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Gene Review

BMP6  -  bone morphogenetic protein 6

Homo sapiens

Synonyms: BMP-6, Bone morphogenetic protein 6, VG-1-R, VG-1-related protein, VGR, ...
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Disease relevance of BMP6

  • Furthermore, this coinactivation of BMP3b and BMP6 is significantly associated with mutation of k-ras codon 12 in lung cancer (P=0.003); those with a k-ras mutation were six times more likely to have concurrent methylation of these BMP loci [1].
  • Cultured BMDMSC were transduced with E1-deleted adenoviral vectors containing either human BMP2 or BMP6 coding sequence under cytomegalovirus (CMV) promoter control [17:1 multiplicities of infection (moi)] and either sustained in monolayer or suspended in 1 mL 1.2% alginate beads for 22 days [2].
  • Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism [3].
  • We tested the hypothesis that BMP-6 contributes to prostate cancer-induced osteosclerosis at bone metastatic sites [3].
  • Osteogenic protein-1 stimulates mRNA levels of BMP-6 and decreases mRNA levels of BMP-2 and -4 in human osteosarcoma cells [4].
  • These data demonstrate that BMP-6 promotes migration and invasion of prostate cancer cells, potentially through activation of Id-1 and MMP activation [5].

High impact information on BMP6


Chemical compound and disease context of BMP6

  • The effects of 17beta-estradiol (E2) and ICI 182,780 (ICI) on activity of a BMP-6 promoter were compared in osteoblast-like and breast cancer cells transiently transfected with ERalpha [9].
  • In further studies where we compared the intracellular distribution of ERalpha associated with these responses, E2-dependent stimulation of the BMP-6 reporter in MCF-7 cells was associated with intranuclear localization of ERalpha, whereas extranuclear localization was seen in rat osteosarcoma cells (ROS) cells treated with ICI [9].
  • Bone sialoprotein and/or bone morphogenetic protein 6 expression correlated with bone metastasis, while thymidine phosphorylase expression was related to local recurrence (p = 0.002 and/or 0.007, and 0.00007, respectively) [10].
  • BMP-6 and retinoic acid synergistically differentiate the IMR-32 human neuroblastoma cells [11].

Biological context of BMP6


Anatomical context of BMP6


Associations of BMP6 with chemical compounds

  • Inhibition of endogenous BMP-6 action by neutralizing antibodies impaired aldosterone production induced by Ang II but not that induced by K [20].
  • Involvement of bone morphogenetic protein-6 in differential regulation of aldosterone production by angiotensin II and potassium in human adrenocortical cells [20].
  • Treatment with the GC triamcinolone (10(-9) M) resulted in a 5- to 8-fold increase in BMP-6 steady-state messenger RNA levels, peaking at 12 h [17].
  • Here, we investigated functional roles of BMP-6, focusing on the differential regulation of aldosterone synthesis induced by angiotensin (Ang) II and potassium (K) [20].
  • In contrast, transcripts for Growth/ Differentiation factor-S (GDF-5) were induced during a cellular condensation, and those for BMP-6 were induced during the formation of cartilage nodules, and declined as the differentiated ATDC5 cells became hypertrophic, and BMP-7 transcripts were only detected after cells became calcified [21].

Physical interactions of BMP6

  • As a member of the TGF-beta super-family, BMP-6 binds to both BMP type I and type II receptors and is involved in the developmental processes of renal and hepatic systems as well as of human foetal intestine [22].

Regulatory relationships of BMP6

  • In human adrenocortical H295R cells, BMP-6 augmented Ang II-induced CYP11B2 transcription and mRNA and aldosterone production but had no effect on K-induced aldosterone production [20].
  • Replacement of BMP6 to SCG explant preparations significantly blunted the injury-induced elevated PACAP expression, with a concomitant decrease in sympathetic PACAP-immunoreactive neuron numbers [23].
  • Recent work has shown that BMP3b is epigenetically inactivated in cancer and suggests that BMP6 can be epigenetically inactivated [1].
  • These findings suggest various BMPs and activin A as components of the conjunctival cytokine meshwork regulating tissue homeostasis and wound healing and provide evidence that alterations in the expression of BMP-6 and activin A, in particular, are associated with conjunctival scarring [24].
  • Furthermore, in CD10(+) B progenitors as well as in Nalm-6 cells, BMP-6 rapidly induced phosphorylation of Smad1/5/8, followed by an upregulation of Id1 and Id3 mRNA levels [25].

Other interactions of BMP6

  • Importantly, myeloma cells not responsive to BMP-2 and -4 may still be sensitive to BMP-6 or -7 [26].
  • In this study, we examined the effects on human myeloma cells of BMP-6 and -7, members of a different BMP subgroup, which mainly utilize Alk-2 as their receptor [26].
  • Alk-2-expressing cell lines responded with growth inhibition and apoptosis to BMP-6 and -7, whereas cell lines lacking both Alk-3 and -6 were resistant to BMP-4 [26].
  • Here, we demonstrate that the BMP3b and BMP6 genes are common targets of epigenetic inactivation in NSCLC, and that they are significantly more likely to be concurrently inactivated (P=0.009) [1].
  • The mRNA and protein expression of both BMP-6 and activin A was found to be significantly increased in scar tissue compared with normal conjunctiva and could be immunolocalized to epithelial cells, vascular endothelia, stromal fibroblasts, and macrophage-like cells [24].

Analytical, diagnostic and therapeutic context of BMP6


  1. Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer. Kraunz, K.S., Nelson, H.H., Liu, M., Wiencke, J.K., Kelsey, K.T. Br. J. Cancer (2005) [Pubmed]
  2. Gene-mediated osteogenic differentiation of stem cells by bone morphogenetic proteins-2 or -6. Zachos, T.A., Shields, K.M., Bertone, A.L. J. Orthop. Res. (2006) [Pubmed]
  3. Bone morphogenetic protein-6 promotes osteoblastic prostate cancer bone metastases through a dual mechanism. Dai, J., Keller, J., Zhang, J., Lu, Y., Yao, Z., Keller, E.T. Cancer Res. (2005) [Pubmed]
  4. Osteogenic protein-1 stimulates mRNA levels of BMP-6 and decreases mRNA levels of BMP-2 and -4 in human osteosarcoma cells. Honda, Y., Knutsen, R., Strong, D.D., Sampath, T.K., Baylink, D.J., Mohan, S. Calcif. Tissue Int. (1997) [Pubmed]
  5. BMP-6 over-expression in prostate cancer is associated with increased Id-1 protein and a more invasive phenotype. Darby, S., Cross, S.S., Brown, N.J., Hamdy, F.C., Robson, C.N. J. Pathol. (2008) [Pubmed]
  6. Bone morphogenetic protein-6 production in human osteoblastic cell lines. Selective regulation by estrogen. Rickard, D.J., Hofbauer, L.C., Bonde, S.K., Gori, F., Spelsberg, T.C., Riggs, B.L. J. Clin. Invest. (1998) [Pubmed]
  7. Recombinant Vgr-1/BMP-6-expressing tumors induce fibrosis and endochondral bone formation in vivo. Gitelman, S.E., Kobrin, M.S., Ye, J.Q., Lopez, A.R., Lee, A., Derynck, R. J. Cell Biol. (1994) [Pubmed]
  8. Bone morphogenetic protein (BMP)-6 signaling and BMP antagonist noggin in prostate cancer. Haudenschild, D.R., Palmer, S.M., Moseley, T.A., You, Z., Reddi, A.H. Cancer Res. (2004) [Pubmed]
  9. Transcriptional regulation of a BMP-6 promoter by estrogen receptor alpha. Ong, D.B., Colley, S.M., Norman, M.R., Kitazawa, S., Tobias, J.H. J. Bone Miner. Res. (2004) [Pubmed]
  10. Bone sialoprotein, bone morphogenetic protein 6 and thymidine phosphorylase expression in localized human prostatic adenocarcinoma as predictors of clinical outcome: a clinicopathological and immunohistochemical study of 43 cases. De Pinieux, G., Flam, T., Zerbib, M., Taupin, P., Bellahcène, A., Waltregny, D., Vieillefond, A., Poupon, M.F. J. Urol. (2001) [Pubmed]
  11. BMP-6 and retinoic acid synergistically differentiate the IMR-32 human neuroblastoma cells. Sumantran, V.N., Brederlau, A., Funa, K. Anticancer Res. (2003) [Pubmed]
  12. Myofibroblast progenitor cells are increased in number in patients with type 1 diabetes and express less bone morphogenetic protein 6: a novel clue to adverse tissue remodelling? Nguyen, T.Q., Chon, H., van Nieuwenhoven, F.A., Braam, B., Verhaar, M.C., Goldschmeding, R. Diabetologia (2006) [Pubmed]
  13. Mutual regulation of follicle-stimulating hormone signaling and bone morphogenetic protein system in human granulosa cells. Miyoshi, T., Otsuka, F., Suzuki, J., Takeda, M., Inagaki, K., Kano, Y., Otani, H., Mimura, Y., Ogura, T., Makino, H. Biol. Reprod. (2006) [Pubmed]
  14. A bone morphogenetic protein subfamily: chromosomal localization of human genes for BMP5, BMP6, and BMP7. Hahn, G.V., Cohen, R.B., Wozney, J.M., Levitz, C.L., Shore, E.M., Zasloff, M.A., Kaplan, F.S. Genomics (1992) [Pubmed]
  15. Different osteogenic potentials of recombinant human BMP-6 adeno-associated virus and adenovirus in two rat strains. Li, J.Z., Li, H., Hankins, G.R., Lieu, A.S., Noh, E., Jacobson, L., Pittman, D.D., Chiorini, J.A., Helm, G.A. Tissue engineering. (2006) [Pubmed]
  16. Molecular basis of oocyte-paracrine signalling that promotes granulosa cell proliferation. Gilchrist, R.B., Ritter, L.J., Myllymaa, S., Kaivo-Oja, N., Dragovic, R.A., Hickey, T.E., Ritvos, O., Mottershead, D.G. J. Cell. Sci. (2006) [Pubmed]
  17. Glucocorticoid-induced differentiation of fetal rat calvarial osteoblasts is mediated by bone morphogenetic protein-6. Boden, S.D., Hair, G., Titus, L., Racine, M., McCuaig, K., Wozney, J.M., Nanes, M.S. Endocrinology (1997) [Pubmed]
  18. Stage-specific expression of decapentaplegic-Vg-related genes 2, 4, and 6 (bone morphogenetic proteins 2, 4, and 6) during human tooth morphogenesis. Heikinheimo, K. J. Dent. Res. (1994) [Pubmed]
  19. Osteogenic differentiation of human mesenchymal stem cells is regulated by bone morphogenetic protein-6. Friedman, M.S., Long, M.W., Hankenson, K.D. J. Cell. Biochem. (2006) [Pubmed]
  20. Involvement of bone morphogenetic protein-6 in differential regulation of aldosterone production by angiotensin II and potassium in human adrenocortical cells. Inagaki, K., Otsuka, F., Suzuki, J., Kano, Y., Takeda, M., Miyoshi, T., Otani, H., Mimura, Y., Ogura, T., Makino, H. Endocrinology (2006) [Pubmed]
  21. Differential expressions of BMP family genes during chondrogenic differentiation of mouse ATDC5 cells. Akiyama, H., Shukunami, C., Nakamura, T., Hiraki, Y. Cell Struct. Funct. (2000) [Pubmed]
  22. Effect of bone morphogenetic protein-6 on haemopoietic stem cells and cytokine production in normal human bone marrow stroma. Ahmed, N., Sammons, J., Carson, R.J., Khokher, M.A., Hassan, H.T. Cell Biol. Int. (2001) [Pubmed]
  23. Bone morphogenetic protein down-regulation of neuronal pituitary adenylate cyclase-activating polypeptide and reciprocal effects on vasoactive intestinal peptide expression. Pavelock, K.A., Girard, B.M., Schutz, K.C., Braas, K.M., May, V. J. Neurochem. (2007) [Pubmed]
  24. Expression of bone morphogenetic proteins (BMPs), their receptors, and activins in normal and scarred conjunctiva: Role of BMP-6 and activin-A in conjunctival scarring? Andreev, K., Zenkel, M., Kruse, F., Jünemann, A., Schlötzer-Schrehardt, U. Exp. Eye Res. (2006) [Pubmed]
  25. BMP-6 inhibits human bone marrow B lymphopoiesis--upregulation of Id1 and Id3. Kersten, C., Dosen, G., Myklebust, J.H., Sivertsen, E.A., Hystad, M.E., Smeland, E.B., Rian, E. Exp. Hematol. (2006) [Pubmed]
  26. Bone morphogenetic protein-5, -6 and -7 inhibit growth and induce apoptosis in human myeloma cells. Ro, T.B., Holt, R.U., Brenne, A.T., Hjorth-Hansen, H., Waage, A., Hjertner, O., Sundan, A., Borset, M. Oncogene (2004) [Pubmed]
  27. Comparison of osteogenic potentials of human rat BMP4 and BMP6 gene therapy using [E1-] and [E1-,E2b-] adenoviral vectors. Li, H., Li, J.Z., Pittman, D.D., Amalfitano, A., Hankins, G.R., Helm, G.A. International journal of medical sciences [electronic resource]. (2006) [Pubmed]
  28. Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis. Lories, R.J., Derese, I., Ceuppens, J.L., Luyten, F.P. Arthritis Rheum. (2003) [Pubmed]
  29. Localization of bone morphogenetic proteins (BMPs)-2, -4, and -6 within megakaryocytes and platelets. Sipe, J.B., Zhang, J., Waits, C., Skikne, B., Garimella, R., Anderson, H.C. Bone (2004) [Pubmed]
  30. Molecular cloning and analysis of the 5'-flanking region of the human bone morphogenetic protein-6 (BMP-6). Tamada, H., Kitazawa, R., Gohji, K., Kamidono, S., Maeda, S., Kitazawa, S. Biochim. Biophys. Acta (1998) [Pubmed]
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