Affinage

BMP2

Bone morphogenetic protein 2 · UniProt P12643

Length
396 aa
Mass
44.7 kDa
Annotated
2026-06-09
100 papers in source corpus 37 papers cited in narrative 36 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

BMP2 is a secreted TGF-β superfamily ligand that drives osteogenic, chondro-dental, cardiac, and tissue-patterning differentiation programs by engaging type I receptors (BMPR1A/ALK3, BMPR1B/ALK6) and type II receptor BMPR2 to activate intracellular SMAD1/5/8 (PMID:15064755, PMID:16314491, PMID:36175474). Receptor engagement depends on a hot-spot interface in which the main-chain atoms of BMP2 Leu51 and Asp53 contact BMPR-IA; the L51P substitution selectively ablates type I binding while sparing type II and noggin binding, converting BMP2 into a receptor-inactive antagonist (PMID:15064755). In skeletal lineages, BMP2/SMAD signaling cooperates with Runx2 to control the osteoblast differentiation program—inducing Osterix through both Runx2-dependent and Runx2-independent (Smad1/Smad4/Msx2) routes (PMID:18703512), activating an ATF6→osteocalcin transcriptional arm (PMID:22102412), and acting as an obligatory node downstream of canonical Wnt to license pre-Osx1 progenitors through the Runx2/Osx1 checkpoint via Grhl3 (PMID:27802170). BMP2 also drives endocardial epithelial-to-mesenchymal transition and AV cushion formation, inducing Twist1, Msx1/2, and Tbx2 and signaling to endocardium through BMPR1A, with crosstalk to Notch1 via Jag1 induction and Smad1/5 interaction with the Notch1 intracellular domain (PMID:16314491, PMID:29853617, PMID:18261719). Beyond canonical SMAD output, BMP2 engages non-SMAD effectors: PI3K-Akt for osteoblast maturation (PMID:19208758), parallel Cdc42 and PI3Kα activation of PAK/LIMK1 for actin remodeling and migration (PMID:19001503), TAK1-p38 MAPK for neurite outgrowth (negatively gated by inhibitory Smad6/7 binding to TAB1) (PMID:11737269), and a BMPR2-XIAP anti-apoptotic axis independent of SMAD and MAPK (PMID:19782107). In a distinct physiological role, angiocrine BMP2 from liver sinusoidal endothelial cells non-redundantly maintains systemic iron homeostasis by sustaining hepcidin expression (PMID:27903529). BMP2 transcription is controlled by Runx2/FGF2, PTH-CREB, PPARα, and adiponectin-AMPK-NF-κB inputs (PMID:15765505, PMID:21695256, PMID:31607484, PMID:20432444), its mRNA is stabilized in a cell-context-dependent manner by a conserved 265-nt 3'UTR element (PMID:15358784), and it predominantly functions in vivo as a heterodimer with BMP7 (PMID:31566563).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 Medium

    Established that BMP2 signals through non-SMAD routes by showing TAK1-p38 MAPK is required for a differentiation output and is gated by inhibitory Smads, broadening BMP2 mechanism beyond canonical R-Smad activation.

    Evidence Dominant-negative TAK1, Smad6/7 overexpression, Co-IP of Smad6/7 with TAB1, and neurite outgrowth assay in PC12 cells

    PMID:11737269

    Open questions at the time
    • Does not establish whether TAK1-p38 operates in osteogenic or cardiac contexts
    • Direct BMP2 receptor-to-TAK1 coupling not resolved
  2. 2004 High

    Defined the structural basis of BMP2 type I receptor recognition, identifying a Leu51/Asp53 hot-spot interface and proving the binding step can be uncoupled from type II and antagonist binding.

    Evidence X-ray crystallography of BMP2:BMPR-IA, site-directed mutagenesis (L51P), and orthogonal binding assays

    PMID:15064755

    Open questions at the time
    • Structure does not address the full ternary signaling complex with type II receptor in vivo
    • Heterodimer interface geometry not addressed
  3. 2004 Medium

    Revealed that BMP2 output is set post-transcriptionally, with a conserved 3'UTR element conferring cell-context-dependent mRNA stability distinct from BMP4.

    Evidence In vitro RNA decay assays, 3'UTR reporter fragments, and cross-species sequence conservation analysis

    PMID:15358784

    Open questions at the time
    • The trans-acting factors binding the 265-nt element are not identified
    • In vivo physiological consequence of stabilization not tested
  4. 2005 High

    Placed BMP2 as an essential effector of endocardial EMT and AV patterning in vivo, mapping downstream transcriptional targets and receptor dependence.

    Evidence Conditional Bmp2 and Bmpr1a knockouts in distinct cardiac compartments with in situ hybridization for Twist1/Msx1/Msx2/Tbx2

    PMID:16314491

    Open questions at the time
    • Does not resolve direct versus indirect target gene regulation
    • Does not address SMAD versus non-SMAD contribution to EMT
  5. 2008 High

    Dissected the osteogenic transcriptional logic of BMP2, showing Osterix induction proceeds through parallel Runx2-dependent and Runx2-independent (Smad/Msx2) pathways.

    Evidence Runx2-null cells, Smad6/Msx2 manipulation, reporter assays, and microarray

    PMID:18703512

    Open questions at the time
    • Quantitative contribution of each arm in vivo unknown
    • Does not address how the two arms are integrated at the Osterix locus
  6. 2008 Medium

    Identified type I receptor specificity for a migratory output, showing BMP2-driven AV cushion mesenchyme migration requires BMPR1B/ALK6 and periostin/Twist/Id1 induction.

    Evidence 3D-collagen culture with constitutively active/dominant-negative viral constructs, noggin antagonism, and migration assays

    PMID:18261719

    Open questions at the time
    • Receptor selectivity (ALK6 vs ALK3) across other tissues not resolved
    • Single-lab in vitro system
  7. 2009 Medium

    Extended BMP2 non-SMAD signaling to actin/migration control via parallel Cdc42 and PI3Kα activation of PAK and LIMK1.

    Evidence Dominant-negative Cdc42, PI3K inhibitors, and kinase activity/phospho-specific assays in C2C12 cells

    PMID:19001503

    Open questions at the time
    • Receptor-proximal events linking BMP2 to Cdc42 not defined
    • Single lab, single cell type
  8. 2009 Medium

    Showed PI3K-Akt is required downstream of BMP2 specifically for osteoblast differentiation, separable from Smad-responsive gene transcription.

    Evidence Dominant-negative Akt, activated Akt, PI3K inhibitors, and metatarsal organ culture

    PMID:19208758

    Open questions at the time
    • Branch point where Akt acts on the osteogenic program unresolved
    • Single lab
  9. 2009 Medium

    Defined a Smad/MAPK-independent anti-apoptotic mechanism in which BMP2/GDF5 stabilize XIAP through BMPR2 binding and reduced XIAP ubiquitination.

    Evidence Co-IP of BMPR2-XIAP, ubiquitination assays, apoptosis assays, and pathway inhibitors in MEFs

    PMID:19782107

    Open questions at the time
    • Physiological contexts using this axis not mapped
    • Reciprocal validation of BMPR2-XIAP interaction limited
  10. 2011 High

    Mapped a BMP2/Runx2→ATF6→osteocalcin transcriptional cascade, adding an unfolded-protein-response transcription factor to the osteogenic gene program.

    Evidence ChIP, promoter mutation, dominant-negative ATF6, and Runx2-null primary osteoblasts

    PMID:22102412

    Open questions at the time
    • Whether ER-stress signaling contributes to ATF6 activation here is unclear
    • Single lab
  11. 2010 Medium

    Established that BMP2 transcription is an integration point for multiple upstream cues, defining direct cis-regulatory inputs from PTH-CREB and from adiponectin-AMPK-p38-NF-κB.

    Evidence ChIP, EMSA, promoter mutagenesis, and pathway inhibitor/siRNA studies in osteoblasts

    PMID:20432444 PMID:21695256

    Open questions at the time
    • Combinatorial interplay of these inputs at the BMP2 promoter not tested
    • In vivo relevance of each input not established
  12. 2010 Medium

    Confirmed BMPR2/BMPR1A-SMAD1/5 specificity at a defined target promoter (Id3) and identified the cis-elements mediating BMP2/SMAD transcription.

    Evidence Promoter deletion/mutation reporters with receptor and SMAD RNAi in gonadotropes

    PMID:21056086

    Open questions at the time
    • Generalizability of the cis-elements to other cell types unknown
  13. 2016 High

    Positioned BMP2 as an obligatory node downstream of canonical Wnt for osteoblast fate, identifying pre-Osx1 progenitors as source and target and Grhl3 as a downstream factor.

    Evidence Stage-specific conditional knockouts and genetic epistasis in limb bud/bone marrow progenitors

    PMID:27802170

    Open questions at the time
    • Mechanism of Wnt-BMP2 dependency at the molecular level not fully resolved
    • Grhl3 direct targets not defined
  14. 2016 High

    Uncovered a distinct angiocrine, non-skeletal role: liver sinusoidal endothelial BMP2 non-redundantly maintains iron homeostasis via hepcidin.

    Evidence Stab2-Cre LSEC-specific Bmp2 deletion with serum/tissue iron and hepcidin measurements

    PMID:27903529

    Open questions at the time
    • Receptor/SMAD circuitry in hepatocytes downstream of LSEC BMP2 not dissected here
    • Relationship to BMP6 cooperation unresolved
  15. 2016 Medium

    Linked BMP2 receptor activation to SMAD1 stability through YAP, inserting a Hippo-pathway node upstream of astrocytic differentiation.

    Evidence Conditional knockouts, Co-IP, and SMAD1 rescue in neural stem cells

    PMID:27381227

    Open questions at the time
    • Mechanism of YAP-mediated SMAD1 stabilization unresolved
    • Single lab
  16. 2018 Medium

    Defined BMP2-Notch crosstalk in cardiac EMT through Jag1 induction and a physical Smad1/5-Notch1 ICD interaction.

    Evidence Transgenic gain-of-function mice, biochemical interaction assays, and in vitro EMT assays

    PMID:29853617

    Open questions at the time
    • Stoichiometry and direct versus indirect Smad1/5-Notch1 binding not resolved
    • Endogenous (non-ectopic) requirement not tested
  17. 2019 High

    Established that BMP2 functions predominantly as a heterodimer with BMP7 (or BMP4) in vivo, redefining the active signaling species during embryogenesis.

    Evidence Bmp7 proteolysis-blocking knock-in mice, compound heterozygous genetics, and Co-IP of endogenous heterodimers

    PMID:31566563

    Open questions at the time
    • Receptor preference and signaling differences of heterodimer vs homodimer not fully resolved
    • Tissue-by-tissue heterodimer requirement incomplete
  18. 2021 Medium

    Identified a co-receptor/modulator, osteomodulin, that binds BMP2 and its receptors to potentiate BMP/SMAD signaling and is itself a SMAD4 target.

    Evidence Co-IP/pulldown, in vitro and in vivo osteogenesis assays, and knockdown

    PMID:33542209

    Open questions at the time
    • Structural basis of OMD-BMP2-receptor complex not defined
    • Single lab
  19. 2024 Medium

    Defined extracellular matrix control of BMP2 bioavailability, mapping a sulfated heparan sulfate motif that binds BMP2 and modulates SMAD1/5/9 activation.

    Evidence Biomimetic surfaces, SMAD phosphorylation assays, integrin silencing, and molecular dynamics simulations

    PMID:38876708

    Open questions at the time
    • In vivo relevance of the HS motif binding not established
    • How HS binding integrates with receptor engagement unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How distinct receptor combinations, SMAD versus non-SMAD branches, heterodimer composition, and extracellular co-factors are integrated to produce tissue-specific BMP2 outputs remains unresolved.
  • No unified model linking receptor/co-receptor choice to specific differentiation programs
  • Quantitative contribution of homodimer vs BMP7 heterodimer per tissue unknown
  • Trans-acting regulators of 3'UTR-mediated mRNA stability unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3 GO:0031012 extracellular matrix 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 2 R-HSA-382551 Transport of small molecules 1
Partners
BMP7BMPR1ABMPR1BBMPR2NOTCH1OMDSMAD1XIAP

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Crystal structure and mutational analysis of BMP-2 bound to BMPR-IA (BRIA) revealed that the main chain atoms of Leu51 and Asp53 of BMP-2 form a hot-spot interface with BRIA. The L51P variant selectively abolished type I receptor binding while preserving type II receptor binding and noggin binding, converting BMP-2 into a receptor-inactive noggin inhibitor. X-ray crystallography, site-directed mutagenesis, binding assays Nature structural & molecular biology High 15064755
2008 BMP2 regulates Osterix expression through two parallel pathways in mesenchymal cells: a Runx2-dependent pathway and a Runx2-independent pathway involving Smad1/Smad4 and Msx2. Smad6 overexpression suppressed BMP2-induced Osterix in Runx2-null cells; Msx2 knockdown blocked BMP2-induced Osterix in Runx2-deficient cells. Genetic (Runx2-/- cells), overexpression/knockdown, reporter assays, microarray The Journal of biological chemistry High 18703512
2005 Conditional deletion of Bmp2 in AV myocardium demonstrated that Bmp2 is required for (1) Has2-dependent cardiac jelly formation, (2) endocardial epithelial-to-mesenchymal transition via induction of Twist1, Msx1, and Msx2, and (3) AV myocardial patterning via Tbx2 expression. Endocardial-specific deletion of Bmpr1a also abrogated cushion formation, placing Bmp2 signaling directly to endocardium through BMPR1A. Conditional knockout (Cre-lox), in situ hybridization, genetic epistasis Development (Cambridge, England) High 16314491
2008 BMP2 stimulation of C2C12 cells induces actin cytoskeleton rearrangement and cell migration through independent and parallel activation of Cdc42 GTPase and PI3K-alpha. BMP2 also activates PAK isoforms and LIMK1 in a PI3K-dependent manner. Dominant-negative Cdc42 overexpression, pharmacological PI3K inhibitors, kinase activity assays, phospho-specific antibodies Journal of cell science Medium 19001503
2016 In developing mouse neocortex, BMP2 activates YAP, and nuclear/active YAP is required for SMAD1 stabilization and subsequent astrocytic differentiation. Expression of SMAD1 in YAP-deficient NSCs partially rescued astrocytic differentiation deficits, placing YAP between BMP2 receptor activation and SMAD1 stability. Conditional knockout (Nestin-Cre; GFAP-Cre), co-immunoprecipitation, rescue experiments, immunofluorescence Development (Cambridge, England) Medium 27381227
2016 Angiocrine Bmp2 from liver sinusoidal endothelial cells (LSECs) is required for normal iron homeostasis. LSEC-specific Bmp2 deletion (Stab2-Cre;Bmp2fl/fl) caused massive hepatic iron overload, decreased hepcidin expression, and systemic iron elevation, demonstrating a non-redundant pathway distinct from Bmp6. Conditional knockout (Stab2-Cre), serum/tissue iron measurements, hepcidin expression analysis Blood High 27903529
2009 PI3K-Akt signaling is required downstream of BMP2 for osteoblast differentiation. Dominant-negative Akt or PI3K inhibitors blocked BMP2-induced osteoblast differentiation without affecting Smad-responsive genes (Sox9, JunB), while activated Akt restored differentiation blocked by IGFBP5 or PI3K inhibition. Dominant-negative Akt, adenoviral activated Akt, pharmacological inhibitors, metatarsal organ culture Journal of cell science Medium 19208758
2003 BMP2 exposure increases PTEN protein levels in MCF-7 cells by decreasing PTEN protein degradation rather than increasing synthesis (cycloheximide did not block accumulation). BMP2 treatment decreased PTEN association with ubiquitin-conjugating enzymes UbCH7 and UbC9. Western blot, cycloheximide chase, co-immunoprecipitation with ubiquitin pathway components Human molecular genetics Medium 12620973
2011 BMP2 activates ATF6 transcription through Runx2-dependent direct binding to the OSE2 motif (-205 to -200 bp) in the Atf6 promoter. ATF6 in turn directly binds the osteocalcin (Oc) promoter to induce osteocalcin expression; dominant-negative ATF6 blocked BMP2- and Runx2-induced osteocalcin expression. ATF6 activation by BMP2 was absent in Runx2-/- primary osteoblasts. ChIP, promoter-reporter assays, dominant-negative constructs, Runx2-/- primary cells The Journal of biological chemistry High 22102412
2005 Runx2 is required for FGF2-induced Bmp2 expression during cranial bone development. Disruption of Runx2 abolished Bmp2, Dlx5, and Msx2 expression in developing bone primordium while Fgf2 expression was maintained. FGF2 could not induce Bmp2 in Runx2-/- cells, but Runx2 transfection restored FGF2-dependent Bmp2 induction. Runx2-/- mouse tissue analysis, cell transfection, in situ hybridization Developmental dynamics Medium 15765505
2001 BMP2-induced neurite outgrowth in PC12 cells requires TAK1 kinase upstream of p38 MAPK. Inhibitory Smads (Smad6 and Smad7) physically interact with TAB1 (TAK1-binding protein) and suppress the TAK1-p38 pathway, thereby inhibiting BMP2-induced neurite outgrowth. Dominant-negative TAK1, Smad6/7 overexpression, co-immunoprecipitation (Smad6/7 with TAB1), neurite outgrowth assay Genes to cells Medium 11737269
2011 BMP2 regulates expression of BMP antagonists Gremlin1 and Gremlin2 in opposite directions during osteoblast differentiation: Gremlin1 is downregulated while Gremlin2 is upregulated in a time- and dose-dependent manner. BMP2-induced Gremlin2 expression requires Smad4 and p38 MAPK signaling. DNA microarray, Smad4 siRNA, p38 MAPK inhibitor (SB203580), dose/time-response assays Calcified tissue international Medium 22644325
2011 BMP2 induces apoptosis in osteoblast lineage cells in a maturation-state-dependent manner, with robust effects in mature osteoblasts (NHOst) but minor effects in MSCs. BMP2-induced apoptosis in committed osteoblasts is mediated through both Smad and TAB/TAK1 signaling pathways and is negatively regulated by Noggin. Caspase-3, BAX/BCL2, p53, DNA fragmentation assays; BMP signaling inhibitors (dorsomorphin, 5Z-7-oxozeaenol, H-8); Noggin knockdown Journal of cellular biochemistry Medium 22628200
2019 BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis. Knock-in mice carrying a Bmp7 mutation preventing proteolytic activation eliminated BMP7 homodimer and BMP7-containing heterodimer function; compound heterozygotes with Bmp7 and Bmp2-null alleles died during embryogenesis. Co-immunoprecipitation confirmed endogenous BMP4/7 heterodimers exist in vivo. Knock-in mouse genetics, genetic epistasis (compound heterozygotes), co-immunoprecipitation of endogenous proteins eLife High 31566563
2016 Canonical Wnt signaling requires Bmp2 to specify osteoblast cell fate. Bmp2-deficient limb bud or bone marrow progenitors fail to progress through the Runx2/Osx1 checkpoint in response to Wnt stimulation. Cells lacking Bmp2 only after Osx1 induction differentiate normally, identifying pre-Osx1+ progenitors as both the source and target of BMP2. Grhl3 transcription factor acts downstream of BMP2 and upstream of Osx1. Conditional knockout, genetic epistasis, gene expression analysis Development (Cambridge, England) High 27802170
2009 Bmp2 and Bmp4 exert opposing roles in hypoxic pulmonary hypertension. Bmp2(+/-) mice develop more severe hypoxic PH than wild-type, associated with reduced eNOS expression and activity in pulmonary vasculature. Exogenous BMP2 upregulates eNOS expression and activity in pulmonary artery and endothelial cell preparations, identifying eNOS as a target of Bmp2 signaling. Heterozygous null mouse model, eNOS expression/activity assays, ex vivo BMP2 treatment American journal of physiology. Regulatory, integrative and comparative physiology Medium 20042692
2011 Conditional deletion of Bmp2 in early-polarizing odontoblasts (3.6Col1a1-Cre) impaired odontoblast maturation and dentin formation, with decreased Osterix, Col1a1, and Dspp expression. Bmp2 in odontoblasts also indirectly controls pulp vascular bed formation and pericyte numbers via VegfA production. Conditional knockout (Cre-lox), immunohistochemistry, gene expression analysis Journal of dental research Medium 21984706
2011 Conditional deletion of Bmp2 (with Bmp4) in dental epithelium (Osx-Cre) caused enamel hypomineralization, loss of prismatic architecture, and incisor defects. Double epithelial Bmp2/Bmp4 knockout demonstrated that BMP/Smad4 signaling in ameloblasts controls MMP20 and KLK4 expression required for enamel matrix processing. Conditional knockout, SEM, microradiography, qRT-PCR, histology Cells, tissues, organs / Scientific reports Medium 21597270 27146352
2011 PTH-CREB signaling pathway activates BMP2 transcription in osteoblasts via a specific CRE element in the BMP2 promoter. ChIP and EMSA confirmed direct CREB binding to this promoter element; genetic/pharmacological modulation of PTH-CREB activity proportionally affected BMP2 expression. ChIP, EMSA, promoter-reporter deletion/mutation assays, siRNA, pharmacological modulation PloS one Medium 21695256
2010 Adiponectin increases BMP-2 expression in osteoblasts via AdipoR1 receptor signaling through sequential activation of AMPK, p38, and NF-κB pathways. AMPK siRNA and inhibitors, p38 inhibitors, and NF-κB pathway inhibitors each attenuated adiponectin-induced BMP-2 expression. siRNA knockdown, pharmacological pathway inhibitors, Western blot, ELISA, qRT-PCR Journal of cellular physiology Medium 20432444
2012 BMP2 and mechanical loading cooperatively regulate BMP signaling by enhancing the intensity and duration of R-Smad phosphorylation. Mechanical signals integrate directly into the BMP pathway at a step upstream of Smad phosphorylation, independent of autocrine BMP2 secretion, suggesting crosstalk at cell-surface receptor level. 3D bioreactor system, time-course phosphorylation assays (Smad, MAPK, Akt), BMP target gene transcription analysis BMC biology Medium 22540193
2021 Osteomodulin (OMD) binds directly to BMP2 via its terminal leucine-rich repeats and forms complexes with BMP2 and BMP2 membrane receptors, promoting BMP/SMAD signal transduction and osteogenesis. OMD is itself a target gene of SMAD4 in this pathway. Co-immunoprecipitation (pulldown), in vitro osteogenesis assays, in vivo bone defect model, gene knockdown Cell death & disease Medium 33542209
2009 GDF5 and BMP2 prevent apoptosis in mouse embryonic fibroblasts via BMPR2, which stabilizes XIAP by stimulating BMPR2-XIAP interaction and reducing XIAP ubiquitination. This anti-apoptotic mechanism is independent of Smad and MAPK signaling. Co-immunoprecipitation (BMPR2-XIAP), ubiquitination assay, apoptosis assays, signaling pathway inhibitors Biochimica et biophysica acta Medium 19782107
2010 Agrin N-terminal domain binds BMP2 (and BMP4, TGFβ1) with Kd in the 10-100 nM range as measured by surface plasmon resonance, and inhibits BMP2 activity in reporter assays with IC50 ~500 nM. Surface plasmon resonance (SPR), reporter assay PloS one Medium 20505824
2013 Progastrin suppresses BMP2 transcription through a CCK2R- and β-arrestin 1/2-dependent pathway in colonic epithelial cells, leading to decreased Smad1/5/8 phosphorylation and suppression of Id4. Recombinant BMP2 blocked progastrin-induced proliferation and symmetric cell division. Microarray, siRNA (β-arrestin 1/2), CCK2R knockout, recombinant BMP2 rescue, colonic crypt cultures Gastroenterology Medium 23891976
2018 Ectopic myocardial Bmp2 expression in mice induces endocardial EMT via Notch1 activation, mediated by Bmp2-driven transcriptional induction of Notch ligand Jag1 and physical interaction between Smad1/5 and the intracellular domain of Notch1 receptor. Transgenic mouse model, biochemical interaction assay (Smad1/5 - Notch1 ICD), gene expression profiling, in vitro EMT assay Development (Cambridge, England) Medium 29853617
2015 BMP2-induced fracture healing requires tight temporal and spatial control of CXCL12 expression. BMP2 induces osteoblastic differentiation of endosteal cells while decreasing CXCL12 expression. Loss of BMP2 in mesenchymal osteoprogenitors causes dysregulated CXCL12 upregulation; blocking CXCR4 (AMD3100) rescued healing in BMP2-deficient mice. Conditional knockout, AMD3100 pharmacological rescue, MSC transplantation, in vitro differentiation assays Journal of bone and mineral research Medium 25967044
2019 PDGF signaling through PDGFRβ inhibits BMP2-induced osteogenesis in periosteal progenitor cells by suppressing the canonical BMP2/Smad pathway and downstream target gene expression. This inhibitory effect is mediated via ERK1/2 MAPK and PI3K/AKT signaling. In vitro differentiation assays, pharmacological pathway inhibitors, gene expression analysis, PDGFRβ-targeted experiments JBMR plus Medium 31131345
2009 Elevated intracellular cAMP enhances BMP2-induced osteoblastic differentiation in C2C12 cells by increasing BMP2-induced MKP1 expression and suppressing Erk1/2 phosphorylation and cell proliferation downstream of BMP2. Pharmacological cAMP elevation (Forskolin, dbcAMP, IBMX), kinase phosphorylation assays, alkaline phosphatase activity Biochemical and biophysical research communications Low 19217886
2010 BMP2 signals through BMPR2 and BMPR1A (ALK3) and intracellular SMADs 1 and 5 to stimulate Id3 transcription in murine gonadotropes. A novel proximal 6-bp cis-element and a more distal enhancer element in the Id3/ID3 promoter each mediate BMP2/SMAD-dependent transcription. Promoter-reporter deletion/mutation assays, RNAi knockdown of receptors and SMADs, qRT-PCR Molecular and cellular endocrinology Medium 21056086
2004 Post-transcriptional regulation of Bmp2 mRNA is conserved across vertebrates. A 265-nt element in the Bmp2 3'UTR, absent from Bmp4, stabilizes Bmp2 mRNA in a cell-type-specific manner. Bmp2 synthetic RNAs decay rapidly in extracts from cells not expressing Bmp2 but are stable in Bmp2-expressing cells, indicating cell-context-dependent RNA decay machinery interactions. In vitro RNA decay assays, reporter gene activation by 3'UTR fragments, evolutionary sequence conservation analysis The Journal of biological chemistry Medium 15358784
2019 Fenofibrate increases BMP2 expression in osteoblasts via PPARα-mediated direct binding to the BMP2 promoter. PPARα knockdown abolished fenofibrate-induced BMP2 expression; ChIP confirmed PPARα occupancy at the BMP2 promoter upon fenofibrate treatment. ChIP, siRNA knockdown, promoter-reporter assay, qRT-PCR Biochemical and biophysical research communications Medium 31607484
2011 BMP-2 induction of cell migration in AV cushion mesenchyme requires signaling through BMPR-1B (ALK6). BMP-2 induces periostin expression (at mRNA and protein levels) and Twist and Id1 transcription; these effects are blocked by noggin or dominant-negative BMPR-1B. 3D-collagen gel culture, constitutively active and dominant-negative viral constructs, noggin antagonism, migration assays, in situ hybridization Developmental biology Medium 18261719
2020 BMP2 upregulates IGFBP3 expression in human endometrial stromal cells via ALK3 receptor → ID1 → IGFBP3 cascade. Knockdown of ALK3 abolished BMP2-induced ID1 upregulation; knockdown of IGFBP3 or ID1 suppressed BMP2-induced MMP2 expression and cell migration. siRNA knockdown (ALK3, ID1, IGFBP3), dose/time-response, Western blot, migration assay in primary and immortalized cells FASEB journal Medium 32975335
2022 BMP2 promotes lung adenocarcinoma metastasis via BMPR2-mediated SMAD1/5/8 pathway activation, independent of KRAS signaling. Depletion of BMP2 or BMPR2 reduced cell migration/invasiveness; SMAD1/5/8 depletion or LDN193189 inhibition blocked BMP2-induced migration. Orthotopic mouse model confirmed BMP2's pro-metastatic role in vivo. siRNA knockdown, LDN193189 inhibitor, orthotopic mouse model, migration/invasion assays Scientific reports Medium 36175474
2024 Heparan sulfate (HS) promotes BMP2 signaling in the extracellular space while chondroitin sulfate enhances BMP2 bioactivity at the cell surface. HS binding to BMP2 involves a central IdoA(2S)-GlcNS(6S) tri-sulfated motif; BMP2 shows adaptability to various HS sulfation types due to N-terminal end flexibility (from molecular dynamics simulations). Co-immobilization of HS with cRGD enhanced BMP2-mediated SMAD1/5/9 phosphorylation and osteogenic differentiation. Biomimetic surface platforms, SMAD1/5/9 phosphorylation assays, integrin silencing, molecular dynamics simulations Carbohydrate polymers Medium 38876708

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 BMP2 regulates Osterix through Msx2 and Runx2 during osteoblast differentiation. The Journal of biological chemistry 427 18703512
2005 Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning. Development (Cambridge, England) 413 16314491
2019 Asymmetric paralog evolution between the "cryptic" gene Bmp16 and its well-studied sister genes Bmp2 and Bmp4. Scientific reports 192 30816280
2004 Molecular recognition of BMP-2 and BMP receptor IA. Nature structural & molecular biology 184 15064755
2003 Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS biology 184 14691541
2009 Akt promotes BMP2-mediated osteoblast differentiation and bone development. Journal of cell science 183 19208758
2016 BMP2 induces chondrogenic differentiation, osteogenic differentiation and endochondral ossification in stem cells. Cell and tissue research 171 27083447
2011 BMP2 protein regulates osteocalcin expression via Runx2-mediated Atf6 gene transcription. The Journal of biological chemistry 166 22102412
2016 Angiocrine Bmp2 signaling in murine liver controls normal iron homeostasis. Blood 142 27903529
1997 Cloning and expression of three members of the zebrafish Bmp family: Bmp2a, Bmp2b and Bmp4. Gene 105 9370264
2008 BMP2 induction of actin cytoskeleton reorganization and cell migration requires PI3-kinase and Cdc42 activity. Journal of cell science 102 19001503
2016 YAP stabilizes SMAD1 and promotes BMP2-induced neocortical astrocytic differentiation. Development (Cambridge, England) 101 27381227
2012 BMP2 and mechanical loading cooperatively regulate immediate early signalling events in the BMP pathway. BMC biology 98 22540193
2003 BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Human molecular genetics 94 12620973
2004 Loss of BMP2, Smad8, and Smad4 expression in prostate cancer progression. The Prostate 92 15042598
2005 Runx2 regulates FGF2-induced Bmp2 expression during cranial bone development. Developmental dynamics : an official publication of the American Association of Anatomists 90 15765505
2019 LncRNA KCNQ1OT1 promoted BMP2 expression to regulate osteogenic differentiation by sponging miRNA-214. Experimental and molecular pathology 88 30703347
2011 Bmp2 is required for odontoblast differentiation and pulp vasculogenesis. Journal of dental research 84 21984706
2014 Sox9 potentiates BMP2-induced chondrogenic differentiation and inhibits BMP2-induced osteogenic differentiation. PloS one 83 24551211
2007 BMP-2 induces cell migration and periostin expression during atrioventricular valvulogenesis. Developmental biology 79 18261719
2023 Hydrogel armed with Bmp2 mRNA-enriched exosomes enhances bone regeneration. Journal of nanobiotechnology 78 37020301
2011 Transcriptional regulation of BMP2 expression by the PTH-CREB signaling pathway in osteoblasts. PloS one 74 21695256
2008 Mypt1-mediated spatial positioning of Bmp2-producing cells is essential for liver organogenesis. Development (Cambridge, England) 74 18776143
2019 Direct electrical stimulation enhances osteogenesis by inducing Bmp2 and Spp1 expressions from macrophages and preosteoblasts. Biotechnology and bioengineering 71 31429922
2015 Tuning cellular responses to BMP-2 with material surfaces. Cytokine & growth factor reviews 71 26704296
1991 Bone morphogenetic protein: chromosomal localization of human genes for BMP1, BMP2A, and BMP3. Genomics 71 2004778
2015 Association Between BMP-2 and Carcinogenicity. Spine 66 26274524
2008 BMP2 and BMP7 play antagonistic roles in feather induction. Development (Cambridge, England) 66 18635609
2004 Regulatory role of BMP2 and BMP7 in spermatogonia and Sertoli cell proliferation in the immature mouse. European journal of endocrinology 64 15476453
2010 Adiponectin increases BMP-2 expression in osteoblasts via AdipoR receptor signaling pathway. Journal of cellular physiology 62 20432444
2020 Inhibition of the epigenetic suppressor EZH2 primes osteogenic differentiation mediated by BMP2. The Journal of biological chemistry 59 32332097
2021 Osteomodulin positively regulates osteogenesis through interaction with BMP2. Cell death & disease 56 33542209
2009 Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. American journal of physiology. Regulatory, integrative and comparative physiology 56 20042692
2020 BMP2 induces hMSC osteogenesis and matrix remodeling. Molecular medicine reports 52 33300084
2021 piRNA-36741 regulates BMP2-mediated osteoblast differentiation via METTL3 controlled m6A modification. Aging 51 34645714
2015 Turning Bone Morphogenetic Protein 2 (BMP2) on and off in Mesenchymal Cells. Journal of cellular biochemistry 46 25776852
2016 Bone morphogenetic protein 2 (BMP2) induces growth suppression and enhances chemosensitivity of human colon cancer cells. Cancer cell international 43 27708551
2019 BMP7 functions predominantly as a heterodimer with BMP2 or BMP4 during mammalian embryogenesis. eLife 42 31566563
2004 An evolutionary and molecular analysis of Bmp2 expression. The Journal of biological chemistry 42 14757762
2001 Inhibition of BMP2-induced, TAK1 kinase-mediated neurite outgrowth by Smad6 and Smad7. Genes to cells : devoted to molecular & cellular mechanisms 42 11737269
2019 PDGF Modulates BMP2-Induced Osteogenesis in Periosteal Progenitor Cells. JBMR plus 41 31131345
2012 BMP2 induces osteoblast apoptosis in a maturation state and noggin-dependent manner. Journal of cellular biochemistry 41 22628200
2006 Conservation and divergence of Bmp2a, Bmp2b, and Bmp4 expression patterns within and between dentitions of teleost fishes. Evolution & development 40 17073935
2017 BMP2 promotes proliferation and invasion of nasopharyngeal carcinoma cells via mTORC1 pathway. Aging 39 28455969
2015 Combined MEK inhibition and BMP2 treatment promotes osteoblast differentiation and bone healing in Nf1Osx -/- mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 39 25043591
2011 Abnormalities in the enamel in bmp2-deficient mice. Cells, tissues, organs 39 21597270
2011 Divergent activities of osteogenic BMP2, and tenogenic BMP12 and BMP13 independent of receptor binding affinities. Growth factors (Chur, Switzerland) 39 21702718
2022 Interleukin-29 Accelerates Vascular Calcification via JAK2/STAT3/BMP2 Signaling. Journal of the American Heart Association 38 36537334
2019 Fenofibrate induces PPARα and BMP2 expression to stimulate osteoblast differentiation. Biochemical and biophysical research communications 38 31607484
2013 Progastrin stimulates colonic cell proliferation via CCK2R- and β-arrestin-dependent suppression of BMP2. Gastroenterology 38 23891976
2018 BMP-2 restoration aids in recovery from liver fibrosis by attenuating TGF-β1 signaling. Laboratory investigation; a journal of technical methods and pathology 37 29789683
2016 Specification of osteoblast cell fate by canonical Wnt signaling requires Bmp2. Development (Cambridge, England) 37 27802170
2015 GDF-5 can act as a context-dependent BMP-2 antagonist. BMC biology 37 26385096
2009 GDF5 and BMP2 inhibit apoptosis via activation of BMPR2 and subsequent stabilization of XIAP. Biochimica et biophysica acta 34 19782107
2018 Bmp2 and Notch cooperate to pattern the embryonic endocardium. Development (Cambridge, England) 33 29853617
2015 BMP2 Regulation of CXCL12 Cellular, Temporal, and Spatial Expression is Essential During Fracture Repair. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32 25967044
2010 BMP2 expression in the adult rat brain. The Journal of comparative neurology 32 20886619
2009 cAMP enhances BMP2-signaling through PKA and MKP1-dependent mechanisms. Biochemical and biophysical research communications 32 19217886
2006 BMP2/4 and BMP5-8 in jellyfish development and transdifferentiation. The International journal of developmental biology 32 16525932
2020 Aberrant BMP2 Signaling in Patients Diagnosed with Osteoporosis. International journal of molecular sciences 31 32967078
2018 MiR-133a inhibits fracture healing via targeting RUNX2/BMP2. European review for medical and pharmacological sciences 31 29771401
1992 The gene for bone morphogenetic protein 2A (BMP2A) is localized to human chromosome 20p12 by radioactive and nonradioactive in situ hybridization. Human genetics 31 1487246
2020 The regulation of IGFBP3 by BMP2 has a role in human endometrial remodeling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 32975335
2018 Myocardial Bmp2 gain causes ectopic EMT and promotes cardiomyocyte proliferation and immaturity. Cell death & disease 30 29540665
2011 BMP-2 and TGFβ2 shared pathways regulate endocardial cell transformation. Cells, tissues, organs 30 21212630
2020 The lncRNA Rhno1/miR-6979-5p/BMP2 Axis Modulates Osteoblast Differentiation. International journal of biological sciences 29 32226305
2012 BMP2 differentially regulates the expression of Gremlin1 and Gremlin2, the negative regulators of BMP function, during osteoblast differentiation. Calcified tissue international 27 22644325
2020 Heparan sulfate co-immobilized with cRGD ligands and BMP2 on biomimetic platforms promotes BMP2-mediated osteogenic differentiation. Acta biomaterialia 26 32673751
2019 Vitamin D-regulated osteocytic sclerostin and BMP2 modulate uremic extraskeletal calcification. JCI insight 26 31292298
2010 Mechanisms of bone morphogenetic protein 2 (BMP2) stimulated inhibitor of DNA binding 3 (Id3) transcription. Molecular and cellular endocrinology 26 21056086
2022 Dual Delivery of BMP2 and IGF1 Through Injectable Hydrogel Promotes Cranial Bone Defect Healing. Tissue engineering. Part A 25 35357948
2014 Bmp2 and Bmp4 accelerate alveolar bone development. Connective tissue research 25 25491151
2022 BMP2 promotes lung adenocarcinoma metastasis through BMP receptor 2-mediated SMAD1/5 activation. Scientific reports 24 36175474
2010 Agrin binds BMP2, BMP4 and TGFbeta1. PloS one 24 20505824
2020 Association Between BMP2 Functional Polymorphisms and Sheep Tail Type. Animals : an open access journal from MDPI 23 32340359
2018 Crosstalk between neuropeptides SP and CGRP in regulation of BMP2-induced bone differentiation. Connective tissue research 23 29745819
2023 PDGF inhibits BMP2-induced bone healing. NPJ Regenerative medicine 22 36631491
2020 Celastrol attenuates arterial and valvular calcification via inhibiting BMP2/Smad1/5 signalling. Journal of cellular and molecular medicine 22 32954678
2017 Select polyphenolic fractions from dried plum enhance osteoblast activity through BMP-2 signaling. The Journal of nutritional biochemistry 22 29413490
2016 Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression. Scientific reports 22 27146352
2011 BMP2 promotes chondrocyte proliferation via the Wnt/β-catenin signaling pathway. Molecular medicine reports 22 21503577
2004 Conservation of Bmp2 post-transcriptional regulatory mechanisms. The Journal of biological chemistry 22 15358784
2021 Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages. Cell death & disease 21 34294700
2020 Investigation of Genetic Polymorphisms in BMP2, BMP4, SMAD6, and RUNX2 and Persistent Apical Periodontitis. Journal of endodontics 21 33245975
2019 Epigenetic regulation of BMP2 gene in osteoporosis: a DNA methylation study. Molecular biology reports 21 30788762
2021 The BMP2 Signaling Axis Promotes Invasive Differentiation of Human Trophoblasts. Frontiers in cell and developmental biology 20 33614644
2016 TIEG1 enhances Osterix expression and mediates its induction by TGFβ and BMP2 in osteoblasts. Biochemical and biophysical research communications 20 26801561
2012 Essential roles of zebrafish bmp2a, fgf10, and fgf24 in the specification of the ventral pancreas. Molecular biology of the cell 20 22219376
2004 Expression of bmp2a and bmp2b in late-stage zebrafish median fin development. Gene expression patterns : GEP 20 15567728
2022 Yap is essential for uterine decidualization through Rrm2/GSH/ROS pathway in response to Bmp2. International journal of biological sciences 19 35414789
2021 Combination of BMP2 and EZH2 Inhibition to Stimulate Osteogenesis in a 3D Bone Reconstruction Model. Tissue engineering. Part A 19 33234056
2024 Glycosaminoglycans exhibit distinct interactions and signaling with BMP2 according to their nature and localization. Carbohydrate polymers 18 38876708
2023 Micro RNA based MSC EV engineering: Targeting the BMP2 cascade for bone repair. Frontiers in cell and developmental biology 18 36846585
2022 Transcriptome study digs out BMP2 involved in adipogenesis in sheep tails. BMC genomics 18 35725366
2021 ILF3 is responsible for hyperlipidemia-induced arteriosclerotic calcification by mediating BMP2 and STAT1 transcription. Journal of molecular and cellular cardiology 18 34343541
2008 BMP2-induced gene profiling in dental epithelial cell line. The journal of medical investigation : JMI 18 18797134
2022 BMP2 inhibits cell proliferation by downregulating EZH2 in gastric cancer. Cell cycle (Georgetown, Tex.) 17 35856444
2018 SHP2 regulates intramembranous ossification by modifying the TGFβ and BMP2 signaling pathway. Bone 17 30471432
2022 BMP2 as a promising anticancer approach: functions and molecular mechanisms. Investigational new drugs 16 36040572
2015 Dynamics and cellular localization of Bmp2, Bmp4, and Noggin transcription in the postnatal mouse skeleton. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 16 25043193

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