Affinage

Showing GDF2 — BMP9 is a alias.

GDF2

Growth/differentiation factor 2 · UniProt Q9UK05

Length
429 aa
Mass
47.3 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GDF2/BMP9 is a liver-derived circulating homodimeric BMP-family cytokine that signals primarily through the type I receptor ALK1 (ACVRL1) with endoglin as co-receptor to maintain vascular endothelial quiescence and barrier function (PMID:17311849, PMID:22566602, PMID:28564608). After secretion its pro-region remains tightly bound but does not block receptor engagement, and BMP9 binds ALK1 and endoglin with high affinity while engaging type II receptors BMPR-II and ActR-IIA to drive canonical Smad1/5/8 phosphorylation and ID1 induction (PMID:15851468, PMID:17311849, PMID:32576665). Structural work defines a tripartite recognition mechanism conferring BMP9/BMP10 specificity for ALK1, shows that two endoglin copies embrace the BMP9 homodimer in a manner compatible with type I but not type II receptor binding, and reveals that activity and protease susceptibility are tuned by a redox-sensitive intermolecular disulfide bond (PMID:25237187, PMID:28564608, PMID:32238803). In endothelium BMP9 enforces quiescence and limits angiogenesis through ID1, Notch (DLL4/Jagged1/Hey), and endoglin-dependent YAP1 programs, regulates the CXCL12/CXCR4 axis, controls retinal and lymphatic vascular remodeling and ductus arteriosus closure, and preserves vascular barrier integrity in part by repressing CCL2 and modulating endothelin-1/apelin balance (PMID:22566602, PMID:23018639, PMID:23741013, PMID:26056270, PMID:26471266, PMID:25909848, PMID:22299030, PMID:32576665, PMID:33320799). Acting on vascular smooth muscle via ALK1, BMP9 and BMP10 induce and maintain the contractile state and set systemic blood pressure (PMID:33334130), and a non-canonical SMAD-dependent MEKK4/GADD45β/p38 MAPK arm controls additional endothelial gene expression and cell-cycle outputs (PMID:38439036). In mesenchymal cells BMP9 potently drives osteogenic differentiation through Smad1/5/8 with cross-talk from IGF/PI3K-AKT and Notch signaling and protects against osteoblast senescence via a Smad1-STAT1-P21 axis (PMID:20499340, PMID:30353129, PMID:35523787), while in liver it is produced by hepatic stellate cells, promotes fibrosis via SMAD/ID1, and regulates lipid metabolism through PPARα (PMID:28336518, PMID:33246954). Loss-of-function GDF2 mutations impair BMP9 cleavage or secretion, reduce circulating BMP9 and BMP10, and cause pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia with vascular malformations (PMID:30578397, PMID:31661308, PMID:33834622, PMID:34904380); conversely, BMP9 loss protects against chronic hypoxia-induced pulmonary hypertension, reflecting context-dependent roles (PMID:30636542).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2005 High

    Establishing how BMP9 is structured and which receptor it uses defined the molecular starting point for all downstream signaling work.

    Evidence X-ray crystallography at 2.3 Å, SPR binding, and ligand-trap cell assays identifying ALK1 as a BMP9 receptor

    PMID:15851468

    Open questions at the time
    • Did not resolve the receptor stoichiometry or type II receptor identity
    • Pro-region's physiological role left undefined
  2. 2007 High

    Defining the endothelial receptor repertoire and functional output showed BMP9 acts as an anti-angiogenic, quiescence-promoting ligand.

    Evidence Receptor-binding in COS cells plus Smad1/5, ID1, and endothelial proliferation/migration and in vivo angiogenesis assays

    PMID:17311849

    Open questions at the time
    • Downstream transcriptional program incompletely mapped
    • In vivo vascular requirement not yet genetically tested
  3. 2010 Medium

    Cross-talk inputs to BMP9 osteogenic signaling were identified, showing IGF-2/PI3K-AKT potentiates Smad nuclear translocation.

    Evidence ALP, Smad reporter, immunofluorescence, PI3K inhibition, and ectopic bone formation in MSCs; separate work in cholinergic neurons via ALK1

    PMID:20499340 PMID:20554873

    Open questions at the time
    • Single-lab mechanistic dissection
    • Direct biochemical link between AKT and Smad complex not defined
  4. 2012 High

    Genetic and antibody loss-of-function established BMP9 as an in vivo regulator of vascular remodeling and the CXCL12/CXCR4 axis.

    Evidence Bmp9-KO and neutralizing antibody in mice, retinal morphometry, microarray/MS, endoglin/ALK1 siRNA, hindlimb ischemia

    PMID:22566602 PMID:23018639

    Open questions at the time
    • Apelin/Notch regulation mechanism not fully resolved
    • Endoglin-dependence detail single lab
  5. 2013 High

    BMP9's roles expanded to lymphatic maturation and hepatocellular autocrine survival signaling, broadening its functional scope.

    Evidence Bmp9-KO lymphatic morphometry and LEC assays; siRNA and ligand-trap proliferation/apoptosis assays in HepG2

    PMID:23741013 PMID:23936038

    Open questions at the time
    • Tumor relevance of HepG2 autocrine signaling not validated in vivo
    • Valve gene regulation mechanism not detailed
  6. 2014 High

    The redox-controlled disulfide isoform and receptor/Smad requirements for VSMC and granulosa responses clarified how BMP9 activity is tuned and transduced.

    Evidence 1.9 Å crystal structure and redox/protease assays; ALK1/Smad4 siRNA in VSMC calcification; ALK1/BMPR-II in granulosa cells

    PMID:25237187 PMID:25297851 PMID:25527306

    Open questions at the time
    • Physiological enzyme controlling the redox switch not identified
    • VSMC calcification relevance in vivo not established
  7. 2015 Medium

    Mechanistic integration of BMP9 with Notch, YAP1/endoglin, and EPC differentiation programs revealed how quiescence and neovascularization outputs are coordinated, alongside a tumor-suppressive role in epithelial cells.

    Evidence Notch and ALK1-Smad inhibitor combinations, endoglin siRNA with zyxin/YAP1 imaging, EPC differentiation with ALK1 blockade, receptor co-IP and anoikis assays

    PMID:25909848 PMID:26229139 PMID:26471266 PMID:26678910

    Open questions at the time
    • Pathway interdependence largely single-lab pharmacology
    • ALK3/ALK6 usage in epithelium contrasts with endothelial ALK1 and is not reconciled
  8. 2015 High

    BMP9 and BMP10 were shown to cooperatively drive ductus arteriosus closure via endothelial-to-mesenchymal differentiation.

    Evidence Bmp9-KO with anti-BMP10 neutralization, TEM, immunofluorescence, gene expression

    PMID:26056270

    Open questions at the time
    • Specific ECM/differentiation genes mediating closure not pinpointed
  9. 2017 High

    The endoglin:BMP9 crystal structure mapped a disease-relevant binding interface and clarified that endoglin engagement is compatible only with type I receptor binding.

    Evidence X-ray crystallography of ENG ectodomain and ENG:BMP9 complex; non-canonical Smad1/p38 ET-1 release in PAECs; HSC-derived BMP9 driving liver fibrosis

    PMID:22299030 PMID:28336518 PMID:28564608

    Open questions at the time
    • How endoglin presents BMP9 to type II receptors mechanistically unresolved
    • Source of circulating vs local BMP9 contributions not fully separated
  10. 2018 Medium

    BMP9/ALK1 was established as a barrier-protective signal in diabetic vasculature and a Notch-dependent osteogenic driver.

    Evidence Hyperglycemic endothelial model, STZ diabetic and Alk1 haploinsufficient mice, AAV BMP9 delivery; Notch inhibitor and dominant-negative Notch1 in MSC osteogenesis

    PMID:29880487 PMID:30353129

    Open questions at the time
    • VE-cadherin/occludin regulation mechanism single lab
    • Notch intermediate-stage requirement not biochemically defined
  11. 2019 High

    Patient genetics and protein biochemistry linked GDF2 loss-of-function to pulmonary hypertension while redefining soluble endoglin as a signaling partner rather than an inhibitory trap; paradoxically, BMP9 loss protected against hypoxic PH.

    Evidence Exome sequencing with secretion/apoptosis assays in PAECs; purified sENG:BMP9 reconstitution; Bmp9-KO/antibody/ALK1ECD across multiple PH models

    PMID:30578397 PMID:30636542 PMID:31431534

    Open questions at the time
    • Protective vs causative roles of BMP9 in PH not mechanistically reconciled
    • sENG complex physiological abundance unclear
  12. 2020 High

    Structural specificity, receptor internalization, VSMC contractility control, hepatic metabolism, and the BMP9/BMP10 interdependence in mutation carriers were defined, yielding a systems-level view.

    Evidence BMP9/BMP10:ALK1 crystal structures with mutagenesis; CAV-1/DNM2 endocytosis and LDL transcytosis assays; conditional Bmp9/Bmp10 and VSMC-Alk1 KO with blood pressure; CRISPR BMP9-KO hepatosteatosis with PPARα; CCL2 receptor dissection; GDF2 mutation plasma BMP9/BMP10 ELISA

    PMID:31661308 PMID:32238803 PMID:32576665 PMID:33097593 PMID:33246954 PMID:33334130

    Open questions at the time
    • Vessel-bed-specific receptor combinations only partially mapped
    • Mechanism coupling BMP9 loss to BMP10 reduction unresolved
  13. 2021 High

    Circulating BMP9 was confirmed as a barrier-protective factor in lung injury, with mutation studies and FOXF1 transcriptional control further defining its production and downstream programs, plus roles in osteoblast senescence and HCC stemness.

    Evidence Anti-BMP9 antibody and LPS lung injury with patient plasma; nonsense-mutation plasma ELISA/bioassay; FOXF1/FLI1 ACVRL1 promoter and neonatal lung models; Smad1-STAT1-P21 in aged mice; BMP9-ID1 Wnt in HCC

    PMID:33320799 PMID:33834612 PMID:33834622 PMID:34904380 PMID:35440116 PMID:35523787

    Open questions at the time
    • Hepatic regulation of BMP9 during injury incompletely characterized
    • FOXF1-BMP9 axis specificity beyond lung not tested
  14. 2022 High

    Comparative genetics dissected BMP9 from BMP10, showing BMP10 is the dominant physiological ENG-ALK1 ligand for arteriovenous network formation.

    Evidence Conditional Bmp10-iKO, Bmp9/10-dKO, and Eng-iKO mice with retinal/AVM morphometry and protein rescue

    PMID:36348215

    Open questions at the time
    • Why GDF2 mutations cause HHT despite limited BMP9 vascular requirement not reconciled
  15. 2024 Medium

    A non-canonical SMAD-dependent MEKK4/GADD45β/p38 MAPK arm was defined, expanding BMP9/BMP10 signaling beyond canonical Smad transcription.

    Evidence Phosphoproteomics with western blot validation, RT-qPCR, and cell-cycle flow cytometry in endothelial cells

    PMID:38439036

    Open questions at the time
    • In vivo relevance of the p38 arm not established
    • Single-lab phosphoproteomic dataset

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular basis for the coupled loss of circulating BMP10 when GDF2/BMP9 is mutated, and the reconciliation of BMP9's protective versus pathogenic roles across vascular beds, remain unresolved.
  • No mechanism linking BMP9 loss to reduced BMP10 stability/secretion
  • Vessel-bed-specific protective vs harmful BMP9 effects not unified
  • Therapeutic targeting window in PAH/HHT undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-109582 Hemostasis 2
Partners
ACVR1ACVR2AACVRL1BMP10BMPR2ENG

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 BMP9 (GDF2) crystal structure resolved to 2.3 Å; the pro-region remains tightly associated with BMP9 after secretion but does not inhibit receptor binding or biological activity in cell-based assays. ALK1 identified as a receptor for BMP9 by surface plasmon resonance (BIAcore) and functional neutralization with soluble ALK1. X-ray crystallography (2.3 Å), surface plasmon resonance (BIAcore), cell-based activity assays with soluble ALK1 as ligand trap The Journal of biological chemistry High 15851468
2007 BMP9 binds with high affinity to ALK1 and endoglin, and weakly to ALK2 and BMPR-II/ActR-II in transfected COS cells; in endothelial cells BMP9 signals predominantly via ALK1 and BMPR-II, activating Smad1/5 and inducing ID1 protein and endoglin mRNA. BMP9 inhibits bFGF-stimulated endothelial cell proliferation/migration and blocks VEGF-induced angiogenesis. Receptor-binding assays in transfected COS cells, western blot (Smad1/5 phosphorylation), qRT-PCR, endothelial cell proliferation/migration assays, in vivo angiogenesis assay Journal of cell science High 17311849
2010 BMP9 induces NGF expression selectively in cholinergic (Chat-positive/p75-positive) basal forebrain neurons via ALK1; secreted NGF acts in an autocrine/paracrine manner to support acetylcholine production and ChAT gene expression. BMP9-induced Ngf expression requires new protein synthesis and is blocked by BMP type I receptor inhibition. Primary embryonic septal cell culture, FACS isolation of cholinergic neurons (GFP/p75), RT-PCR, pharmacological inhibition of BMP type I receptors, NGF ELISA The Journal of neuroscience Medium 20554873
2010 IGF-2 potentiates BMP9-induced osteogenic differentiation of mesenchymal stem cells by enhancing BMPR-Smad reporter activity and Smad1/5/8 nuclear translocation via PI3K/AKT signaling; PI3K inhibitor LY294002 abolishes this cross-talk and directly inhibits BMP9 activity. Alkaline phosphatase activity assay, Smad reporter assays, Smad1/5/8 nuclear translocation (immunofluorescence), pharmacological PI3K inhibition, ectopic bone formation in vivo Journal of bone and mineral research Medium 20499340
2012 BMP9 is required for postnatal retinal vascular remodeling; neutralizing anti-BMP9 antibody increases retinal vascular density. BMP9 promotes endothelial quiescence and upregulates Notch pathway genes (Jagged1, Dll4, Hey1, Hey2, Hes1) while decreasing apelin expression in endothelial cells. Neutralizing antibody treatment in neonatal mice, Bmp9-KO mice, retinal vascular morphometry, gene expression analysis Blood High 22566602
2012 BMP9 regulates the CXCL12/SDF1-CXCR4 chemokine axis in endothelial cells in an endoglin- and ALK1-dependent manner; RNA knockdown of endoglin or ALK1 impairs SDF1/CXCR4 regulation by BMP9 and impairs SDF1 expression in vivo in endoglin-deficient mice. cDNA microarray, quantitative mass spectrometry, siRNA knockdown of endoglin and ALK1, hindlimb ischemia mouse model Blood Medium 23018639
2013 BMP9 promotes proliferation and survival (anti-apoptotic function) in HepG2 hepatocellular carcinoma cells via autocrine signaling, activating Smad1/5/8 phosphorylation and Id1 upregulation; BMP9 also triggers cell cycle progression in these cells. siRNA knockdown, chemical inhibitors (ligand trap), proliferation assays, apoptosis assays (low-serum), Smad1/5/8 phosphorylation western blot PloS one Medium 23936038
2013 BMP9 controls lymphatic vessel maturation and valve formation via ALK1; Bmp9-KO mice show hyperplastic mesenteric collecting vessels retaining LYVE-1 expression, and BMP9 inhibits LYVE-1 expression in lymphatic endothelial cells in an ALK1-dependent manner. BMP9 upregulates valve formation genes (Foxc2, Connexin37, EphrinB2, Neuropilin1) in LECs. Bmp9-KO mice, lymphatic vessel morphometry, in vitro LEC treatment with BMP9, ALK1 dependency confirmed by inhibition, lymphatic drainage assay Blood High 23741013
2014 BMP9 induces VSMC osteogenic differentiation and calcification via ALK1 and Smad-dependent pathways; BMP9 activates Smad1/5/8 and Smad2/3 phosphorylation, both of which bind Smad4 to activate target genes. Smad4 siRNA knockdown significantly reduces BMP9-induced ALP activity and calcium deposition. In vitro VSMC calcification assay, soluble ALK1 chimeric protein inhibition, Smad siRNA, ALP inhibitor, western blot for Smad phosphorylation Journal of cellular and molecular medicine Medium 25297851
2014 BMP9 stability and activity are regulated by a redox-dependent mechanism: BMP9 dimers form with (D-form, disulfide-bonded) or without (M-form) an intermolecular disulfide bond, resolved by a 1.9 Å crystal structure. The M-form shows less sustained Smad1/5/8 phosphorylation and greater susceptibility to redox-dependent protease cleavage from serum. Chromatography, X-ray crystallography (1.9 Å), redox conversion assays, Smad1/5/8 phosphorylation kinetics, protease susceptibility assays The Journal of biological chemistry High 25237187
2014 BMP9 potently suppresses FSH-induced progesterone production in rat granulosa cells via a receptor complex of ALK1 and BMPR-II, activating Smad1/5/8 phosphorylation and Id-1 transcription; actions are not mediated by ALK2, ALK3, or ALK6 based on inhibitor analysis. Rat primary granulosa cell culture, ALK inhibitors, extracellular domain receptor constructs for receptor identification, Smad1/5/8 phosphorylation assay, cAMP measurement, steroidogenic gene expression The Journal of steroid biochemistry and molecular biology Medium 25527306
2015 BMP9 and BMP10 are required for ductus arteriosus closure; Bmp9-KO mice show imperfect DA closure, and combined BMP10 neutralization causes reopening. The mechanism involves a defect in intimal cell differentiation from endothelium to mesenchyme with lack of extracellular matrix deposition; several genes involved in this process are regulated by BMP9 and BMP10. Bmp9-KO mice, neutralizing anti-BMP10 antibody, transmission electron microscopy, immunofluorescence, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 26056270
2015 DLL4/Notch1 and BMP9/ALK1 signaling pathways are interdependent for induction of endothelial quiescence: canonical BMP9 signaling via ALK1-Smad1/5/9 is disrupted by Notch inhibition, and DLL4 activity is suppressed when basal ALK1-Smad pathway is inhibited. The combined pathway acts through P27KIP1 induction and thrombospondin-1 upregulation. Loss of Dll4 in vivo leads to compensatory upregulation of pSmad1/5/9. Human endothelial cell culture, Notch inhibitors, ALK1-Smad pathway inhibitors, proteomics, Dll4(+/-) mouse lung endothelial cell analysis Arteriosclerosis, thrombosis, and vascular biology Medium 26471266
2015 BMP9-induced endothelial quiescence requires endoglin expression; endoglin regulates subcellular localization of zyxin in focal adhesions in response to BMP9. BMP9-dependent nuclear localization of YAP1 (Hippo pathway transcriptional coactivator) occurs via endoglin, modulating expression of CCN1, CCN2, and CCL2. RNA knockdown of endoglin, confocal immunofluorescence of zyxin/YAP1 localization, gene expression analysis (YAP1 target genes) PloS one Medium 25909848
2015 BMP9 induces EPC-to-endothelial cell differentiation and neovascularization via ALK1; blockade of ALK1 signaling impairs EPC-mediated neovascularization in a hindlimb ischemia model. Gene expression profiling of EPCs, in vitro ALK1-dependent differentiation assay, hindlimb ischemia mouse model, ALK1 signaling blockade Arteriosclerosis, thrombosis, and vascular biology Medium 26229139
2015 In ovarian and breast epithelial cells, GDF2/BMP9 activates the SMAD1/5 signaling axis through increased complex formation between ALK3/ALK6 (type I receptors) and BMPRII (type II receptor); this activation promotes anoikis sensitivity and suppresses anchorage-independent growth, independent of SMAD2 cross-talk. GDF2 promoter methylation silences this tumor-suppressive function in cancer cell lines. Receptor co-immunoprecipitation, SMAD1/5 phosphorylation assays, anchorage-independent growth assays, promoter methylation analysis Neoplasia (New York, N.Y.) Medium 26678910
2017 Crystal structure of the human endoglin ectodomain in complex with BMP9 resolved; BMP9 interacts with a hydrophobic surface of the N-terminal orphan domain of endoglin. The interface involves HHT1-mutated residues and overlaps with the TRC105 antibody epitope. Structurally, two endoglin copies embrace homodimeric BMP9 in a manner compatible with type I but not type II receptor binding. X-ray crystallography of ENG ectodomain and ENG:BMP9 complex Cell reports High 28564608
2017 BMP9 stimulates ET-1 release from human pulmonary artery endothelial cells via Smad1 and p38 MAPK, independent of the canonical Smad4 pathway; ALK1 or BMPR-II knockdown attenuates BMP9-stimulated ET-1 release. BMP9-induced ET-1 is involved in inhibition of endothelial cell migration and promotion of tubule formation. Western blot, RT-PCR, ELISA, siRNA knockdown of ALK1 and BMPR-II, migration assay, tubule formation assay PloS one Medium 22299030
2017 BMP9 promotes liver fibrosis via SMAD/ID1 signaling directly in hepatic stellate cells; hepatic stellate cells (quiescent and activated) are identified as major BMP9-producing cells in the liver. Adenovirus-mediated Bmp9 knockdown or BMP9 antagonist ALK1-Fc attenuates fibrosis in chronic liver injury mouse models. Primary liver cell culture, BMP9 stimulation of HSCs and hepatocytes, partial hepatectomy and CCl4 mouse models, adenoviral Bmp9 knockdown, anti-BMP9 monoclonal antibody, SMAD signaling western blot Gut High 28336518
2018 BMP9/ALK1 signaling prevents hyperglycemia-induced vascular permeability by preventing VEGF-induced VE-cadherin phosphorylation and by inducing occludin expression; ALK1 haploinsufficiency worsens vascular leakage in diabetic mice, and adenoviral BMP9 delivery reduces retinal barrier dysfunction. In vitro hyperglycemic endothelial cell model, streptozotocin diabetic mouse model, Alk1 haploinsufficient mice, adenoviral BMP9 delivery, VE-cadherin phosphorylation western blot, occludin expression assay Arteriosclerosis, thrombosis, and vascular biology Medium 29880487
2018 BMP9-induced osteoblastic differentiation in MSCs requires functional Notch signaling; Notch inhibitor and dominant-negative Notch1 inhibit BMP9-induced osteogenic differentiation in vitro and ectopic bone formation in vivo. BMP9 upregulates expression of Notch receptors and ligands at the intermediate stage of osteogenic differentiation, while early-responsive BMP9 target genes are not affected by Notch disruption. Notch inhibitor treatment, dominant-negative Notch1 expression, Notch pathway genetic disruption, in vivo ectopic bone formation, gene expression analysis Laboratory investigation Medium 30353129
2019 Soluble endoglin (sENG) purified from human placenta and plasma is primarily monomeric; monomeric sENG binds circulating prodomain-bound BMP9, causing prodomain release and formation of a sENG:BMP9 complex. This complex signals with comparable potency and specificity to BMP9 alone on endothelial cells; full signaling requires transmembrane ENG. Thus sENG does not act as an inhibitory ligand trap for BMP9. Protein purification, biochemical characterization (size exclusion chromatography), in vitro endothelial cell signaling assay, prodomain release assay Proceedings of the National Academy of Sciences of the United States of America High 31431534
2019 Loss of BMP9 (genetic deletion or antibody neutralization) substantially protects against chronic hypoxia-induced pulmonary hypertension in mice. BMP9 affects the balance between endothelin-1, apelin, and adrenomedullin in pulmonary endothelial cells; Bmp9-/- mice show lower ET-1 and higher apelin/ADM mRNA. BMP9-mediated vasoconstriction is inhibited by the endothelin receptor antagonist bosentan. Bmp9-/- mouse model, neutralizing anti-BMP9 antibodies, ALK1ECD ligand trap in monocrotaline/SuHx rat models, right ventricular systolic pressure measurement, in vitro human pulmonary endothelial cells, chick chorioallantoic membrane assay Circulation research High 30636542
2019 BMP9 mutations (missense) identified in IPAH patients impair BMP9 secretion and reduce anti-apoptotic activity in pulmonary arterial endothelial cells; patients with BMP9 mutations have lower plasma BMP9 levels. Exome sequencing, in vitro mutant protein expression, secretion assay, apoptosis assay in PAECs, plasma BMP9 ELISA The European respiratory journal Medium 30578397
2020 Crystal structures of BMP10:ALK1 complex (2.3 Å) and prodomain-bound BMP9:ALK1 complex (3.3 Å) reveal a tripartite recognition mechanism defining BMP9/BMP10 specificity for ALK1. Introduction of BMP10-specific residues into BMP9 yields ligands with diminished C2C12 signaling, validating the mechanism. Crossveinless 2 is predicted and experimentally confirmed not to inhibit BMP9. X-ray crystallography (2.3 Å and 3.3 Å), mutagenesis (BMP10 residues introduced into BMP9), C2C12 signaling assay, in vivo bone formation assay Nature communications High 32238803
2020 GDF2 missense mutations found in PAH patients cause impaired BMP9 cellular processing and secretion; patients carrying these mutations have reduced plasma BMP9 levels and reduced BMP activity. Unexpectedly, plasma BMP10 levels are also markedly reduced in individuals with GDF2 mutations. In vitro mutant BMP9 protein expression, secretion assay, plasma ELISA for BMP9 and BMP10, endothelial Smad signaling bioassay American journal of respiratory and critical care medicine Medium 31661308
2020 BMP9 and BMP10 act directly on vascular smooth muscle cells (VSMCs) via ALK1 to induce and maintain the contractile state; combined genetic inactivation of Bmp9 and Bmp10 causes decreased systemic blood pressure and diminished VSMC layer. ALK1 deletion in VSMCs recapitulates the Bmp9/10 phenotype in pulmonary but not aortic arteries, indicating vessel-bed specific receptor combinations. Cell-type specific conditional KO mouse models, blood pressure measurement, pulmonary VSMC isolation and phenotypic analysis, single molecule FISH, bulk RNA-seq, Smad7 VSMC-specific overexpression Circulation High 33334130
2020 BMP9-induced ALK1 endocytosis in endothelial cells is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin; knockdown of CAV-1 reduces BMP9-mediated ALK1 internalization, BMP9-dependent Smad1/5 signaling and gene expression. BMP9 treatment strongly reduces LDL transcytosis via ALK1 internalization. Endothelial cell imaging, siRNA knockdown of CAV-1/DNM2/clathrin, SMAD1/5 phosphorylation western blot, LDL transcytosis assay The Journal of biological chemistry Medium 33097593
2020 CRISPR-mediated BMP9 ablation in mice causes hepatosteatosis due to downregulated PPARα expression and reduced fatty acid oxidation; BMP9 activates PPARα promoter activity via p-Smad signaling. AAV-mediated BMP9 overexpression in mouse liver relieves liver steatosis. CRISPR BMP9 knockout mice, lipid accumulation assays, PPARα promoter activity assay, p-Smad western blot, PPARα antagonist GW6471, AAV-mediated overexpression Science advances High 33246954
2020 BMP9 and BMP10 repress basal CCL2 expression and release from human pulmonary artery and aortic endothelial cells via ALK1, co-dependent on ACTR-IIA and BMPR-II, and requiring Smad4; Smad1/5 signaling contributes only at near-circulating BMP9 concentrations. siRNA knockdown of ALK1, ACTR-IIA, BMPR-II, Smad4; Smad1/5 inhibition; CCL2 ELISA; Smad signaling western blot Journal of cell science Medium 32576665
2021 Endogenous circulating BMP9 is a pulmonary endothelial-protective factor that maintains vascular barrier function; BMP9 neutralization in mice increases lung vascular permeability, interstitial edema, and neutrophil extravasation. During LPS-induced lung injury, circulating BMP9 is markedly reduced due to decreased hepatic BMP9 mRNA and increased elastase activity. Exogenous BMP9 prevents LPS-induced lung injury. BMP9-neutralizing antibody in mice, lung vascular permeability assay, neutrophil extravasation measurement, murine acute lung injury (inhaled LPS) model, hepatic BMP9 mRNA quantification, plasma elastase activity, patient plasma BMP9 ELISA American journal of respiratory and critical care medicine High 33320799
2021 Homozygous GDF2 nonsense mutations result in undetectable plasma BMP9 and BMP10 levels, demonstrating that loss of circulating BMP9 also abolishes circulating BMP10; heterozygous carriers have reduced but functional BMP9/BMP10 levels. Alternate translation at Met57 in one nonsense mutant does not yield secreted functional BMP9. Plasma ELISA for BMP9 and BMP10, endothelial BRE-luciferase reporter serum bioassay, in vitro mutant protein expression and secretion assay Molecular genetics & genomic medicine Medium 33834622
2021 BMP9 reduces osteoblast senescence by activating Smad1, which suppresses STAT1 transcriptional activity and thereby inhibits P21 expression and SASP production; this Smad1-Stat1-P21 axis mediates BMP9's protection against age-related bone loss in aged mice. Aged mouse model, Smad1 signaling inhibition in vivo, Stat1 and P21 expression analysis, SASP markers, bone mass measurement Cell death discovery Medium 35523787
2021 BMP9-ID1 signaling promotes EpCAM-positive HCC cancer stem cell properties via enhancing Wnt/β-catenin signaling; ID1 knockdown represses BMP9-promoted HCC-CSC properties. BMP receptor inhibitors (K02288, LDN-212854) block BMP9-ID1 signaling and suppress HCC tumor growth in vivo. siRNA knockdown of ID1, BMP receptor inhibitor treatment, EpCAM/ID1 expression, in vivo HCC xenograft, Wnt/β-catenin signaling assay Molecular oncology Medium 33834612
2022 FOXF1 transcription factor activates BMP9/ACVRL1/SMAD1 signaling in pulmonary endothelial progenitor cells; FOXF1 synergizes with ETS transcription factor FLI1 to activate the ACVRL1 promoter. Nanoparticle-mediated ACVRL1 silencing in newborn mice decreases neonatal lung angiogenesis, and exogenous BMP9 restores angiogenesis in ACVRL1-deficient and Foxf1 mutant mice. scRNA-seq, Foxf1 mutant mice (ACDMPV model), ACVRL1 promoter activation assay, nanoparticle siRNA knockdown in neonatal mice, BMP9 rescue treatment Nature communications High 35440116
2022 BMP10 is the critical physiological ligand for ENG-ALK1 arteriovenous network formation, while BMP9 has limited compensatory function; Bmp10-iKO mice develop AVMs while Bmp9-KO mice show no noticeable vascular defects. BMP10 protein (but not BMP9 protein) prevents retinal AVM in Bmp9/10-dKO and endothelial Eng-iKO mice. Conditional Bmp10-iKO and Bmp9/10-dKO mouse models, retinal vascular morphometry, brain/skin AVM analysis, BMP9 and BMP10 protein rescue injections Angiogenesis High 36348215
2024 BMP9 and BMP10 activate a non-canonical transcriptional SMAD-dependent MAPK pathway (MEKK4/GADD45β/P38) in endothelial cells, which is required for expression of GADD45β; activated P38 phosphorylates HSP27 and Eps15, and regulates specific gene expression (E-selectin, hyaluronan synthase 2, COX-2). BMP10 induces G1 cell cycle arrest by modulating CDK4/6 pathway and inhibiting E2F2, cyclinD1, cyclinA1 mRNA expression. Large-scale phosphoproteomics, western blot validation of phosphosites, RT-qPCR, flow cytometry cell cycle analysis Cell communication and signaling Medium 38439036
2021 A heterozygous GDF2 variant causes HHT with pulmonary AVMs; in vitro, the mutant construct expresses the proprotein but lacks active mature BMP9 dimer, indicating the mutation disrupts correct protein cleavage. Plasma BMP9 levels in patients are significantly lower than controls. In vitro mutant BMP9 expression, protein processing/cleavage assay, plasma BMP9 ELISA American journal of medical genetics. Part A Medium 34904380

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. Journal of cell science 441 17311849
2005 Crystal structure of BMP-9 and functional interactions with pro-region and receptors. The Journal of biological chemistry 244 15851468
2010 Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 230 20499340
2001 BMP-2 and BMP-9 promotes chondrogenic differentiation of human multipotential mesenchymal cells and overcomes the inhibitory effect of IL-1. Journal of cellular physiology 214 11748585
2012 BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood 205 22566602
2013 BMP9 signaling in stem cell differentiation and osteogenesis. American journal of stem cells 160 23671813
2010 BMP-9 induces proliferation of multiple types of endothelial cells in vitro and in vivo. Journal of cell science 143 20406889
2011 BMP-9 induced osteogenic differentiation of mesenchymal stem cells: molecular mechanism and therapeutic potential. Current gene therapy 142 21453282
2017 BMP-9 interferes with liver regeneration and promotes liver fibrosis. Gut 131 28336518
2017 Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1. Cell reports 123 28564608
2013 Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation. Blood 117 23741013
2019 Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension. The European respiratory journal 116 30578397
2019 Selective BMP-9 Inhibition Partially Protects Against Experimental Pulmonary Hypertension. Circulation research 107 30636542
2020 Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine 103 31661308
2015 Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia. Frontiers in genetics 98 25620979
2019 The wonders of BMP9: From mesenchymal stem cell differentiation, angiogenesis, neurogenesis, tumorigenesis, and metabolism to regenerative medicine. Genes & diseases 96 32042861
2019 Role of soluble endoglin in BMP9 signaling. Proceedings of the National Academy of Sciences of the United States of America 69 31431534
2012 BMP9 regulates endoglin-dependent chemokine responses in endothelial cells. Blood 69 23018639
2020 Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms. Nature communications 68 32238803
2018 BMP9-induced osteoblastic differentiation requires functional Notch signaling in mesenchymal stem cells. Laboratory investigation; a journal of technical methods and pathology 64 30353129
2013 BMP9 is a proliferative and survival factor for human hepatocellular carcinoma cells. PloS one 64 23936038
2020 BMP9 and BMP10 Act Directly on Vascular Smooth Muscle Cells for Generation and Maintenance of the Contractile State. Circulation 63 33334130
2021 BMP9 and BMP10: Two close vascular quiescence partners that stand out. Developmental dynamics : an official publication of the American Association of Anatomists 62 34240497
2014 BMP-9 regulates the osteoblastic differentiation and calcification of vascular smooth muscle cells through an ALK1 mediated pathway. Journal of cellular and molecular medicine 62 25297851
2022 Different cardiovascular and pulmonary phenotypes for single- and double-knock-out mice deficient in BMP9 and BMP10. Cardiovascular research 60 34086873
2021 Circulating BMP9 Protects the Pulmonary Endothelium during Inflammation-induced Lung Injury in Mice. American journal of respiratory and critical care medicine 56 33320799
2015 DLL4/Notch1 and BMP9 Interdependent Signaling Induces Human Endothelial Cell Quiescence via P27KIP1 and Thrombospondin-1. Arteriosclerosis, thrombosis, and vascular biology 55 26471266
2015 Mutations in RASA1 and GDF2 identified in patients with clinical features of hereditary hemorrhagic telangiectasia. Human genome variation 55 27081547
2015 BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus. Proceedings of the National Academy of Sciences of the United States of America 54 26056270
2014 BMP9 inhibits proliferation and metastasis of HER2-positive SK-BR-3 breast cancer cells through ERK1/2 and PI3K/AKT pathways. PloS one 54 24805814
2001 Morphologic analysis of BMP-9 gene therapy-induced osteogenesis. Human gene therapy 54 11426468
2013 BMP9 and COX-2 form an important regulatory loop in BMP9-induced osteogenic differentiation of mesenchymal stem cells. Bone 53 23981660
2022 Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling. Nature communications 52 35440116
2014 BMP-9 as a potent brown adipogenic inducer with anti-obesity capacity. Biomaterials 50 24439409
2014 Potential roles of bone morphogenetic protein (BMP)-9 in human liver diseases. International journal of molecular sciences 50 24670474
2011 BMP9 inhibits the proliferation and invasiveness of breast cancer cells MDA-MB-231. Journal of cancer research and clinical oncology 50 21892652
2021 Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations. American journal of medical genetics. Part A 49 34904380
2020 Osteogenic differentiation cues of the bone morphogenetic protein-9 (BMP-9) and its recent advances in bone tissue regeneration. Materials science & engineering. C, Materials for biological applications 48 33545890
2020 Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis. EBioMedicine 47 32454407
2018 BMP9 (Bone Morphogenetic Protein-9)/Alk1 (Activin-Like Kinase Receptor Type I) Signaling Prevents Hyperglycemia-Induced Vascular Permeability. Arteriosclerosis, thrombosis, and vascular biology 47 29880487
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 47 28214873
2016 Regulation of the ALK1 ligands, BMP9 and BMP10. Biochemical Society transactions 47 27528761
2016 Bone morphogenetic protein 9 (BMP9) induces effective bone formation from reversibly immortalized multipotent adipose-derived (iMAD) mesenchymal stem cells. American journal of translational research 47 27725853
2020 Dysregulation of BMP9/BMPR2/SMAD signalling pathway contributes to pulmonary fibrosis and pulmonary hypertension induced by bleomycin in rats. British journal of pharmacology 46 33080042
2012 BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production. PloS one 45 22299030
2020 BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 43 31914211
2020 Leptin Potentiates BMP9-Induced Osteogenic Differentiation of Mesenchymal Stem Cells Through the Activation of JAK/STAT Signaling. Stem cells and development 43 32041483
2017 Targeting secreted cytokine BMP9 gates the attenuation of hepatic fibrosis. Biochimica et biophysica acta. Molecular basis of disease 41 29223735
2014 Regulation of bone morphogenetic protein 9 (BMP9) by redox-dependent proteolysis. The Journal of biological chemistry 41 25237187
2016 LPS-stimulated inflammation inhibits BMP-9-induced osteoblastic differentiation through crosstalk between BMP/MAPK and Smad signaling. Experimental cell research 39 26794904
2010 BMP9 (bone morphogenetic protein 9) induces NGF as an autocrine/paracrine cholinergic trophic factor in developing basal forebrain neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 39 20554873
2020 CRISPR-mediated BMP9 ablation promotes liver steatosis via the down-regulation of PPARα expression. Science advances 38 33246954
2019 Dentinogenesis and Tooth-Alveolar Bone Complex Defects in BMP9/GDF2 Knockout Mice. Stem cells and development 38 30816068
2014 Potential roles of BMP9 in liver fibrosis. International journal of molecular sciences 38 25393508
2022 BMP9-ID1 Signaling Activates HIF-1α and VEGFA Expression to Promote Tumor Angiogenesis in Hepatocellular Carcinoma. International journal of molecular sciences 35 35163396
2021 Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an "HHT-like" syndrome in children. Molecular genetics & genomic medicine 35 33834622
2015 BMP9 Crosstalk with the Hippo Pathway Regulates Endothelial Cell Matricellular and Chemokine Responses. PloS one 35 25909848
2020 BMP9 signaling promotes the normalization of tumor blood vessels. Oncogene 32 32042114
2018 BMP9 Promotes the Proliferation and Migration of Bladder Cancer Cells through Up-Regulating lncRNA UCA1. International journal of molecular sciences 31 29642505
2018 FAK and BMP-9 synergistically trigger osteogenic differentiation and bone formation of adipose derived stem cells through enhancing Wnt-β-catenin signaling. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 31 29909342
2018 BMP9 counteracts the tumorigenic and pro-angiogenic potential of glioblastoma. Cell death and differentiation 31 29977042
2015 BMP9 Induces Cord Blood-Derived Endothelial Progenitor Cell Differentiation and Ischemic Neovascularization via ALK1. Arteriosclerosis, thrombosis, and vascular biology 31 26229139
2019 Highly expressed BMP9/GDF2 in postnatal mouse liver and lungs may account for its pleiotropic effects on stem cell differentiation, angiogenesis, tumor growth and metabolism. Genes & diseases 30 32215293
2022 BMP10 functions independently from BMP9 for the development of a proper arteriovenous network. Angiogenesis 28 36348215
2020 BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in endothelial cells. The Journal of biological chemistry 28 33097593
2016 Effects of BMP-9 and BMP-2 on the PI3K/Akt Pathway in MC3T3-E1 Preosteoblasts. Tissue engineering. Part A 28 27477105
2021 CHRDL2 promotes osteosarcoma cell proliferation and metastasis through the BMP-9/PI3K/AKT pathway. Cell biology international 27 33245175
2019 FAK mediates BMP9-induced osteogenic differentiation via Wnt and MAPK signaling pathway in synovial mesenchymal stem cells. Artificial cells, nanomedicine, and biotechnology 27 31240956
2021 BMP9-ID1 signaling promotes EpCAM-positive cancer stem cell properties in hepatocellular carcinoma. Molecular oncology 25 33834612
2020 Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells. Journal of cell science 24 32576665
2015 Epigenetic Regulation of GDF2 Suppresses Anoikis in Ovarian and Breast Epithelia. Neoplasia (New York, N.Y.) 24 26678910
2024 Disrupted BMP-9 Signaling Impairs Pulmonary Vascular Integrity in Hepatopulmonary Syndrome. American journal of respiratory and critical care medicine 23 38626313
2015 BMP9-Induced Survival Effect in Liver Tumor Cells Requires p38MAPK Activation. International journal of molecular sciences 23 26343646
2014 Regulatory role of BMP-9 in steroidogenesis by rat ovarian granulosa cells. The Journal of steroid biochemistry and molecular biology 23 25527306
2020 New insights into BMP9 signaling in organ fibrosis. European journal of pharmacology 22 32574673
2016 BMP-9 enhances fibroblast growth factor 21 expression and suppresses obesity. Biochimica et biophysica acta 22 27085971
2016 Identification of bone morphogenetic protein 9 (BMP9) as a novel profibrotic factor in vitro. Cellular signalling 22 27208502
2015 Synergistic effect of BMP9 and TGF-β in the proliferation and differentiation of osteoblasts. Genetics and molecular research : GMR 21 26214439
2022 BMP9 reduces age-related bone loss in mice by inhibiting osteoblast senescence through Smad1-Stat1-P21 axis. Cell death discovery 20 35523787
2020 BMP-9 Modulates the Hepatic Responses to LPS. Cells 20 32143367
2022 Resveratrol Synergistically Promotes BMP9-Induced Osteogenic Differentiation of Mesenchymal Stem Cells. Stem cells international 19 35923297
2021 Clinical manifestations of patients with GDF2 mutations associated with hereditary hemorrhagic telangiectasia type 5. American journal of medical genetics. Part A 19 34611981
2020 BMP9 is a potential therapeutic agent for use in oral and maxillofacial bone tissue engineering. Biochemical Society transactions 19 32510140
2020 Homozygous GDF2-Related Hereditary Hemorrhagic Telangiectasia in a Chinese Family. Pediatrics 19 32669404
2019 Advances in the molecular regulation of endothelial BMP9 signalling complexes and implications for cardiovascular disease. Biochemical Society transactions 19 31127068
2020 BMP9 exhibits dual and coupled roles in inducing osteogenic and angiogenic differentiation of mesenchymal stem cells. Bioscience reports 18 32478395
2019 BMP9 promotes osteogenic differentiation of SMSCs by activating the JNK/Smad2/3 signaling pathway. Journal of cellular biochemistry 18 31680322
2021 The Dual Effect of the BMP9-ALK1 Pathway in Blood Vessels: An Opportunity for Cancer Therapy Improvement? Cancers 17 34771575
2020 BMP9 attenuates occurrence of venous malformation by maintaining endothelial quiescence and strengthening vessel walls via SMAD1/5/ID1/α-SMA pathway. Journal of molecular and cellular cardiology 17 32730768
2017 Intranasal BMP9 Ameliorates Alzheimer Disease-Like Pathology and Cognitive Deficits in APP/PS1 Transgenic Mice. Frontiers in molecular neuroscience 17 28228716
2024 Impact of heterozygous ALK1 mutations on the transcriptomic response to BMP9 and BMP10 in endothelial cells from hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension donors. Angiogenesis 16 38294582
2021 Long non-coding RNA (LncRNA) HOTAIR regulates BMP9-induced osteogenic differentiation by targeting the proliferation of mesenchymal stem cells (MSCs). Aging 16 33461171
2010 Effect of BMP-9 and its derived peptide on the differentiation of human white preadipocytes. Growth factors (Chur, Switzerland) 16 20102315
2022 The SIRT1 activator SRT2104 promotes BMP9-induced osteogenic and angiogenic differentiation in mesenchymal stem cells. Mechanisms of ageing and development 15 35985370
2021 A functional autophagy pathway is essential for BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs). American journal of translational research 15 34150011
2021 BMP-9 downregulates StAR expression and progesterone production by activating both SMAD1/5/8 and SMAD2/3 signaling pathways in human granulosa-lutein cells obtained from gonadotropins induced ovarian cycles. Cellular signalling 15 34265413
2024 Large-scale phosphoproteomics reveals activation of the MAPK/GADD45β/P38 axis and cell cycle inhibition in response to BMP9 and BMP10 stimulation in endothelial cells. Cell communication and signaling : CCS 14 38439036
2023 BMP-9 Improves the Osteogenic Differentiation Ability over BMP-2 through p53 Signaling In Vitro in Human Periosteum-Derived Cells. International journal of molecular sciences 14 37894931
2021 New insights into BMP9 signaling in liver diseases. Molecular and cellular biochemistry 14 34019202
2016 BMP-9 dependent pathways required for the chondrogenic differentiation of pluripotent stem cells. Differentiation; research in biological diversity 14 27056281

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