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Gene Review

GDF5  -  growth differentiation factor 5

Homo sapiens

Synonyms: BDA1C, BMP-14, BMP14, Bone morphogenetic protein 14, CDMP-1, ...
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Disease relevance of GDF5

  • We show here that GDF5 is expresed in the developing CNS including the mesencephalon and acts as a neurotrophic, survival promoting molecule for rat dopaminergic midbrain neurons, which degenerate in Parkinson's disease [1].
  • GDF5 also protects dopaminergic neurons against the toxicity of N-methylpyridinium ion (MPP+), which selectively damages dopaminergic neurons through mechanisms currently debated in the etiology of Parkinson's disease (PD) [1].
  • Here, we report that the gene encoding growth differentiation factor 5 (GDF5) is associated with osteoarthritis in Asian populations [2].
  • A SNP in the 5' UTR of GDF5 (+104T/C; rs143383) showed significant association (P = 1.8 x 10(-13)) with hip osteoarthritis in two independent Japanese populations [2].
  • A new syndrome of symphalangism, multiple frenula, postaxial polydactyly, dysplastic ears, dental anomalies, and exclusion of NOG and GDF5 [3].

High impact information on GDF5


Biological context of GDF5

  • Here we demonstrate that all three components are involved in GDF5 induced regulation of chondrogenesis [7].
  • Heterozygous missense mutations in the serine-threonine kinase receptor BMPR1B result typically in brachydactyly type A2 (BDA2), whereas mutations in the corresponding ligand GDF5 cause brachydactyly type C (BDC) [8].
  • Disturbances of NOG-GDF5-BMPR1B signaling cascade can result in similar clinical manifestations depending on the quantitative effect and mode of action of the specific mutations within the same functional pathway.European Journal of Human Genetics (2006) 14, 1248-1254. doi:10.1038/sj.ejhg.5201708; published online 6 September 2006 [8].
  • Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12 [9].
  • GDF5 may control the morphogenesis of cartilaginous tissue, including joints, in the skeletal development of limbs [10].

Anatomical context of GDF5


Associations of GDF5 with chemical compounds

  • We studied the biological activities of recombinant CDMP-1 and CDMP-2 in chondrogenic and osteogenic differentiation and investigated their binding properties to type I and type II serine/threonine kinase receptors [13].
  • Growth/differentiation factor 5 (GDF5) is a neurotrophin which protects the rat nigrostriatal dopaminergic pathway from 6-hydroxydopamine-induced damage [14].
  • We identified a missense mutation, c.1322T>C, causing substitution of a leucine with a proline at amino acid residue 441 within the active signalling domain of GDF5 [15].
  • Expression of the type II collagen gene, a hallmark of chondrogenesis in vertebrates, was also induced by GDF-5 treatment and strongly suppressed by SB202190 [16].
  • Inactivation of the Gdf6 gene causes defects in joint, ligament, and cartilage formation at sites distinct from those seen in Gdf5 mutants, including the wrist and ankle, the middle ear, and the coronal suture between bones in the skull [17].

Regulatory relationships of GDF5


Other interactions of GDF5

  • A recent study of mice carrying different combinations of mutations in the genes for two bone morphogenetic factors (BMPs), BMP5 and GDF5, indicates that BMPs have specific and synergistic functions in the regulation of skeleton development [21].
  • Cells were grown as monolayer cultures for 7 days in a chemically defined serum-free basal medium (BM) in the presence of recombinant CDMP-1, -2, and OP-1 [12].
  • In the present study, we used immunohistochemical methods to investigate the distribution of BMP-2, -3, -5, -6, -7 and CDMP-1, -2, -3 in human osteophytes (abnormal bony outgrowths) isolated from osteoarthritic hip and knee joints from patients undergoing total joint replacement surgery [22].
  • Single-cell clonal growth proliferation assays were performed using recombinant human GDF-5 and TGF-beta1 [11].
  • Expression of bone morphogenetic proteins and cartilage-derived morphogenetic proteins during osteophyte formation in humans [22].

Analytical, diagnostic and therapeutic context of GDF5


  1. Trophic and protective effects of growth/differentiation factor 5, a member of the transforming growth factor-beta superfamily, on midbrain dopaminergic neurons. Krieglstein, K., Suter-Crazzolara, C., Hötten, G., Pohl, J., Unsicker, K. J. Neurosci. Res. (1995) [Pubmed]
  2. A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis. Miyamoto, Y., Mabuchi, A., Shi, D., Kubo, T., Takatori, Y., Saito, S., Fujioka, M., Sudo, A., Uchida, A., Yamamoto, S., Ozaki, K., Takigawa, M., Tanaka, T., Nakamura, Y., Jiang, Q., Ikegawa, S. Nat. Genet. (2007) [Pubmed]
  3. A new syndrome of symphalangism, multiple frenula, postaxial polydactyly, dysplastic ears, dental anomalies, and exclusion of NOG and GDF5. Kantaputra, P.N., Pongprot, Y., Praditsap, O., Pho-iam, T., Limwongse, C. Am. J. Med. Genet. A (2003) [Pubmed]
  4. Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Thomas, J.T., Kilpatrick, M.W., Lin, K., Erlacher, L., Lembessis, P., Costa, T., Tsipouras, P., Luyten, F.P. Nat. Genet. (1997) [Pubmed]
  5. A human chondrodysplasia due to a mutation in a TGF-beta superfamily member. Thomas, J.T., Lin, K., Nandedkar, M., Camargo, M., Cervenka, J., Luyten, F.P. Nat. Genet. (1996) [Pubmed]
  6. Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. Seemann, P., Schwappacher, R., Kjaer, K.W., Krakow, D., Lehmann, K., Dawson, K., Stricker, S., Pohl, J., Plöger, F., Staub, E., Nickel, J., Sebald, W., Knaus, P., Mundlos, S. J. Clin. Invest. (2005) [Pubmed]
  7. Modulation of GDF5/BRI-b signalling through interaction with the tyrosine kinase receptor Ror2. Sammar, M., Stricker, S., Schwabe, G.C., Sieber, C., Hartung, A., Hanke, M., Oishi, I., Pohl, J., Minami, Y., Sebald, W., Mundlos, S., Knaus, P. Genes Cells (2004) [Pubmed]
  8. A novel R486Q mutation in BMPR1B resulting in either a brachydactyly type C/symphalangism-like phenotype or brachydactyly type A2. Lehmann, K., Seemann, P., Boergermann, J., Morin, G., Reif, S., Knaus, P., Mundlos, S. Eur. J. Hum. Genet. (2006) [Pubmed]
  9. The mutational spectrum of brachydactyly type C. Everman, D.B., Bartels, C.F., Yang, Y., Yanamandra, N., Goodman, F.R., Mendoza-Londono, J.R., Savarirayan, R., White, S.M., Graham, J.M., Gale, R.P., Svarch, E., Newman, W.G., Kleckers, A.R., Francomano, C.A., Govindaiah, V., Singh, L., Morrison, S., Thomas, J.T., Warman, M.L. Am. J. Med. Genet. (2002) [Pubmed]
  10. Recombinant human growth/differentiation factor 5 stimulates mesenchyme aggregation and chondrogenesis responsible for the skeletal development of limbs. Hötten, G.C., Matsumoto, T., Kimura, M., Bechtold, R.F., Kron, R., Ohara, T., Tanaka, H., Satoh, Y., Okazaki, M., Shirai, T., Pan, H., Kawai, S., Pohl, J.S., Kudo, A. Growth Factors (1996) [Pubmed]
  11. Bone morphogenetic proteins and growth and differentiation factors in the human cornea. You, L., Kruse, F.E., Pohl, J., Völcker, H.E. Invest. Ophthalmol. Vis. Sci. (1999) [Pubmed]
  12. Cartilage-derived morphogenetic protein-1 and -2 are endogenously expressed in healthy and osteoarthritic human articular chondrocytes and stimulate matrix synthesis. Bobacz, K., Gruber, R., Soleiman, A., Graninger, W.B., Luyten, F.P., Erlacher, L. Osteoarthr. Cartil. (2002) [Pubmed]
  13. Cartilage-derived morphogenetic proteins and osteogenic protein-1 differentially regulate osteogenesis. Erlacher, L., McCartney, J., Piek, E., ten Dijke, P., Yanagishita, M., Oppermann, H., Luyten, F.P. J. Bone Miner. Res. (1998) [Pubmed]
  14. Neuroprotective effects of growth/differentiation factor 5 depend on the site of administration. Sullivan, A.M., Opacka-Juffry, J., Pohl, J., Blunt, S.B. Brain Res. (1999) [Pubmed]
  15. A mutation in the receptor binding site of GDF5 causes Mohr-Wriedt brachydactyly type A2. Kjaer, K.W., Eiberg, H., Hansen, L., van der Hagen, C.B., Rosendahl, K., Tommerup, N., Mundlos, S. J. Med. Genet. (2006) [Pubmed]
  16. p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells. Nakamura, K., Shirai, T., Morishita, S., Uchida, S., Saeki-Miura, K., Makishima, F. Exp. Cell Res. (1999) [Pubmed]
  17. Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Settle, S.H., Rountree, R.B., Sinha, A., Thacker, A., Higgins, K., Kingsley, D.M. Dev. Biol. (2003) [Pubmed]
  18. Upregulation of ID protein by growth and differentiation factor 5 (GDF5) through a smad-dependent and MAPK-independent pathway in HUVSMC. Chen, X., Zankl, A., Niroomand, F., Liu, Z., Katus, H.A., Jahn, L., Tiefenbacher, C. J. Mol. Cell. Cardiol. (2006) [Pubmed]
  19. Recombinant growth/differentiation factor-5 stimulates osteogenic differentiation of fat-derived stromal cells in vitro. Zeng, Q., Li, X., Choi, L., Beck, G., Balian, G., Shen, F.H. Connect. Tissue Res. (2006) [Pubmed]
  20. Growth/differentiation factor-5 induces angiogenesis in vivo. Yamashita, H., Shimizu, A., Kato, M., Nishitoh, H., Ichijo, H., Hanyu, A., Morita, I., Kimura, M., Makishima, F., Miyazono, K. Exp. Cell Res. (1997) [Pubmed]
  21. Defining the skeletal elements. Vortkamp, A. Curr. Biol. (1997) [Pubmed]
  22. Expression of bone morphogenetic proteins and cartilage-derived morphogenetic proteins during osteophyte formation in humans. Zoricic, S., Maric, I., Bobinac, D., Vukicevic, S. J. Anat. (2003) [Pubmed]
  23. Stimulatory effects of cartilage-derived morphogenetic proteins 1 and 2 on osteogenic differentiation of bone marrow stromal cells. Gruber, R., Mayer, C., Schulz, W., Graninger, W., Peterlik, M., Watzek, G., Luyten, F.P., Erlacher, L. Cytokine (2000) [Pubmed]
  24. GDF5 is a second locus for multiple-synostosis syndrome. Dawson, K., Seeman, P., Sebald, E., King, L., Edwards, M., Williams, J., Mundlos, S., Krakow, D. Am. J. Hum. Genet. (2006) [Pubmed]
  25. Isolation of a cDNA sequence of rabbit GDF5 (mature form) and pattern of its mRNA expression during periosteal chondrogenesis. Sanyal, A., Sarkar, G., Fitzsimmons, J.S., O'Driscoll, S.W. Mol. Biotechnol. (2000) [Pubmed]
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