NTBI transporter, the quantitative contribution of BMP6 versus BMP2 under distinct physiological iron states, and whether BMP6's metabolic functions (glucose, lipid) operate independently of hepcidin in vivo.
  • No structure of BMP6-HJV-receptor ternary complex available
  • NTBI import pathway in LSECs uncharacterized
  • In vivo relevance of BMP6 in glucose homeostasis not established in conditional models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 5
Localization
GO:0005576 extracellular region 5 GO:0031012 extracellular matrix 1
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-1430728 Metabolism 6 R-HSA-382551 Transport of small molecules 6 R-HSA-1266738 Developmental Biology 5
Partners
ACVR2AALK2ALK6ERFEHFEHJVMYO10TMPRSS6

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 BMP6 acts as a key endogenous ligand for hemojuvelin (HJV) to regulate hepcidin expression and iron metabolism in vivo. Physical interaction between HJV.Fc and BMP6 was demonstrated, and Bmp6-null mice develop hereditary hemochromatosis-like iron overload with reduced hepcidin. A neutralizing anti-BMP6 antibody inhibits hepcidin expression and increases serum iron in vivo. Co-immunoprecipitation/pulldown (HJV.Fc-BMP6 physical interaction), neutralizing antibody treatment in vivo, Bmp6 knockout mouse model with iron and hepcidin phenotyping Nature genetics High 19252486
2009 Targeted disruption of Bmp6 in mice causes massive iron accumulation in liver, pancreas, heart and renal tubules, with reduced phosphorylated Smad1/5/8 and reduced nuclear Smad translocation in the liver, and markedly reduced hepcidin synthesis, establishing BMP6 as the non-redundant endogenous activator of the BMP/SMAD/hepcidin axis. Bmp6 knockout mouse model; immunohistochemistry and Western blot for phospho-Smad1/5/8; qRT-PCR for hepcidin Nature genetics High 19252488
2007 Crystal structure of BMP-6 was solved, revealing the structural basis for receptor binding specificity at type I and type II receptor interfaces. X-ray crystallography; surface plasmon resonance (BIAcore) binding assays; Smad-based luciferase reporter assays Biochemistry High 17924656
2007 BMP6 induces myosin-X (Myo10) expression in endothelial cells; Myo10 localizes to filopodia after BMP6 stimulation and is required for BMP6-dependent filopodial assembly, directional cell migration, and Smad activation. BMP6 receptor ALK6 co-localizes with Myo10 in filopodia, and Myo10 is required for amplification of BMP6 signaling. Microarray; siRNA knockdown; live imaging; co-localization by immunofluorescence; Smad phosphorylation assay; directional migration assay The Journal of cell biology High 18158328
2018 Erythroferrone (ERFE) suppresses hepcidin by acting as a ligand trap that preferentially binds BMP5, BMP6, and BMP7 but not BMP2, BMP4, or BMP9, thereby inhibiting hepatic BMP/SMAD signaling. Cell-free HTRF assays showed BMP5/6/7 compete with anti-ERFE for ERFE binding. In vitro SMAD1/5/8 phosphorylation assay; hepcidin luciferase reporter; cell-free homogeneous time-resolved fluorescence (HTRF) binding competition assay; neutralizing antibody Blood High 30097509
2019 Nrf2 transcription factor, activated by iron-induced mitochondria-derived pro-oxidants, drives Bmp6 expression in liver sinusoidal endothelial cells (LSECs), which in turn increases hepcidin synthesis in neighboring hepatocytes. Nrf2 knockout mice have impaired Bmp6-hepcidin response to iron loading. Nrf2 knockout mice; pharmacological Nrf2 activation; qRT-PCR; ChIP for Nrf2 binding to Bmp6 promoter; iron loading experiments Nature metabolism High 31276102
2023 Liver sinusoidal endothelial cells (LSECs) sense systemic iron overload via non-transferrin-bound iron (NTBI) internalization, which promotes oxidative stress and transcriptionally induces Bmp6 via Nrf2, leading to paracrine hepcidin induction in hepatocytes. Endothelial-specific Tfr1 knockout mice showed transiently impaired Bmp6 induction. Endothelial cell-specific Tfr1 conditional knockout mice; single-cell transcriptomics; correlation analysis of serum NTBI with liver Bmp6/Hamp mRNA; iron loading experiments Blood High 36351237
2010 HFE interacts with the BMP6-SMAD signaling pathway to regulate hepcidin: HFE transgenic mice show increased BMP6-SMAD target gene expression, and anti-BMP6 antibody reverses hepcidin excess in these mice. Exogenous BMP6 administration overcomes the BMP6-SMAD signaling impairment in Hfe-/- mice and restores hepcidin. Hfe transgenic and knockout mice; anti-BMP6 neutralizing antibody treatment; exogenous BMP6 injection; hepatic SMAD phosphorylation and target gene expression Gastroenterology High 20682319
2009 In Hfe-deficient mice, despite increased Bmp6 mRNA and protein due to iron accumulation, levels of phosphorylated Smads 1/5/8 and Id1 mRNA are not elevated, indicating that HFE facilitates signal transduction downstream of BMP6 binding. Hfe knockout mice of multiple genetic backgrounds; Western blot for phospho-Smad1/5/8; qRT-PCR for Id1 and hepcidin Blood High 19622835
2017 Endothelial cell-derived BMP2 has a non-redundant role in hepcidin regulation by iron in addition to BMP6. Conditional endothelial Bmp2 knockout mice develop hepcidin deficiency and iron overload; a BMP2/4 neutralizing antibody blocks residual hepcidin induction by dietary iron in Bmp6-/- mice. Endothelial conditional Bmp2 knockout; global Bmp6 knockout; neutralizing antibody treatment; dietary iron loading; hepcidin and SMAD signaling assays American journal of hematology High 28815688
2018 Hemojuvelin (HJV) is required for inflammatory induction of hepcidin by maintaining a threshold of Bmp6/Smad signaling; in primary hepatocytes, Hjv deficiency severely impairs BMP6/Smad signaling and abolishes synergism with the IL-6/Stat pathway, though BMP2/Smad signaling is only slightly inhibited. Hjv-/- mice; primary hepatocyte cultures; Smad phosphorylation assays; LPS/FSL1/E.coli infection models; ferroportin immunohistochemistry Blood High 30213871
2017 Loss of Bmp6 further represses SMAD signaling and hepcidin in Hjv-/- mice, demonstrating that BMP6 can signal to hepcidin partially independently of hemojuvelin, and that BMP6 and HJV together set the level of hepcidin that determines the inflammatory hepcidin response. Double Hjv-/-;Bmp6-/- knockout mice; SMAD phosphorylation; hepcidin qRT-PCR; LPS challenge Blood High 29021231
2010 The anemia and elevated hepcidin of Tmprss6-/- mice is corrected by co-deletion of Bmp6, demonstrating that elevated hepcidin in iron-refractory iron deficiency anemia results from excess signaling through the Bmp6/Hjv pathway and placing matriptase-2 as a negative regulator of BMP6 signaling to hepcidin. Genetic epistasis: Tmprss6-/-;Bmp6-/- double knockout mice; hepcidin qRT-PCR; hematological analysis Blood High 20940420
2011 BMP6 stimulates TMPRSS6 (matriptase-2) expression at mRNA and protein levels via the BMP-SMAD pathway, with inhibitor of DNA binding 1 (Id1) identified as the key mediator; this creates a negative feedback loop on hepcidin regulation. In vitro BMP6 treatment of hepatic cells; qRT-PCR; Western blot for TMPRSS6; matriptase-2 activity assay; in vivo BMP6 injection and neutralizing antibody; Id1 knockdown Blood High 21622652
1994 Recombinant vgr-1/BMP-6 protein is secreted and proteolytically processed to the mature form; continuous secretion of BMP-6 from CHO cells in vivo induces surrounding host mesenchymal cells to differentiate along the endochondral bone pathway, producing cartilage and bone. Western blot for protein secretion and processing; subcutaneous implantation of BMP-6-expressing CHO cells in athymic nude mice; histological analysis; neutralizing antibody blocking The Journal of cell biology High 8089189
1995 Vgr-1/BMP-6 overexpression in pluripotential mesenchymal cells (ROB-C26) enhances osteoblastic differentiation in vitro and induces ectopic bone formation via extracellular matrix; the osteoinductive effect of BMP-6-conditioned matrix is blocked by neutralizing anti-vgr-1 antibody but not anti-TGF-β1, and requires matrix presentation rather than soluble BMP-6. Stable transfection; in vitro differentiation assay; subcutaneous implantation in vivo; neutralizing antibody blocking; MyoD overexpression competition assay Cell growth & differentiation High 7547504
1998 Bmp6 null mice are viable and fertile but show a consistent delay in ossification specifically in the developing sternum, with Bmp2 co-expressed in hypertrophic cartilage suggesting functional compensation. Bmp5/6 double mutants show exacerbated sternal defects. Gene targeting (knockout); skeletal analysis; in situ hybridization; Bmp5/Bmp6 double mutant analysis Developmental genetics High 9664685
2001 Bmp6 and Bmp7 are co-expressed in overlapping domains in cardiac cushions; Bmp6;Bmp7 double mutants (but not single mutants) show marked delay in outflow tract endocardial cushion formation, valve morphogenesis defects, and chamber septation defects causing embryonic lethality, establishing BMP6 as genetically required for cardiac cushion development. In situ hybridization; Bmp6/Bmp7 double knockout mice; histological analysis of cardiac development Developmental biology High 11437450
2005 BMP2 and BMP6 cooperatively regulate bone formation in vivo; Bmp2+/-;Bmp6-/- compound-deficient mice show reduced trabecular bone volume with suppressed bone formation and impaired endochondral (but not intramembranous) bone repair after fracture, whereas single-gene-deficient mice do not. Compound knockout mice; micro-CT and histomorphometry; fracture model; bone marrow cell culture for osteogenic differentiation The Journal of biological chemistry High 16109715
1998 BMP-6 induces LMP-1 (LIM mineralization protein-1) expression in osteoblast precursors; LMP-1 is required for BMP-6-induced osteoblast differentiation (antisense knockdown blocks differentiation) and its overexpression is sufficient to induce de novo bone formation, positioning LMP-1 as an essential intermediate in the BMP-6 signaling pathway. Antisense oligonucleotide knockdown; mammalian expression vector overexpression; in vitro bone nodule formation; subcutaneous implant in vivo Endocrinology Medium 9832452
2010 BMP-2/6 heterodimer is more potent than either BMP-2 or BMP-6 homodimers in inducing differentiation of human embryonic stem cells and activates Smad1/5 and MAPK (ERK, p38) signaling more effectively. Treatment of hES cells with recombinant proteins; qPCR for differentiation markers; flow cytometry; Western blot for Smad1/5 and MAPK phosphorylation PloS one Medium 20567515
2013 Iron-induced increase in Bmp6 expression originates predominantly from non-parenchymal liver cells (NPCs), particularly hepatic stellate cells, not hepatocytes; iron-saturated transferrin induces Bmp6 mRNA in isolated stellate cells but not in isolated hepatocytes, and this induction is independent of the BMP signaling pathway. Cell fractionation of liver; isolated primary hepatocytes and hepatic stellate cells; iron-saturated transferrin treatment; qRT-PCR; dietary iron manipulation in vivo PloS one Medium 23565256
2010 Iron overload induces Bmp6 mRNA and protein expression in the liver but not in the duodenum across multiple mouse strains, establishing the liver as the primary source of BMP6 for iron homeostasis regulation. Quantitative PCR; immunohistochemistry; Western blot; dietary iron loading and Hfe knockout models in three mouse strains Haematologica Medium 20952515
2012 Estrogen regulates hepcidin expression via a GPR30-BMP6-dependent mechanism: GPR30 activation by estrogen induces BMP6 expression in hepatocytes, and GPR30 silencing abolishes estrogen-induced BMP6 and hepcidin upregulation. OVX mouse model; GPR30 siRNA knockdown; G1 agonist treatment; qRT-PCR for BMP6 and hepcidin PloS one Medium 22792339
2015 Heterozygous missense mutations in the BMP6 pro-peptide (p.Pro95Ser, p.Leu96Pro, p.Gln113Glu) cause defective BMP6 secretion, reduced SMAD1/5/8 signaling, and loss of hepcidin production in transfected cells, establishing the propeptide as functionally required for BMP6 processing and iron homeostasis. Transfection of mutant BMP6 constructs; immunofluorescence for secretion; qRT-PCR and Western blot for SMAD signaling and hepcidin; immunohistochemistry of patient biopsy Gastroenterology Medium 26582087
2009 BMP-6 inhibits miR-21 transcription in breast cancer cells through reducing expression of deltaEF1 and c-Fos/c-Jun, and physically dislodging deltaEF1 from the E2-box of the miR-21 promoter (miPPR-21), thereby inhibiting MDA-MB-231 cell invasion. Luciferase reporter assay; ChIP assay; site-directed mutation of promoter; RT-PCR; invasion assay Cell research Medium 19308091
2007 BMP-6 promotes E-cadherin expression in breast cancer cells by inhibiting deltaEF1 transcription and physically dislodging deltaEF1 from the E-cadherin proximal promoter; deltaEF1 knockdown abolishes E-cadherin transactivation by BMP-6. Luciferase reporter assay; ChIP assay; siRNA knockdown of deltaEF1; RT-PCR and Western blot BMC cancer Medium 17997862
2005 BMP-6 inhibits proliferation of mature human B cells and B progenitor cells via phosphorylation of Smad1/5/8 followed by upregulation of Id1 (but not Id2 or Id3); the antiproliferative effect is completely neutralized by noggin. Primary human B cell and pre-B cell line cultures; Western blot for phospho-Smad1/5/8; RT-PCR for Id1-Id3; proliferation assay; noggin neutralization BMC immunology Medium 15877825
2008 BMP-6 in prostate cancer cells induces nuclear translocation of SMADs and activates Id-1; BMP-6 also increases migration and invasion, upregulates MMP-1 and MMP-9 at both mRNA and protein levels via direct transcriptional activation of their promoters, and activates MAPK signaling. Doxycycline-inducible BMP-6 expression system; SMAD nuclear translocation imaging; luciferase reporter assay for MMP-1/MMP-9 promoters; migration/invasion assay; Western blot for phospho-MAPK The Journal of pathology Medium 18072288
2011 BMP-6 derived from prostate cancer cells induces IL-6 expression in macrophages via crosstalk between Smad1 and NF-κB1 p50; IL-6 in turn induces neuroendocrine differentiation of prostate cancer cells. Disruption of BMP-6 or IL-6 with neutralizing antibodies blocks neuroendocrine differentiation. Co-culture of prostate cancer and macrophage cell lines; neutralizing antibodies to BMP-6 and IL-6; IL-6 knockout mice; macrophage-depleted mice; conditioned media experiments The Prostate Medium 21374653
2011 Intraocular BMP6 protein injection in mice upregulates retinal hepcidin expression and alters retinal labile iron levels; Bmp6-/- mice develop age-dependent retinal iron accumulation and degeneration. BMP6 is expressed in retinal pigment epithelium and is regulated by oxidative stress and iron. Intraocular BMP6 protein injection; Bmp6 knockout mice; qRT-PCR; labile iron measurement; histological analysis of retinal degeneration The American journal of pathology Medium 21703414
2010 BMP-6 treatment of recombinant BMP-6-expressing CHO cells and in vivo injection in mice increases hepcidin expression and reduces serum iron; BMP6 acts through phosphorylation of Smad1/5/8 to regulate hepcidin in the liver. Exogenous BMP6 injection in mice; phospho-Smad1/5/8 Western blot; hepcidin qRT-PCR; serum iron measurements Nature genetics High 19252486 19252488
2018 BMP6 regulates VEGFR2 expression in endothelial cells and acts via Hippo signaling effector TAZ to modulate angiogenesis; in a matrigel plug assay in mice, BMP6 induces neovascularization. In vitro endothelial cell assays; VEGFR2 expression analysis; TAZ knockdown/overexpression; matrigel plug assay in vivo Angiogenesis Medium 33021694
2018 BMP6 acts on pancreatic and liver cells through Alk3, Alk6, and ActRIIA serine/threonine kinase receptors to regulate glucose metabolism; BMP6 inhibits gluconeogenesis in rat hepatoma cells via downregulation of PEPCK expression, confirmed by chromatin immunoprecipitation. Receptor-specific Fc fusion protein inhibitors; luciferase reporter gene assay; glucose output assay in H4IIE and INS1 cells; ChIP; ob/ob mouse treatment with BMP6 Acta diabetologica Medium 30539233
2018 BMP6 downregulates GDNF expression in human granulosa cells through ALK2 and ALK3 receptors, activating SMAD1 and SMAD5 as well as ERK1/2 (but not AKT or p38); complete reversal of GDNF suppression requires dual inhibition of both SMAD4 and ERK1/2. ALK receptor kinase inhibitors; siRNA knockdown of ALK2, ALK3, SMAD1, SMAD5, SMAD4; Western blot for phospho-SMAD1/5/8 and ERK1/2; qRT-PCR for GDNF in SVOG and primary granulosa-lutein cells Endocrinology Medium 29750278
2014 Recombinant BMP6 inhibits activation of hepatic stellate cells (HSCs) and reduces proinflammatory and profibrogenic gene expression in activated HSCs; steatosis-induced BMP6 upregulation is hepatoprotective, and Bmp6-/- mice develop more severe hepatic fibrosis on MCD and high-fat diets. Bmp6-/- mice on MCD and high-fat dietary models; in vitro primary human HSC treatment with recombinant BMP6; histological analysis of fibrosis Gut Medium 25011936
2007 BMP-6 exerts its osteoinductive effect at least in part through upregulation of IGF-I and EGF pathway gene expression in bone; gene set enrichment analysis and qPCR confirmed IGF-I and EGF upregulation in BMP-6-treated mouse bone and primary human osteoblasts. In vivo gene expression profiling (microarray) in oophorectomized mice treated with BMP-6; gene set enrichment analysis; qPCR confirmation; primary human osteoblast culture International orthopaedics Low 17634942
2022 BMP6 expression in salivary gland monocytic cells in Sjögren's syndrome is stimulated by HSP70 acting as an endogenous TLR4 ligand; HSP70 is released via LAMP3-induced lysosomal exocytosis from epithelial cells. LAMP3 overexpression in mice induces BMP6 expression and an SS-like phenotype. RNA ISH on salivary gland sections; RNA-Seq; single-cell transcriptomics of PBMCs; in vitro TLR4 signaling assays; LAMP3 overexpression in mice; RT-PCR correlation analysis The Journal of clinical investigation Medium 35113815
2007 BMP6 is produced by myotubes and mature Schwann cells and is retrogradely transported in mature motor axons; BMP6 supports motoneuron survival in vitro through BMPRII, which is highly expressed in motoneurons. Laser microdissection of motoneurons for receptor mRNA quantification; immunostaining for BMPRII; retrograde transport assay; in vitro motoneuron survival assay Molecular and cellular neurosciences Medium 17321145
2018 BMP6 signaling through the BMP/SMAD pathway is absolutely required for hepcidin induction by acute serum iron (oral iron gavage), whereas BMP2 plays only a partially redundant role; Bmp6-/- or Bmp6 CKO mice fail to induce hepcidin after oral iron gavage. Global and endothelial conditional Bmp6 knockout mice; acute oral iron gavage; serum iron and liver SMAD5 phosphorylation; hepcidin qRT-PCR American journal of hematology High 30478858
2018 BMP6-induced inhibition of hair follicle telogen-anagen transition is mediated by reciprocal antagonism with Wnt10b: BMP6 overexpression in vivo inhibits hair follicle stem cell activation, suppresses Wnt10b signaling, and is itself suppressed by Wnt10b. Adenovirus-mediated BMP6 overexpression in mouse skin; in situ hybridization; immunofluorescence; BrdU tracing; comparison with AdWnt10b-treated skins Cell communication and signaling Medium 30791955
2014 BMP-6 inhibits MMP-1 expression in breast cancer cells by inhibiting AP-1-mediated transcription; ChIP and luciferase assays show BMP-6 decreases recruitment of c-Jun/c-Fos to the endogenous MMP-1 promoter AP-1 response element, and MMP-1 overexpression rescues BMP-6-mediated inhibition of invasion. Luciferase reporter assay; ChIP assay; RT-PCR; MMP-1 overexpression rescue; Boyden chamber invasion assay Oncology reports Medium 26751737
2010 BMP-6 inhibits MMP-9 secretion in MCF-7 breast cancer cells through upregulation of HO-1 via Smad1/5 recruitment to a Smad-responsive element on the HO-1 promoter; BMP-6/HO-1-mediated MMP-9 suppression operates via MAPK/p38/AP-1 signaling, and HO-1 knockdown abolishes BMP-6 anti-invasive effects. Luciferase reporter assay; ChIP for Smad1/5 on HO-1 promoter; HO-1 knockdown by ZnPPIX; RT-PCR; Boyden chamber assay Journal of cancer research and clinical oncology Medium 21136273
2018 HIF-1α directly represses BMP6 expression by binding to the hypoxia-response element (HRE) in the BMP6 promoter, and HIF-1α-mediated BMP6 suppression promotes hyperproliferation and abnormal differentiation of keratinocytes. HIF-1α overexpression in primary human keratinocytes; luciferase reporter with HRE in BMP6 promoter; ChIP for HIF-1α binding; cell cycle analysis; differentiation markers Experimental dermatology Medium 30230035

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 Involvement of Bone Morphogenetic Protein-4 (BMP-4) and Vgr-1 in morphogenesis and neurogenesis in the mouse. Development (Cambridge, England) 630 1893873
2009 BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nature genetics 609 19252486
2009 Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nature genetics 474 19252488
1989 Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-beta-like genes coordinately regulate aspects of embryonic development. Genes & development 419 2481605
1998 Mice lacking Bmp6 function. Developmental genetics 279 9664685
1996 Effects of BMP-2, BMP-4, and BMP-6 on osteoblastic differentiation of bone marrow-derived stromal cell lines, ST2 and MC3T3-G2/PA6. Biochemical and biophysical research communications 273 8645311
2007 Reduced chondrogenic potential of adipose tissue derived stromal cells correlates with an altered TGFbeta receptor and BMP profile and is overcome by BMP-6. Journal of cellular physiology 261 17238135
2018 Erythroferrone inhibits the induction of hepcidin by BMP6. Blood 222 30097509
2010 Increased BMP6 levels in the brains of Alzheimer's disease patients and APP transgenic mice are accompanied by impaired neurogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 195 20844121
1989 Vgr-1, a mammalian gene related to Xenopus Vg-1, is a member of the transforming growth factor beta gene superfamily. Proceedings of the National Academy of Sciences of the United States of America 175 2734307
2001 Bmp6 and Bmp7 are required for cushion formation and septation in the developing mouse heart. Developmental biology 170 11437450
2020 BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF. Angiogenesis 141 33021694
1994 Recombinant Vgr-1/BMP-6-expressing tumors induce fibrosis and endochondral bone formation in vivo. The Journal of cell biology 131 8089189
2019 Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin. Nature metabolism 119 31276102
2005 Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation. The Journal of biological chemistry 119 16109715
1998 LMP-1, a LIM-domain protein, mediates BMP-6 effects on bone formation. Endocrinology 114 9832452
2009 BMP-6 and mesenchymal stem cell differentiation. Cytokine & growth factor reviews 113 19900832
2012 Estrogen regulates hepcidin expression via GPR30-BMP6-dependent signaling in hepatocytes. PloS one 108 22792339
2017 Bone morphogenetic protein 2 controls iron homeostasis in mice independent of Bmp6. American journal of hematology 95 28815688
2011 Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood 94 21622652
2007 BMP-3 and BMP-6 structures illuminate the nature of binding specificity with receptors. Biochemistry 92 17924656
2009 BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood 91 19622835
2010 BMP6 treatment compensates for the molecular defect and ameliorates hemochromatosis in Hfe knockout mice. Gastroenterology 88 20682319
2007 Sequential roles for myosin-X in BMP6-dependent filopodial extension, migration, and activation of BMP receptors. The Journal of cell biology 88 18158328
2010 BMP-2/6 heterodimer is more effective than BMP-2 or BMP-6 homodimers as inductor of differentiation of human embryonic stem cells. PloS one 86 20567515
2009 BMP-6 inhibits microRNA-21 expression in breast cancer through repressing deltaEF1 and AP-1. Cell research 81 19308091
2012 The transcription factor osterix (SP7) regulates BMP6-induced human osteoblast differentiation. Journal of cellular physiology 80 21898406
2004 The role of BMP-6, IL-6, and BMP-4 in mesenchymal stem cell-dependent bone development: effects on osteoblastic differentiation induced by parathyroid hormone and vitamin D(3). Stem cells and development 80 15186723
2004 Bone morphogenetic protein (BMP)-6 signaling and BMP antagonist noggin in prostate cancer. Cancer research 79 15548695
2002 Ectopic osteogenesis using adenoviral bone morphogenetic protein (BMP)-4 and BMP-6 gene transfer. Molecular therapy : the journal of the American Society of Gene Therapy 76 12377187
2015 Heterozygous Mutations in BMP6 Pro-peptide Lead to Inappropriate Hepcidin Synthesis and Moderate Iron Overload in Humans. Gastroenterology 71 26582087
2014 Evolved tooth gain in sticklebacks is associated with a cis-regulatory allele of Bmp6. Proceedings of the National Academy of Sciences of the United States of America 68 25205810
1995 Vgr-1/BMP-6 induces osteoblastic differentiation of pluripotential mesenchymal cells. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 67 7547504
2007 BMP-6 promotes E-cadherin expression through repressing deltaEF1 in breast cancer cells. BMC cancer 64 17997862
2015 Bmp6 expression in murine liver non parenchymal cells: a mechanism to control their high iron exporter activity and protect hepatocytes from iron overload? PloS one 62 25860887
2010 Does bone morphogenetic protein 6 (BMP6) affect female fertility in the mouse? Biology of reproduction 61 20702851
2008 BMP-6 over-expression in prostate cancer is associated with increased Id-1 protein and a more invasive phenotype. The Journal of pathology 60 18072288
2005 BMP-6 inhibits growth of mature human B cells; induction of Smad phosphorylation and upregulation of Id1. BMC immunology 58 15877825
2014 Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease. Gut 57 25011936
2013 Increased iron loading induces Bmp6 expression in the non-parenchymal cells of the liver independent of the BMP-signaling pathway. PloS one 57 23565256
1992 Isolation of Vgr-2, a novel member of the transforming growth factor-beta-related gene family. Molecular endocrinology (Baltimore, Md.) 57 1480182
2018 Hepcidin-mediated hypoferremic response to acute inflammation requires a threshold of Bmp6/Hjv/Smad signaling. Blood 56 30213871
2002 Bone morphogenetic proteins BMP-6 and BMP-7 have differential effects on survival and neurite outgrowth of cerebellar granule cell neurons. Journal of neuroscience research 55 11948661
2023 Naotaifang formula attenuates OGD/R-induced inflammation and ferroptosis by regulating microglial M1/M2 polarization through BMP6/SMADs signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 53 37713988
2011 Direct delayed human adenoviral BMP-2 or BMP-6 gene therapy for bone and cartilage regeneration in a pony osteochondral model. Osteoarthritis and cartilage 52 21683796
2018 Promoting Induced Pluripotent Stem Cell-driven Biomineralization and Periodontal Regeneration in Rats with Maxillary-Molar Defects using Injectable BMP-6 Hydrogel. Scientific reports 51 29311578
2013 BMP-6 inhibits cell proliferation by targeting microRNA-192 in breast cancer. Biochimica et biophysica acta 51 24012720
2019 The balance of Bmp6 and Wnt10b regulates the telogen-anagen transition of hair follicles. Cell communication and signaling : CCS 50 30791955
2010 Iron overload induces BMP6 expression in the liver but not in the duodenum. Haematologica 50 20952515
1992 A bone morphogenetic protein subfamily: chromosomal localization of human genes for BMP5, BMP6, and BMP7. Genomics 50 1427904
1998 Induction of bone morphogenetic protein-6 in skin wounds. Delayed reepitheliazation and scar formation in BMP-6 overexpressing transgenic mice. The Journal of investigative dermatology 49 9856831
2011 Macrophages induce neuroendocrine differentiation of prostate cancer cells via BMP6-IL6 Loop. The Prostate 44 21374653
2011 Bmp6 regulates retinal iron homeostasis and has altered expression in age-related macular degeneration. The American journal of pathology 43 21703414
2010 The effects of BMP6 overexpression on adipose stem cell chondrogenesis: Interactions with dexamethasone and exogenous growth factors. Journal of biomedical materials research. Part A 42 19722282
2010 FGF-2 abolishes the chondrogenic effect of combined BMP-6 and TGF-beta in human adipose derived stem cells. Journal of biomedical materials research. Part A 42 20730935
2006 BMP-6 inhibits human bone marrow B lymphopoiesis--upregulation of Id1 and Id3. Experimental hematology 42 16413393
2010 Post-treatment circulating plasma BMP6 mRNA and H3K27 methylation levels discriminate metastatic prostate cancer from localized disease. Clinica chimica acta; international journal of clinical chemistry 41 20573596
2019 Suppression of miR-451a accelerates osteogenic differentiation and inhibits bone loss via Bmp6 signaling during osteoporosis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 40 31541885
2015 Cross-Talk Between VEGF and BMP-6 Pathways Accelerates Osteogenic Differentiation of Human Adipose-Derived Stem Cells. Journal of cellular physiology 40 25753222
2023 An H2 S-BMP6 Dual-Loading System with Regulating Yap/Taz and Jun Pathway for Synergistic Critical Limb Ischemia Salvaging Therapy. Advanced healthcare materials 39 37531238
2017 Deletion of BMP6 worsens the phenotype of HJV-deficient mice and attenuates hepcidin levels reached after LPS challenge. Blood 38 29021231
2020 Vitellogenin Receptor (VgR) Mediates Oocyte Maturation and Ovarian Development in the Pacific White Shrimp (Litopenaeus vannamei). Frontiers in physiology 37 32499719
2020 Endothelial Bone Morphogenetic Protein 2 (Bmp2) Knockout Exacerbates Hemochromatosis in Homeostatic Iron Regulator (Hfe) Knockout Mice but not Bmp6 Knockout Mice. Hepatology (Baltimore, Md.) 36 31778583
2017 Identification of new BMP6 pro-peptide mutations in patients with iron overload. American journal of hematology 36 28335084
1995 Developmental alteration and neuron-specific expression of bone morphogenetic protein-6 (BMP-6) mRNA in rodent brain. Brain research. Molecular brain research 35 7707865
2017 Insulin-like growth factor-1 (IGF-1) enhances the osteogenic activity of bone morphogenetic protein-6 (BMP-6) in vitro and in vivo, and together have a stronger osteogenic effect than when IGF-1 is combined with BMP-2. Journal of biomedical materials research. Part A 34 28256809
2014 Quercetin prevents ethanol-induced iron overload by regulating hepcidin through the BMP6/SMAD4 signaling pathway. The Journal of nutritional biochemistry 34 24746831
2020 miR-765 inhibits the osteogenic differentiation of human bone marrow mesenchymal stem cells by targeting BMP6 via regulating the BMP6/Smad1/5/9 signaling pathway. Stem cell research & therapy 32 32059748
2017 Sequential IGF-1 and BMP-6 releasing chitosan/alginate/PLGA hybrid scaffolds for periodontal regeneration. International journal of biological macromolecules 32 28601648
2007 BMP-6 exerts its osteoinductive effect through activation of IGF-I and EGF pathways. International orthopaedics 31 17634942
2020 A fully human anti-BMP6 antibody reduces the need for erythropoietin in rodent models of the anemia of chronic disease. Blood 30 32438400
2010 Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6. Blood 30 20940420
2018 HIF-1α-mediated BMP6 down-regulation leads to hyperproliferation and abnormal differentiation of keratinocytes in vitro. Experimental dermatology 29 30230035
2014 Study of circulating hepcidin in association with iron excess, metabolic syndrome, and BMP-6 expression in granulosa cells in women with polycystic ovary syndrome. Fertility and sterility 29 24875397
2008 The aberrant promoter methylation of BMP3b and BMP6 in malignant pleural mesotheliomas. Oncology reports 29 18949431
2015 BMP-6 inhibits the metastasis of MDA-MB-231 breast cancer cells by regulating MMP-1 expression. Oncology reports 28 26751737
2003 Transcriptional regulation of a BMP-6 promoter by estrogen receptor alpha. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 28 15040833
2023 Liver sinusoidal endothelial cells induce BMP6 expression in response to non-transferrin-bound iron. Blood 27 36351237
2018 BMP6-induced modulation of the tumor micro-milieu. Oncogene 27 30171260
2015 Poly(lactic-co-glycolide) polymer constructs cross-linked with human BMP-6 and VEGF protein significantly enhance rat mandible defect repair. Cell and tissue research 27 26475719
2014 Exogenous BMP7 corrects plasma iron overload and bone loss in Bmp6-/- mice. International orthopaedics 27 25300398
2001 Upregulation of bone morphogenetic protein GDF-3/Vgr-2 expression in adipose tissue of FABP4/aP2 null mice. Cytokine 27 11396990
2019 The role of BMP6 in the proliferation and differentiation of chicken cartilage cells. PloS one 26 31260450
2014 Mechanism of pro-tumorigenic effect of BMP-6: neovascularization involving tumor-associated macrophages and IL-1a. The Prostate 26 24185914
2010 BMP-6 inhibits MMP-9 expression by regulating heme oxygenase-1 in MCF-7 breast cancer cells. Journal of cancer research and clinical oncology 26 21136273
2022 Lysosomal exocytosis of HSP70 stimulates monocytic BMP6 expression in Sjögren's syndrome. The Journal of clinical investigation 25 35113815
2018 BMP6 Downregulates GDNF Expression Through SMAD1/5 and ERK1/2 Signaling Pathways in Human Granulosa-Lutein Cells. Endocrinology 25 29750278
1997 Osteogenic protein-1 stimulates mRNA levels of BMP-6 and decreases mRNA levels of BMP-2 and -4 in human osteosarcoma cells. Calcified tissue international 25 9069169
2018 A novel role of bone morphogenetic protein 6 (BMP6) in glucose homeostasis. Acta diabetologica 24 30539233
2018 Long-term evaluation of osteoarthritis sheep knee, treated with TGF-β3 and BMP-6 induced multipotent stem cells. Experimental gerontology 23 29421350
2018 Iron, erythropoietin, and inflammation regulate hepcidin in Bmp2-deficient mice, but serum iron fails to induce hepcidin in Bmp6-deficient mice. American journal of hematology 23 30478858
2015 A 190 base pair, TGF-β responsive tooth and fin enhancer is required for stickleback Bmp6 expression. Developmental biology 23 25732776
2018 An intronic enhancer of Bmp6 underlies evolved tooth gain in sticklebacks. PLoS genetics 22 29902209
2017 Bone mesenchymal stem cells co-expressing VEGF and BMP-6 genes to combat avascular necrosis of the femoral head. Experimental and therapeutic medicine 22 29399103
2012 Chondrogenesis from umbilical cord blood cells stimulated with BMP-2 and BMP-6. Rheumatology international 22 22238025
2012 BMP-6 and BMPR-1a are up-regulated in the growth plate of the fractured tibia. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 22 23097200
2007 BMP6 is axonally transported by motoneurons and supports their survival in vitro. Molecular and cellular neurosciences 22 17321145
2022 Transcriptomic Analysis Provides Insights to Reveal the bmp6 Function Related to the Development of Intermuscular Bones in Zebrafish. Frontiers in cell and developmental biology 20 35646941
2020 Modulatory effects of TGF-β1 and BMP6 on thecal angiogenesis and steroidogenesis in the bovine ovary. Reproduction (Cambridge, England) 20 31967968
2018 Interaction of Melatonin and BMP-6 in Ovarian Steroidogenesis. Vitamins and hormones 20 29544628