Affinage

GDF5

Growth/differentiation factor 5 · UniProt P43026

Length
501 aa
Mass
55.4 kDa
Annotated
2026-04-28
100 papers in source corpus 35 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GDF5 is a secreted BMP-family ligand that orchestrates skeletal patterning, joint formation, connective tissue maturation, and chondrogenic differentiation by signaling primarily through BMPR-IB — to which a single residue, Arg57, confers ~12-fold binding selectivity over BMPR-IA — activating canonical Smad1/5/8 and non-canonical p38 MAPK pathways, and cooperating with the co-receptor Ror2 to modulate Smad-dependent versus Smad-independent outputs required for chondrogenesis (PMID:15890363, PMID:15569154, PMID:18363966). GDF5 promotes mesenchymal cell condensation and chondroprogenitor aggregation through increased cell adhesion, sustains Sox9 expression to drive cartilage differentiation, specifies joint interzones via continuous recruitment of Gdf5-lineage progenitors, and regulates collagen fibril assembly in tendons and ligaments (PMID:11263662, PMID:10208739, PMID:27292641, PMID:11913489). Its activity is tightly controlled by extracellular antagonists — NOGGIN and DAN-family members such as Gremlin-2, which occlude overlapping receptor-binding epitopes — and disease-causing mutations at the antagonist/receptor interface (N445K/T, W414R, S94N) produce gain-of-function joint fusions (multiple synostosis syndrome) or loss-of-function brachydactyly through dual pathomechanisms (PMID:19956691, PMID:24098149, PMID:21976273, PMID:27524626). Transcription of GDF5 is regulated by an array of modular enhancers spanning >100 kb, by the transcription factors SP1, SP3, DEAF-1, and SOX11, and by CpG methylation at the OA-susceptibility SNP rs143383, where the risk T allele shows reduced promoter activity and diminished joint expression, establishing a direct genetic link to osteoarthritis susceptibility (PMID:17384641, PMID:17616513, PMID:23825960, PMID:24861163, PMID:27902701).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Establishing that GDF5 processing and secretion are essential for function: a dominant-negative cysteine-to-tyrosine mutation in the mature domain blocked secretion and trapped wild-type BMPs via heterodimer formation, revealing prodomain processing and disulfide-dependent folding as critical for ligand activity.

    Evidence In vitro secretion and co-expression assays in transfected cells

    PMID:9288098

    Open questions at the time
    • No structural basis for heterodimer-mediated trapping
    • Dominant-negative mechanism not tested in vivo
  2. 1999 High

    Defining GDF5 as both necessary and sufficient for cartilage formation and joint patterning resolved the fundamental question of its developmental role: brachypodism mice showed skeletal deficits while exogenous GDF5 induced ectopic cartilage and restricted joint sites across species.

    Evidence Brachypodism mouse genetics, recombinant GDF5 application to chick and mouse limb explants; transgenic overexpression in mice

    PMID:10208739 PMID:9885252

    Open questions at the time
    • How GDF5 restricts versus promotes joint formation at the molecular level remained unclear
    • Downstream transcriptional targets not identified
  3. 2004 Medium

    Revealing how GDF5 promotes early chondrogenesis through cell adhesion-mediated condensation, distinct from BMP4 which drives internodular chondrogenesis, established that GDF5 acts at a specific stage — progenitor aggregation — and sustains Sox9 to a greater extent.

    Evidence Mouse embryonic limb micromass cultures comparing GDF5 versus BMP4 effects on condensation, Sox9, and Col10

    PMID:11263662 PMID:15048875

    Open questions at the time
    • Adhesion molecules downstream of GDF5 not identified
    • Whether Sox9 is a direct transcriptional target of GDF5-Smad signaling was not tested
  4. 2004 High

    Identifying Ror2 as a co-receptor that forms a ligand-independent complex with BMPR-IB and is transphosphorylated by it answered how GDF5 activates both Smad and Smad-independent pathways during chondrogenesis, with Ror2 acting as a molecular switch between these outputs.

    Evidence Reciprocal Co-IP, transphosphorylation assays, luciferase reporters, and genetic epistasis using Ror2/BMPR-IB/Gdf5-deficient mouse crosses

    PMID:15569154

    Open questions at the time
    • Identity of the Smad-independent pathway downstream of Ror2 not fully resolved
    • Structural basis for the BMPR-IB/Ror2 complex unknown
  5. 2005 High

    Pinpointing Arg57 as the single residue conferring GDF5's 12-fold selectivity for BMPR-IB over BMPR-IA resolved how GDF5 achieves receptor specificity within the BMP family despite high structural homology.

    Evidence SPR binding analysis, structural modeling, and R57A mutagenesis

    PMID:15890363

    Open questions at the time
    • No crystal structure of the GDF5–BMPR-IB complex at that time
    • How receptor selectivity translates to distinct biological outputs in vivo not tested
  6. 2006 Medium

    Demonstrating GDF5's role in collagen fibril maturation — increasing fibril diameter and shifting procollagen type ratios — extended its function beyond cartilage to tendon and ligament repair.

    Evidence GDF5-null mouse tendon ultrastructure (EM), rat MCL injury model with GDF5 treatment and biomechanical testing

    PMID:11913489 PMID:16419971

    Open questions at the time
    • Direct molecular target of GDF5 in collagen fibril assembly not identified
    • Whether effect is Smad-dependent unknown
  7. 2007 High

    Identifying the rs143383 T allele as reducing GDF5 promoter activity in chondrogenic cells and joint cartilage in vivo established the first direct mechanistic link between reduced GDF5 expression and osteoarthritis susceptibility.

    Evidence Luciferase reporter assays in chondrogenic cells, allelic expression analysis in OA patient articular cartilage

    PMID:17384641 PMID:17616513

    Open questions at the time
    • Trans-acting factors mediating allelic differential expression not yet identified at this point
    • Whether reduced GDF5 is causal versus correlative for OA progression
  8. 2008 Medium

    Showing that GDF5 signals through BMPR-IB to activate p38 MAPK and upregulate the transcription factor Trps1 identified a non-Smad effector branch that promotes chondrocyte differentiation and apoptosis.

    Evidence ATDC5 cells treated with GDF5, dominant-negative Alk6, SB203580 inhibitor, western blot

    PMID:18363966

    Open questions at the time
    • Direct Trps1 target genes downstream not identified
    • Whether p38-Trps1 axis operates in vivo during joint development unknown
  9. 2009 High

    Mapping GDF5 mutations (N445K/T) to the overlapping NOGGIN/receptor interface revealed that gain-of-function joint fusions in multiple synostosis syndrome arise from antagonist resistance rather than enhanced receptor binding, establishing a unified structure–function model for disease mutations.

    Evidence Chicken micromass chondrogenesis, in vivo chick ectopic expression, site-directed mutagenesis, BMP9 variant engineering

    PMID:19956691

    Open questions at the time
    • Crystal structure of GDF5–NOGGIN complex not available
    • Whether all SYNS mutations share the same NOGGIN-resistance mechanism
  10. 2012 High

    The S94N mutation in the BMPR-II binding knuckle epitope showed simultaneous loss of receptor and antagonist binding, demonstrating that a single amino acid can produce context-dependent gain- or loss-of-function depending on the tissue's balance of receptor versus antagonist availability.

    Evidence SPR, reporter assays, ATDC5 and mouse micromass chondrogenesis assays

    PMID:21976273

    Open questions at the time
    • Quantitative modeling of receptor-versus-antagonist balance in specific tissues not done
  11. 2013 High

    Identification of SP1, SP3, and DEAF-1 as allele-differential repressors of GDF5 at rs143383, with DEAF-1 preferentially repressing the T allele, provided the trans-acting mechanism underlying the OA-susceptibility expression difference.

    Evidence Competition/supershift EMSA, oligonucleotide pulldown with quantitative MS, ChIP, RNAi, and overexpression

    PMID:19565498 PMID:23825960

    Open questions at the time
    • How SP1/DEAF-1 cooperate at the chromatin level not structurally resolved
    • Whether these factors explain allelic imbalance across all joint tissues
  12. 2013 High

    The W414R dual-mechanism mutation showed simultaneous NOGGIN resistance (causing SYNS2) and reduced BMPR-IA signaling (causing BDA1), proving that a single GDF5 residue can independently modulate antagonist and receptor interactions to produce composite phenotypes.

    Evidence Primary mesenchymal cell chondrogenesis, luciferase reporters, SPR

    PMID:24098149

    Open questions at the time
    • Whether therapeutic rescue of one arm (antagonist or receptor) suffices to correct the phenotype
  13. 2014 High

    CpG methylation at the +37 site within the SP1/SP3 binding footprint modulates allele-specific transcription factor binding and attenuates repression of GDF5, with differential methylation between hip and knee cartilage potentially explaining joint-site-specific OA susceptibility.

    Evidence Bisulfite sequencing, demethylation treatment, EMSA, luciferase reporters, comparative hip/knee methylation

    PMID:21642387 PMID:24861163

    Open questions at the time
    • Causal role of +37 methylation in OA onset not proven in vivo
    • Which methyltransferases set joint-specific methylation patterns at the GDF5 locus
  14. 2016 High

    Resolution of the Gremlin-2–GDF5 crystal structure at 2.9 Å showed how DAN-family antagonists use a conformationally dynamic N-terminus to simultaneously occlude type I and type II receptor sites, revealing a mechanistically distinct inhibition mode from NOGGIN.

    Evidence X-ray crystallography, SPR, structural comparison with NOGGIN mechanism

    PMID:27524626

    Open questions at the time
    • No in vivo evidence for Gremlin-2 as a physiological GDF5 antagonist in joint tissues
    • Whether DAN-family antagonism is relevant in joint disease
  15. 2016 High

    Genetic lineage tracing with Gdf5-CreERT2 demonstrated that joints form through continuous influx of Gdf5-expressing progenitors into the interzone over time, rather than from a single founder population, redefining the cellular mechanism of joint morphogenesis.

    Evidence Knockin Gdf5-CreERT2 mouse with temporal Cre activation and tdTomato reporter

    PMID:27292641

    Open questions at the time
    • Signals directing Gdf5-lineage progenitor influx not identified
    • Whether the same mechanism operates in synovial joint repair in adults
  16. 2016 High

    Systematic enhancer mapping revealed that GDF5's joint-specific expression is controlled by modular enhancers distributed over >100 kb, with distinct elements driving axial versus limb joint expression, and a downstream GROW1 enhancer required for growth plate expression and normal bone length.

    Evidence Transgenic mouse enhancer survey, functional rescue assays; GROW1 knockout and enhancer activity assays

    PMID:27902701 PMID:28671685

    Open questions at the time
    • Transcription factors acting through individual enhancers largely unidentified
    • How enhancer–promoter looping is organized across the >100-kb locus

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the structural basis of the GDF5–BMPR-IB complex, the identity of adhesion molecules mediating GDF5-driven mesenchymal condensation, the in vivo relevance of DAN-family antagonism at joints, and the mechanism by which the >100-kb enhancer landscape is coordinately regulated across different joint types.
  • No GDF5–BMPR-IB co-crystal structure
  • Adhesion molecules downstream of GDF5 in condensation unknown
  • Enhancer-promoter 3D topology at the Gdf5 locus not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-1474244 Extracellular matrix organization 2
Partners
BMPR1ABMPR1BBMPR2DEAF1GREM2NOGROR2SP1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 GDF5 shows pronounced binding specificity for BMPR-IB over BMPR-IA (approximately 12-fold higher affinity), and a single residue, Arg57 in the pre-helix loop, is solely responsible for this high binding specificity to BMPR-IB. The variant GDF5-R57A binds BMPR-IA and BMPR-IB with comparable high affinity. Biosensor analysis (SPR), structural analysis, and site-directed mutagenesis Journal of molecular biology High 15890363
1999 GDF5 is necessary and sufficient for both cartilage development and restriction of joint formation to appropriate locations in digit development. Loss-of-function brachypodism mice show reduced limb bone length, altered joint and sternum formation, and reduced digit bone number; recombinant GDF5 applied to developing chick and mouse limbs induces ectopic cartilage and restricts joint site. Mouse loss-of-function genetics (brachypodism mutant analysis), recombinant protein application to chick and mouse limb explants Developmental biology High 10208739
1997 A dominant-negative mutation in CDMP1/GDF5 (substituting the first conserved cysteine in the mature domain with tyrosine) results in a protein that is not secreted, is inactive in vitro, and prevents secretion of other related BMP family members, likely through heterodimer formation. In vitro secretion assay, dominant-negative co-expression assay, heterodimer formation analysis Nature genetics High 9288098
2004 Ror2 (tyrosine kinase receptor) and BMPR-IB (BRI-b, serine/threonine kinase receptor) form a ligand-independent heteromeric complex requiring the frizzled-like CRD domain of Ror2. Within this complex, Ror2 is transphosphorylated by BRI-b. Ror2 modulates GDF5 signaling by inhibiting Smad1/5 signaling and activating a Smad-independent pathway, both required for chondrogenic differentiation. Co-immunoprecipitation, transphosphorylation assays, luciferase reporter assays (Smad pathway), dominant-negative constructs in ATDC5 cells, epistasis analysis in Ror2/BRI-b/Gdf5 deficient mouse crosses Genes to cells High 15569154
2009 Two GDF5 mutations (N445K, N445T) identified in multiple synostosis syndrome patients cause resistance to the BMP antagonist NOGGIN due to substitution at residue N445, which lies within overlapping receptor and antagonist interfaces. This NOGGIN resistance results in gain-of-function, causing massive ectopic cartilage induction in vivo. Residue N445 is highly conserved among BMPs except BMP9 and BMP10, which naturally carry lysine at this position and are similarly NOGGIN-insensitive. Chicken micromass culture chondrogenesis assay, in vivo chick ectopic expression, site-directed mutagenesis, functional BMP9 variant engineering PLoS genetics High 19956691
2013 A GDF5 point mutation (W414R) simultaneously causes gain-of-function (NOGGIN resistance, leading to SYNS2) and loss-of-function (reduced signaling via BMPR-IA, leading to BDA1) through a dual pathomechanism, as the mutation lies within the overlapping antagonist and receptor binding interface of GDF5. Chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays, Surface Plasmon Resonance (SPR) binding analysis PLoS genetics High 24098149
2012 The GDF5 mutation S94N, located in the BMPR-II interaction site (knuckle epitope), impairs BMPR-II binding, reduces Smad and non-Smad signaling, and decreases chondrogenic differentiation of ATDC5 cells, but causes gain-of-function in mouse micromass cultures due to strongly reduced affinity for the antagonist NOGGIN, resulting in the SYNS phenotype. SPR binding assays, reporter gene assays, ALP assay, qPCR, ATDC5 and mouse micromass chondrogenesis assays Journal of bone and mineral research High 21976273
2016 The crystal structure of Gremlin-2 (a DAN-family BMP antagonist) in complex with GDF5 at 2.9-Å resolution reveals two Grem2 dimers binding perpendicularly to each GDF5 monomer in an H-like structure. The dynamic Grem2 N-terminus undergoes conformational change upon binding to simultaneously interact with both type I and type II receptor motifs on GDF5, blocking signaling. DAN-family members can interact with BMP type I receptor complexes, whereas Noggin outcompetes the type I receptor. X-ray crystallography (2.9-Å resolution), SPR binding studies, structural comparison Cell reports High 27524626
2008 GDF5 promotes chondroprogenitor cell aggregation by increasing cell adhesiveness and enhances skeletal element growth by increasing proliferation within epiphyseal cartilage. GDF5 acts at two distinct stages: promoting initial chondrogenesis via cell adhesion promotion, and increasing skeletal element size via proliferation. Chick embryo retroviral overexpression (RCAS), micromass and single-cell suspension cultures of limb mesenchymal cells, autoradiography of S-phase cells, histological analysis The Journal of bone and joint surgery. American volume High 11263662
1999 CDMP-1/GDF5 overexpression in transgenic mice promotes mesenchymal cell recruitment, increases number of chondroprogenitor cells, and accelerates chondrocyte differentiation to hypertrophy; expression in the notochord inhibits vertebral body formation by blocking sclerotome cell migration, antagonizing ventralization signals from the notochord. Transgenic mouse overexpression with histological and phenotypic analysis The Journal of cell biology High 9885252
2004 GDF5, in contrast to BMP4, increases the number of prechondrogenic mesenchymal cell condensations and promotes chondroprogenitor cell aggregation without inducing internodular cells toward chondrogenesis; GDF5 causes a more sustained elevation of Sox9 and a transient (not sustained) increase in Col10 expression, indicating distinct mechanisms from BMP4. Mouse embryonic limb bud mesenchyme micromass cultures with comparative BMP4/GDF5 treatment, gene expression analysis Journal of cellular biochemistry Medium 15048875
2008 GDF5 signals through the Alk6 (BMPR-IB) receptor to enhance Trps1 protein levels and p38 MAPK phosphorylation and nuclear translocation in chondrogenic cells; Trps1 acts downstream of GDF5 signaling to promote chondrocyte differentiation and apoptosis. Dominant-negative Alk6 blocks GDF5-induced Trps1 upregulation and differentiation. ATDC5 cell treatment with GDF5, dominant-negative Alk6 construct, SB203580 p38 inhibitor, western blot, Trps1 overexpression/knockdown Genes to cells Medium 18363966
2009 GDF5 and BMP2 prevent apoptosis induced by serum starvation in mouse embryonic fibroblasts via BMPR2, which stabilizes XIAP by stimulating BMPR2-XIAP interaction and reducing XIAP ubiquitination; increased XIAP then counteracts apoptosis by binding and inactivating activated caspases. This mechanism is independent of Smad and MAPK signaling. Cell viability assays, Co-IP (BMPR2-XIAP interaction), ubiquitination assays, caspase activity assays, BMPR2-deficient cell analysis Biochimica et biophysica acta Medium 19782107
2007 The rs143383 T/C SNP in the 5' UTR of GDF5 (located in the core promoter) exerts allelic differences in transcriptional activity in chondrogenic cells, with the OA susceptibility T allele showing reduced promoter activity. Luciferase reporter assays in chondrogenic cell lines Nature genetics High 17384641
2007 The OA-susceptibility T allele of rs143383 shows up to 27% reduction in GDF5 expression relative to the C allele in vivo in articular cartilage of OA patients, confirming that the functional effect of this regulatory SNP is active in joint tissue. Allelic expression analysis of RNA extracted from OA patient cartilage (in vivo differential allelic expression assay) Human molecular genetics High 17616513
2009 The transcription factor DEAF-1 binds differentially to the two alleles of rs143383 in the GDF5 5'UTR and acts as a trans-acting repressor of GDF5 expression; a second polymorphism in the 3'UTR also independently influences allelic expression of GDF5. Electrophoretic mobility shift assay (EMSA), luciferase reporter assays, allelic expression analysis in multiple joint tissue types Arthritis and rheumatism Medium 19565498
2013 Four trans-acting factors—Sp1, Sp3, P15, and DEAF-1—bind to the GDF5 5'UTR at the rs143383 locus. Sp1, Sp3, and DEAF-1 are repressors of GDF5 expression; DEAF-1 represses the T allele of rs143383 to a significantly greater extent than the C allele, contributing to differential allelic expression. Sp1 and DEAF-1 together have the greatest repressive activity. Competition and supershift EMSAs, oligonucleotide pulldown with quantitative mass spectrometry, ChIP, RNAi knockdown, and overexpression PLoS genetics High 23825960
2014 CpG methylation at the +37 site within the SP1/SP3 binding site modulates the allele-specific binding of SP1 and SP3 to rs143383, attenuating the repressive effects of SP1, SP3, and DEAF-1 on GDF5 promoter activity. The +37 CpG site is differentially methylated between osteoarthritic hip and knee cartilage, potentially explaining knee-specific OA susceptibility. Bisulfite sequencing, demethylation agent treatment, EMSA, luciferase reporter assays, comparative cartilage methylation analysis Human genetics High 24861163
2011 DNA methylation of the GDF5 promoter and 5'UTR regulates GDF5 expression; demethylation correlates with increased GDF5 expression. The CpG sites created by the C alleles at rs143383 and rs143384 are variably methylated, and demethylating agent treatment further increases allelic expression imbalance between C and T alleles. Bisulfite sequencing of cell lines and joint tissues, demethylating agent (5-azacytidine) treatment, allelic expression quantification Human molecular genetics High 21642387
2013 SOX11 directly binds conserved SOX family binding sites in the 5'UTR region of the GDF5 gene and activates GDF5 expression in vitro and in chick micromass cultures. SOX11 overexpression in developing chick limbs enhances (but does not ectopically induce) Gdf5 expression. Reporter gene assays, micromass cell cultures, chromatin binding assays (SOX11 binding to GDF5 5'UTR), RCAS viral overexpression in chick limbs BMC developmental biology Medium 23356643
2016 Separate modular enhancers in the Gdf5 locus control joint-specific expression in axial versus limb joints and in specific subsets of composite joints; predicted transcription factor binding sites within these enhancers are required for expression in particular joints. Functional rescue tests in mice confirm that large flanking regions (>100 kb including up- and downstream sequences) are required for normal joint formation and patterning. Systematic regulatory element survey using transgenic mice, in vivo enhancer functional rescue assays PLoS genetics High 27902701
2017 A novel downstream regulatory region (GROW1) is required for normal Gdf5 expression at the ends of developing bones and for normal bone lengths in vivo. A human GROW1 common base-pair change decreases enhancer activity and colocalizes with peaks of positive selection; the derived allele is found in Neandertals and Denisovans. Transgenic mouse regulatory survey, in vivo Gdf5 expression analysis, enhancer activity assays Nature genetics High 28671685
2016 Joints develop through a continuous influx of Gdf5-positive cells into the interzone, which contribute differentially to forming joint tissues including articular cartilage, capsule, and ligaments. Early labeling of Gdf5-positive interzone cells fails to mark the entire joint organ, while multiple Cre activation steps show contribution to various compartments over time. Knockin Gdf5-CreERT2 mouse lineage tracing with temporal Cre activation steps and tdTomato reporter Cell reports High 27292641
2013 GDF5 stimulation of human chondrocytes inhibits canonical Wnt signaling through upregulation of the Wnt inhibitors DKK1 and FRZB, and GDF5-mediated inhibition of MMP13 expression is specifically mediated by DKK1. GDF5 also upregulates anabolic genes ACAN and SOX9 and inhibits ADAMTS4. Human chondrocyte pellet mass culture, qPCR, ELISA, canonical Wnt stimulation (Wnt3a/CHIR-99021) and DKK1 blockade (WAY-262611) experiments Osteoarthritis and cartilage Medium 24561281
2013 BMP2 and GDF5 induce neuronal differentiation (neurite outgrowth) of SH-SY5Y human neuronal cells via a direct mechanism dependent on BMP type I receptor activation of canonical Smad1/5/8 signaling. SH-SY5Y cell culture, neurite outgrowth assay, BMP receptor inhibition, Smad1/5/8 phosphorylation assay Molecular and cellular neurosciences Medium 23831389
2008 A GDF5 mutation (p.L373R in the prodomain) allows secretion of mature GDF5 protein and causes proximal symphalangism (gain-of-function/altered function), while a different mutation (p.Y487X truncating the C-terminus) prevents secretion of mature GDF5 and causes brachydactyly type C (loss-of-function), demonstrating that distinct parts of the GDF5 protein govern distinct functional outcomes. Transfection of COS-7 cells with WT and mutant GDF5 cDNAs, western blot of conditioned medium for mature GDF5 protein detection Journal of human genetics Medium 18283415
2007 A novel ENU-induced GDF5 mutation (W408R) in a highly conserved region of the active signaling domain produces a protein that is secreted and dimerizes normally but inhibits wild-type GDF5 in a dominant-negative fashion, causing severe skeletal abnormalities and early-onset osteoarthritis in mice. ENU mutagenesis screen, secretion assay, dimerization assay, in vivo skeletal phenotyping including OA assessment Human molecular genetics Medium 17656374
2015 TGF-β1 and GDF5 synergistically drive nucleopulpogenic differentiation of human adipose stromal cells; Smad2/3 signaling mainly governs acquisition of NP cell molecular identity while Smad1/5/8 controls NP cell morphology during this differentiation process. Human adipose stromal cell differentiation, gene expression analysis, Smad pathway inhibition, in vivo transplantation in nude mice Stem cells Medium 26661057
2020 Gdf5 upregulation in articular cartilage and synovium following joint injury requires downstream regulatory sequence of the Gdf5 locus; in progenitors, Gdf5 expression is inversely correlated with YAP expression, and YAP overexpression suppresses Gdf5 expression in chondroprogenitors in vitro. Gdf5-LacZ reporter mouse lines, DMM experimental OA model, acute cartilage injury model, YAP overexpression in chondroprogenitors Scientific reports Medium 31932746
2019 CaVβ1E (an embryonic isoform of the CaV1.1 β subunit) boosts downstream GDF5 signaling to counteract muscle loss after denervation; aged muscle expresses lower CaVβ1E and shows an altered GDF5-dependent response to denervation. CaVβ1E overexpression improves mass wasting in aging muscle by increasing GDF5 expression. Sciatic denervation mouse model, Dnmt3a-KO mice, CaVβ1E overexpression, muscle mass and gene expression analysis Science translational medicine Medium 31694926
2018 Dnmt3a methylates the Gdf5 promoter in satellite cells; loss of Dnmt3a leads to reduced Gdf5 promoter methylation, markedly increased Gdf5 mRNA expression, suppressed satellite cell differentiation, and impaired skeletal muscle regeneration. Treatment with DNA methylation inhibitor azacytidine also increases Gdf5 expression in wild-type satellite cells. Skeletal muscle-specific Dnmt3a-KO mice, microarray analysis, promoter methylation analysis, azacytidine treatment, satellite cell differentiation assays FASEB journal Medium 29146735
2016 miR-7 directly targets GDF5 in nucleus pulposus cells; miR-7 overexpression enhances IL-1β-induced extracellular matrix degeneration, while inhibition of miR-7 prevents this, an effect that is reversed by GDF5 siRNA. This establishes GDF5 as a downstream mediator of miR-7 action on disc ECM. Dual-luciferase reporter assay (direct 3'UTR targeting), gain- and loss-of-function with miR-7 mimic/antagomiR, GDF5 siRNA rescue Biomedicine & pharmacotherapy Medium 27583982
2004 GDF5 deficiency in mice results in altered collagen fibril size distribution (increased proportion of medium-diameter fibrils at the expense of larger fibrils) in tail tendons, leading to altered time-dependent mechanical behavior (slower stress-relaxation), suggesting GDF5 regulates collagen fibril assembly in tendon. Electron microscopy ultrastructural analysis, biomechanical testing of GDF5-/- vs. control littermate tail tendons Connective tissue research Medium 11913489
2006 GDF5 treatment of rat medial collateral ligament injury increased collagen fibril diameter in repair tissue, enhanced type I procollagen expression, and reduced type III procollagen relative to type I, with decorin and fibromodulin expression also relatively reduced against type I collagen, explaining increased fibril diameter and improved biomechanical strength. Rat MCL gap injury model, transmission electron microscopy, quantitative PCR, in situ hybridization, biomechanical testing Journal of orthopaedic research Medium 16419971
2003 GDF5 regulates connexin 43 (Cx43) expression and enhances chondrogenesis in a gap junction-dependent manner, with concordant mRNA expression profiles of GDF5 and Cx43 during embryonic development in limb, spine, and heart. Expression correlation analysis during embryogenesis, functional studies linking GDF5 action to gap junction activity The anatomical record Low 14613311

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis. Nature genetics 370 17384641
2008 Common variants in the GDF5-UQCC region are associated with variation in human height. Nature genetics 315 18193045
1999 GDF5 coordinates bone and joint formation during digit development. Developmental biology 309 10208739
1997 Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nature genetics 270 9288098
2007 An SNP in the 5'-UTR of GDF5 is associated with osteoarthritis susceptibility in Europeans and with in vivo differences in allelic expression in articular cartilage. Human molecular genetics 167 17616513
1999 Role of CDMP-1 in skeletal morphogenesis: promotion of mesenchymal cell recruitment and chondrocyte differentiation. The Journal of cell biology 147 9885252
2015 TGF-β1, GDF-5, and BMP-2 stimulation induces chondrogenesis in expanded human articular chondrocytes and marrow-derived stromal cells. Stem cells (Dayton, Ohio) 127 25377511
2001 Growth/differentiation factor-5 (GDF-5) and skeletal development. The Journal of bone and joint surgery. American volume 126 11263662
2005 A single residue of GDF-5 defines binding specificity to BMP receptor IB. Journal of molecular biology 125 15890363
2016 Joint Development Involves a Continuous Influx of Gdf5-Positive Cells. Cell reports 119 27292641
2004 Distinct functions of BMP4 and GDF5 in the regulation of chondrogenesis. Journal of cellular biochemistry 116 15048875
2011 Tendon tissue engineering: adipose-derived stem cell and GDF-5 mediated regeneration using electrospun matrix systems. Biomedical materials (Bristol, England) 112 21436509
2011 Expression of the osteoarthritis-associated gene GDF5 is modulated epigenetically by DNA methylation. Human molecular genetics 95 21642387
2007 BMP-14 gene therapy increases tendon tensile strength in a rat model of Achilles tendon injury. The Journal of bone and joint surgery. American volume 95 17545436
2009 Functional analysis of the osteoarthritis susceptibility-associated GDF5 regulatory polymorphism. Arthritis and rheumatism 92 19565498
2003 GDF-5 deficiency in mice delays Achilles tendon healing. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 92 12919870
2006 Growth and differentiation factor-5 (GDF-5) stimulates osteogenic differentiation and increases vascular endothelial growth factor (VEGF) levels in fat-derived stromal cells in vitro. Bone 87 17070126
2014 CpG methylation regulates allelic expression of GDF5 by modulating binding of SP1 and SP3 repressor proteins to the osteoarthritis susceptibility SNP rs143383. Human genetics 85 24861163
2004 Modulation of GDF5/BRI-b signalling through interaction with the tyrosine kinase receptor Ror2. Genes to cells : devoted to molecular & cellular mechanisms 80 15569154
2017 Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk. Nature genetics 79 28671685
2014 GDF5 reduces MMP13 expression in human chondrocytes via DKK1 mediated canonical Wnt signaling inhibition. Osteoarthritis and cartilage 78 24561281
2004 Repair of articular cartilage defects in rabbits using CDMP1 gene-transfected autologous mesenchymal cells derived from bone marrow. Rheumatology (Oxford, England) 78 15187242
2009 Mutations in GDF5 reveal a key residue mediating BMP inhibition by NOGGIN. PLoS genetics 76 19956691
2018 Heparin functionalization increases retention of TGF-β2 and GDF5 on biphasic silk fibroin scaffolds for tendon/ligament-to-bone tissue engineering. Acta biomaterialia 75 29550439
2019 3D-bioprinting a genetically inspired cartilage scaffold with GDF5-conjugated BMSC-laden hydrogel and polymer for cartilage repair. Theranostics 70 31660079
2015 TGF-β1 and GDF5 Act Synergistically to Drive the Differentiation of Human Adipose Stromal Cells toward Nucleus Pulposus-like Cells. Stem cells (Dayton, Ohio) 68 26661057
2004 Multiple effects of GDF-5 deficiency on skeletal tissues: implications for therapeutic bioengineering. Annals of biomedical engineering 67 15095821
2008 Freeze-dried tendon allografts as tissue-engineering scaffolds for Gdf5 gene delivery. Molecular therapy : the journal of the American Society of Gene Therapy 66 18180771
2008 Association of the DVWA and GDF5 polymorphisms with osteoarthritis in UK populations. Annals of the rheumatic diseases 64 19054821
2002 Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome). Clinical genetics 64 12121354
2020 Regulation of Gdf5 expression in joint remodelling, repair and osteoarthritis. Scientific reports 61 31932746
2016 Heads, Shoulders, Elbows, Knees, and Toes: Modular Gdf5 Enhancers Control Different Joints in the Vertebrate Skeleton. PLoS genetics 60 27902701
2010 Evidence of association between GDF5 polymorphisms and congenital dislocation of the hip in a Caucasian population. Osteoarthritis and cartilage 59 20633687
2001 GDF-5 deficiency in mice leads to disruption of tail tendon form and function. Connective tissue research 59 11913489
2007 A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice. Human molecular genetics 55 17656374
2018 Genome-wide association study of developmental dysplasia of the hip identifies an association with GDF5. Communications biology 54 30273415
2013 Photo-cured hyaluronic acid-based hydrogels containing growth and differentiation factor 5 (GDF-5) for bone tissue regeneration. Bone 54 24291420
2008 Genetic variation in the GDF5 region is associated with osteoarthritis, height, hip axis length and fracture risk: the Rotterdam study. Annals of the rheumatic diseases 54 19029166
2013 The effect of a bioactive collagen membrane releasing PDGF or GDF-5 on bone regeneration. Biomaterials 52 24388383
2004 Brachydactyly type C caused by a homozygous missense mutation in the prodomain of CDMP1. American journal of medical genetics. Part A 52 14735582
2013 The identification of trans-acting factors that regulate the expression of GDF5 via the osteoarthritis susceptibility SNP rs143383. PLoS genetics 51 23825960
2003 Release of active and depot GDF-5 after adenovirus-mediated overexpression stimulates rabbit and human intervertebral disc cells. Journal of molecular medicine (Berlin, Germany) 51 14669002
2003 Broad phenotypic spectrum caused by an identical heterozygous CDMP-1 mutation in three unrelated families. American journal of medical genetics. Part A 50 12567410
2019 Genome-wide association study of knee pain identifies associations with GDF5 and COL27A1 in UK Biobank. Communications biology 49 31482140
2013 BMP2 and GDF5 induce neuronal differentiation through a Smad dependant pathway in a model of human midbrain dopaminergic neurons. Molecular and cellular neurosciences 47 23831389
2002 Frameshift mutation in the cartilage-derived morphogenetic protein 1 (CDMP1) gene and severe acromesomelic chondrodysplasia resembling Grebe-type chondrodysplasia. American journal of medical genetics 46 12124730
2019 Sustained release of GDF5 from a designed coacervate attenuates disc degeneration in a rat model. Acta biomaterialia 45 30660009
2008 Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism. Journal of human genetics 45 18283415
2016 Structure of Gremlin-2 in Complex with GDF5 Gives Insight into DAN-Family-Mediated BMP Antagonism. Cell reports 41 27524626
2016 MicroRNA-7 regulates IL-1β-induced extracellular matrix degeneration by targeting GDF5 in human nucleus pulposus cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 40 27583982
2013 SOX11 contributes to the regulation of GDF5 in joint maintenance. BMC developmental biology 39 23356643
2008 Trps1 plays a pivotal role downstream of Gdf5 signaling in promoting chondrogenesis and apoptosis of ATDC5 cells. Genes to cells : devoted to molecular & cellular mechanisms 39 18363966
2013 Enhanced reconstruction of long bone architecture by a growth factor mutant combining positive features of GDF-5 and BMP-2. Biomaterials 37 23680368
2012 Genetic association analysis of GDF5 and ADAM12 for knee osteoarthritis. Joint bone spine 36 22284607
2006 Differential regulation of GDF-5 and FGF-2/4 by immobilisation in ovo exposes distinct roles in joint formation. Developmental dynamics : an official publication of the American Association of Anatomists 36 16425226
2009 GDF5 and BMP2 inhibit apoptosis via activation of BMPR2 and subsequent stabilization of XIAP. Biochimica et biophysica acta 34 19782107
2013 A GDF5 point mutation strikes twice--causing BDA1 and SYNS2. PLoS genetics 33 24098149
2011 Time kinetics of bone defect healing in response to BMP-2 and GDF-5 characterised by in vivo biomechanics. European cells & materials 33 21312163
2023 Skeletal Muscle-Derived Exosomal miR-146a-5p Inhibits Adipogenesis by Mediating Muscle-Fat Axis and Targeting GDF5-PPARγ Signaling. International journal of molecular sciences 32 36901991
2022 Regulatory Mechanisms of Prg4 and Gdf5 Expression in Articular Cartilage and Functions in Osteoarthritis. International journal of molecular sciences 32 35563063
2016 Inhibition of microRNA-34a prevents IL-1β-induced extracellular matrix degradation in nucleus pulposus by increasing GDF5 expression. Experimental biology and medicine (Maywood, N.J.) 32 27385596
2005 The role of growth/differentiation factor 5 (GDF5) in the induction and survival of midbrain dopaminergic neurones: relevance to Parkinson's disease treatment. Journal of anatomy 32 16185246
2017 MiR-615-3p inhibits the osteogenic differentiation of human lumbar ligamentum flavum cells via suppression of osteogenic regulators GDF5 and FOXO1. Cell biology international 31 28460412
2019 microRNA-132 inhibits osteogenic differentiation of periodontal ligament stem cells via GDF5 and the NF-κB signaling pathway. Pathology, research and practice 30 31718857
2018 microRNA-665 promotes the proliferation and matrix degradation of nucleus pulposus through targeting GDF5 in intervertebral disc degeneration. Journal of cellular biochemistry 30 29761869
2018 Injured Achilles Tendons Treated with Adipose-Derived Stem Cells Transplantation and GDF-5. Cells 30 30200326
2010 Combined use of bFGF and GDF-5 enhances the healing of medial collateral ligament injury. Biochemical and biophysical research communications 30 20937261
2006 Effect of GDF-5 on ligament healing. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 30 16419971
2013 Analysis of association between IL-1β, CASP-9, and GDF5 variants and low-back pain in Chinese male soldier: clinical article. Journal of neurosurgery. Spine 29 23725396
2018 Reduced Dnmt3a increases Gdf5 expression with suppressed satellite cell differentiation and impaired skeletal muscle regeneration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28 29146735
2012 GDF5 regulates TGFß-dependent angiogenesis in breast carcinoma MCF-7 cells: in vitro and in vivo control by anti-TGFß peptides. PloS one 28 23226264
2006 A novel mutation in GDF5 causes autosomal dominant symphalangism in two Chinese families. American journal of medical genetics. Part A 28 16892395
2012 New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): mutation within the GDF5 knuckle epitope causes noggin-resistance. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 27 21976273
2008 A novel insertion mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene underlies Grebe-type chondrodysplasia in a consanguineous Pakistani family. BMC medical genetics 27 19038017
2005 A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2. Journal of medical genetics 27 16014698
2020 Knockout of miR-21-5p alleviates cartilage matrix degradation by targeting Gdf5 in temporomandibular joint osteoarthritis. Bone & joint research 26 33231490
2016 Adenovirus-mediated GDF-5 promotes the extracellular matrix expression in degenerative nucleus pulposus cells. Journal of Zhejiang University. Science. B 26 26739524
2005 Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene. American journal of medical genetics. Part A 26 16222676
2004 Altered hypertrophic chondrocyte kinetics in GDF-5 deficient murine tibial growth plates. Journal of orthopaedic research : official publication of the Orthopaedic Research Society 26 15099634
2019 An embryonic CaVβ1 isoform promotes muscle mass maintenance via GDF5 signaling in adult mouse. Science translational medicine 25 31694926
2024 Decellularized nucleus pulposus matrix/chitosan hybrid hydrogel combined with nucleus pulposus stem cells and GDF5-loaded microspheres for intervertebral disc degeneration prevention. Molecular medicine (Cambridge, Mass.) 24 38200442
2012 Positive selection on the osteoarthritis-risk and decreased-height associated variants at the GDF5 gene in East Asians. PloS one 24 22905146
2018 BMP14 induces tenogenic differentiation of bone marrow mesenchymal stem cells in vitro. Experimental and therapeutic medicine 23 30116367
2014 Association between GDF5 rs143383 polymorphism and knee osteoarthritis: an updated meta-analysis based on 23,995 subjects. BMC musculoskeletal disorders 23 25467786
2014 Growth and differentiation factor-5 (GDF-5) in the human intervertebral annulus cells and its modulation by IL-1ß and TNF-α in vitro. Experimental and molecular pathology 22 24582800
2013 Rs143383 in the growth differentiation factor 5 (GDF5) gene significantly associated with osteoarthritis (OA)-a comprehensive meta-analysis. International journal of medical sciences 22 23423687
2010 Mutations in GDF5 presenting as semidominant brachydactyly A1. Human mutation 22 20683927
2003 Correlation of GDF5 and connexin 43 mRNA expression during embryonic development. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology 22 14613311
2017 Novel homozygous sequence variants in the GDF5 gene underlie acromesomelic dysplasia type-grebe in consanguineous families. Congenital anomalies 21 27577507
2022 Long non-coding RNA SNHG5 promotes the osteogenic differentiation of bone marrow mesenchymal stem cells via the miR-212-3p/GDF5/SMAD pathway. Stem cell research & therapy 19 35346361
2019 DNA hypermethylation of GDF5 in developmental dysplasia of the hip (DDH). Molecular genetics & genomic medicine 18 31338995
2018 The role of Gdf5 regulatory regions in development of hip morphology. PloS one 18 30388100
2016 Mutant GDF5 enhances ameloblast differentiation via accelerated BMP2-induced Smad1/5/8 phosphorylation. Scientific reports 18 27030100
2015 Association of GDF5, SMAD3 and RUNX2 polymorphisms with temporomandibular joint osteoarthritis in female Han Chinese. Journal of oral rehabilitation 18 25757091
2014 Human chondrocytes respond discordantly to the protein encoded by the osteoarthritis susceptibility gene GDF5. PloS one 18 24466161
2014 Superior angiogenic potential of GDF-5 and GDF-5(V453/V456) compared with BMP-2 in a rabbit long-bone defect model. The Journal of bone and joint surgery. American volume 18 25320196
2011 Deep sequencing of GDF5 reveals the absence of rare variants at this important osteoarthritis susceptibility locus. Osteoarthritis and cartilage 17 21281725
2009 Synergistic effects of growth and differentiation factor-5 (GDF-5) and insulin on expanded chondrocytes in a 3-D environment. Osteoarthritis and cartilage 17 19470416
2021 Genetic Study of IL6, GDF5 and PAPPA2 in Association with Developmental Dysplasia of the Hip. Genes 16 34203285
2003 Grebe dysplasia and the spectrum of CDMP1 mutations. Pediatric pathology & molecular medicine 16 12687891