Bone morphogenetic protein

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Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens [1]. Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue architecture throughout the body [2]. The important functioning of BMP signals in physiology is emphasized by the multitude of roles for dysregulated BMP signalling in pathological processes. Especially cancerous disease often involves misregulation of the BMP signalling system. Absence of BMP signalling is, for instance, an important factor in the progression of colon cancer [3] and conversely overactivation of BMP signalling following reflux-induced esophagitis provokes Barrett's esophagus and is thus instrumental in the development of adenocarcinoma in the proximal portion of the gastrointestinal tract [4]. Bias and conflict of interest of relevant research is under investigation. [1] (http://www.google.com/search?q=Infuse&ie=utf-8&oe=utf8&aq=t&rls=org.mozilla:en-US:official&client=firefox-a#sclient=psy&hl=en&client=firefox-a&hs=ojv&rls=org.mozilla:enUS%3Aofficial&tbm=nws&source=hp&q=Infuse+bone+medtronic&aq=f&aqi=&aql=&oq=&pbx=1&bav=on.2,or.r_gc.r_pw.&fp=8d34541290d36aa1&biw=1408&bih=740)

Contents
1 Types 2 Applications 3 Function 4 Discovery 5 List of Bone Morphogenetic Proteins 6 Clinical uses 7 References 8 External links

Types
Originally, seven such proteins were discovered. Of these, six (BMP2 through BMP7) belong to the Transforming growth factor beta superfamily of proteins. BMP1 is a metalloprotease. Since then, thirteen more BMPs have been discovered, bringing the total to twenty.

Applications
BMPs are now produced using recombinant DNA technology. Oral[5][6] and orthopaedic surgery have benefited greatly from commercially available BMP formulations. In regenerative medicine, BMPs are delivered to the site of the fracture by being incorporated into a bone implant, and released gradually to allow bone formation, as the growth stimulation by BMPs must be localized and sustained for some weeks. Currently, two BMPs products have been approved by the Food and Drug Administration (FDA) for clinical applications (fractures of long bones, intervertebral disk regeneration), by delivery in a purified collagen matrix (which is implanted in the site of the fracture). These are Infuse BMP-2 (http://wwwp.medtronic.com/Newsroom/LinkedItemDetails.do?itemId=1101769224707&itemType=fact_sheet&lang=en_US) (Medtronic) and OP-1 BMP-7 (http://www.stryker.com/en-us/products/Orthobiologicals/Osteoinductive/OP-1/index.htm) (Stryker Biotech). The Medtronic Infuse product has been approved for certain dental applications as well. [7]

Function
BMPs interact with specific receptors on the cell surface, referred to as bone morphogenetic protein receptors (BMPRs). Signal transduction through BMPRs results in mobilization of members of the SMAD family of proteins. The signaling pathways involving BMPs, BMPRs and Smads are important in the development of the heart, central nervous system, and cartilage, as well as post-natal bone development. They have an important role during embryonic development on the embryonic patterning and early skeletal formation. As such, disruption of BMP signaling can affect the body plan of the developing embryo. For example, BMP4 and its inhibitors noggin and chordin help regulate polarity of the embryo (i.e. back to front patterning). Mutations in BMPs and their inhibitors (such as sclerostin) are associated with a number of human disorders which affect the skeleton. Several BMPs are also named 'cartilage-derived morphogenetic proteins' (CDMPs), while others are refer to as 'growth differentiation factors' (GDFs).

Discovery
For a detailed history of the discovery and isolation of bone morphogenetic proteins read "Bone Morphogenetic Proteins: an Unconventional Approach to Isolation of First Mammalian Morphogens" in Cytokine & Growth Factor Reviews.[8] or "Bone morphogenetic proteins in tissue engineering: the road from laboratory to the clinic" in Journal of Tissue Engineering and Regenerative Medicine.[9] From the time of Hippocrates it has been known that bone has considerable potential for regeneration and repair. Senn, a surgeon at Rush Medical College in Chicago, described the utility of antiseptic decalcified bone implants in the treatment of osteomyelitis and certain bone deformities.[10] Pierre Lacroix proposed that there might be a hypothetical substance, osteogenin, that might initiate bone growth.[11] The biological basis of bone morphogenesis was shown by Marshall R. Urist. Urist made the key discovery that demineralized, lyophilized segments of bone induced new bone formation when implanted in muscle pouches in rabbits. This seminal discovery was published in 1965 by Urist in Science.[12] Marshall Urist proposed the name "Bone Morphogenetic Protein" in the scientific literature in the Journal of Dental Research in 1971.[13] Marshall Urist died on February 4, 2001. A tribute to him and his research was

written in the Journal of Bone and Joint Surgery.[14] Bone induction is a sequential multistep cascade. The key steps in this cascade are chemotaxis, mitosis, and differentiation. Early studies by Hari Reddi unraveled the sequence of events involved in bone matrix-induced bone morphogenesis.[15] On the basis of the above work, it seemed likely that morphogens were present in the bone matrix. Using a battery of bioassays for bone formation, a systematic study was undertaken to isolate and purify putative bone morphogenetic proteins. A major stumbling block to purification was the insolubility of demineralized bone matrix. To overcome this hurdle, A. Hari Reddi and Kuber Sampath used dissociative extractants, such as 4M guanidine HCL, 8M Urea, or 1% SDS.[16] The soluble extract alone or the insoluble residues alone were incapable of new bone induction. This work suggested that the optimal osteogenic activity requires a synergy between soluble extract and the insoluble collagenous substratum. It not only represented a significant advance toward the final purification of bone morphogenetic proteins (BMPs) by the Reddi laboratory,[17][18] but ultimately also enabled the cloning of BMPs by John Wozney and colleagues at Genetics Institute.[19]

List of Bone Morphogenetic Proteins

BMP Known functions Gene Locus Chromosome: 8; Location: 8p21 *BMP1 does not belong to the TGF- family of proteins. It is a metalloprotease that acts on procollagen I, II, and III. It is BMP1 involved in cartilage development. BMP2

Acts as a disulfide-linked homodimer and induces bone and cartilage formation. It is a candidate as a retinoid mediator. Plays a key Chromosome: 20; Location: role in osteoblast differentiation. 20p12 Chromosome: 14; Location: 14p22 Chromosome: 14; Location: 14q22-q23 Chromosome: 6; Location: 6p12.1 Chromosome: 6; Location: 6p12.1 Chromosome: 20; Location: 20q13 Chromosome: 1; Location: 1p35-p32 Chromosome: 1; Location: 1p35-p32 Chromosome: 2; Location: 2p14 Chromosome: X; Location: Xp11.2

BMP3 Induces bone formation. BMP4 Regulates the formation of teeth, limbs and bone from mesoderm. It also plays a role in fracture repair. BMP5 Performs functions in cartilage development. BMP6 Plays a role in joint integrity in adults. BMP7 Plays a key role in osteoblast differentiation. It also induces the production of SMAD1. Also key in renal development and repair. BMP8a Involved in bone and cartilage development. BMP8b Expressed in the hippocampus. BMP10 May play a role in the trabeculation of the embryonic heart. BMP15 May play a role in oocyte and follicular development.

Clinical uses
Members of the BMP family are potentially useful as therapeutics in areas such as spinal fusion. BMP-2 and BMP-7 have been shown in clinical studies to be beneficial in the treatment of a variety of bone-related conditions including delayed union and non-union. BMP-2 and BMP-7 have received Food and Drug Administration (FDA) approval for human clinical uses. At between $6000 and $10,000 for a typical treatment, BMPs can be costly compared with other techniques such as bone grafting. However, this cost is often far less than the costs required with orthopaedic revision in multiple surgeries. BMP-7 has also recently found use in the treatment of chronic kidney disease (CKD). BMP-7 has been shown in murine animal models to reverse the loss of glomeruli due to sclerosis. Curis has been in the forefront of developing BMP-7 for this use. In 2002, Curis licensed BMP-7 to Ortho Biotech Products, a subsidiary of Johnson & Johnson.

References
1. ^ Reddi AH, Reddi A (2009). "Bone morphogenetic proteins (BMPs): from morphogens to metabologens". Cytokine & growth factor reviews 20 (5-6): 3412. doi:10.1016/j.cytogfr.2009.10.015 (http://dx.doi.org/10.1016%2Fj.cytogfr.2009.10.015) . PMID 19900831 (http://www.ncbi.nlm.nih.gov/pubmed/19900831) . 2. ^ Bleuming SA, He XC, Kodach LL, Hardwick JC, Koopman FA, Ten Kate FJ, van Deventer SJ, Hommes DW, Peppelenbosch MP, Offerhaus GJ, Li L, van den Brink GR. (2007). "Bone morphogenetic protein signaling suppresses tumorigenesis at gastric epithelial transition zones in mice.". Cancer Research 67 (17): 814955. doi:10.1158/0008-5472.CAN-064659 (http://dx.doi.org/10.1158%2F0008-5472.CAN-06-4659) . PMID 17804727 (http://www.ncbi.nlm.nih.gov/pubmed/17804727) . 3. ^ Kodach LL, Wiercinska E, de Miranda NF, Bleuming SA, Musler AR, Peppelenbosch MP, Dekker E, van den Brink GR, van Noesel CJ, Morreau H, Hommes DW, Ten Dijke P, Offerhaus GJ, Hardwick JC. (2008). "The bone morphogenetic protein pathway is inactivated in the majority of sporadic colorectal cancers.". Gastroenterology 134 (5): 133241. doi:10.1053/j.gastro.2008.02.059 (http://dx.doi.org/10.1053%2Fj.gastro.2008.02.059) . PMID 18471510 (http://www.ncbi.nlm.nih.gov/pubmed/18471510) . 4. ^ Milano F, van Baal JW, Buttar NS, Rygiel AM, de Kort F, DeMars CJ, Rosmolen WD, Bergman JJ, Van Marle J, Wang KK, Peppelenbosch MP, Krishnadath KK (2007). "Bone morphogenetic protein 4 expressed in esophagitis induces a columnar phenotype in esophageal squamous cells.". Gastroeneterology 132 (7): 241221. doi:10.1053/j.gastro.2007.03.026 (http://dx.doi.org/10.1053%2Fj.gastro.2007.03.026) . PMID 17570215 (http://www.ncbi.nlm.nih.gov/pubmed/17570215) . 5. ^ Wikesj et al., UME; Qahash, M; Huang, Y-H; Xiropaidis, A; Polimeni, G; Susin, C (2009). "Bone morphogenetic proteins for periodontal and alveolar indications; biological observations clinical implications" (http://www3.interscience.wiley.com/journal/122510612/abstract?CRETRY=1&SRETRY=0) . Orthodontics & Craniofacial Research 12 (3): 263270. doi:10.1111/j.1601-6343.2009.01461.x (http://dx.doi.org/10.1111%2Fj.1601-6343.2009.01461.x) . http://www3.interscience.wiley.com/journal/122510612/abstract? CRETRY=1&SRETRY=0. 6. ^ Moghadam HG et al., HG; Urist, MR; Sandor, GK; Clokie, CM (2001). "Successful mandibular reconstruction using a BMP bioimplant.". J Craniofac Surg. 12 (2): 119127. doi:10.1097/00001665-200103000-00005 (http://dx.doi.org/10.1097%2F00001665-200103000-00005) . PMID 11314620 (http://www.ncbi.nlm.nih.gov/pubmed/11314620) . 7. ^ "Medtronic Receives Approval to Market Infuse Bone Graft for Certain Oral Maxillofacial And Dental Regenerative Applications"

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(http://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=1173788328615&lang=en_US) . http://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do? itemId=1173788328615&lang=en_US. Retrieved January 19, 2011. ^ Reddi, A. H. (1997). "Bone Morphogenetic Proteins: an Unconventional Approach to Isolation of First Mammalian Morphogens". Cytokine & Growth Factor Reviews 8 (1): 1120. doi:10.1016/S1359-6101(96)00049-4 (http://dx.doi.org/10.1016%2FS1359-6101%2896%2900049-4) . ^ Bessa, P.C.; Casal, M; Reis, RL (2008). "Bone morphogenetic proteins in tissue engineering: the road from laboratory to the clinic. Part I - Basic concepts" (http://www3.interscience.wiley.com/journal/117916474/abstract?CRETRY=1&SRETRY=0) . Journal of Tissue Engineering and Regenerative Medicine 2 (1): 113. doi:10.1002/term.63 (http://dx.doi.org/10.1002%2Fterm.63) . PMID 18293427 (http://www.ncbi.nlm.nih.gov/pubmed/18293427) . http://www3.interscience.wiley.com/journal/117916474/abstract?CRETRY=1&SRETRY=0. ^ Senn, N. (1889). "On the healing of aseptic bone cavities by implantation of antiseptic decalcified bone". American Journal of the Medical Sciences 98 (3): 219243. doi:10.1097/00000441-188909000-00001 (http://dx.doi.org/10.1097%2F00000441-188909000-00001) . ^ Lacroix, P. (1945). "Recent investigation on the growth of bone". Nature 156 (3967): 576. doi:10.1038/156576a0 (http://dx.doi.org/10.1038%2F156576a0) . ^ Urist, Marshall R. (1965). "Bone: formation by autoinduction". Science 12:150 (698): 893899. doi:10.1126/science.150.3698.893 (http://dx.doi.org/10.1126%2Fscience.150.3698.893) . PMID 5319761 (http://www.ncbi.nlm.nih.gov/pubmed/5319761) . ^ Urist, Marshall R.; Strates, Basil S. (1971). "Bone Morphogenetic Protein" (http://jdr.sagepub.com/cgi/reprint/50/6/1392) . Journal of Dental Research 1971 50 (6): 13921406. doi:10.1177/00220345710500060601 (http://dx.doi.org/10.1177%2F00220345710500060601) . http://jdr.sagepub.com/cgi/reprint/50/6/1392. ^ Reddi, A. H. (1 August 2003). "Marshall R. Urist: a renaissance scientist and orthopaedic surgeon" (http://www.ejbjs.org/cgi/content/extract/85/suppl_3/3) . Journal of Bone and Joint Surgery 85 (Suppl. 3): 37. PMID 12925602 (http://www.ncbi.nlm.nih.gov/pubmed/12925602) . http://www.ejbjs.org/cgi/content/extract/85/suppl_3/3. ^ Reddi, A. H.; Huggins, C. (1972). "Biochemical Sequences in the Transformation of Normal Fibroblasts in Adolescent Rat" (http://www.pnas.org/content/69/6/1601.abstract) . PNAS 69 (6): 16011605. doi:10.1073/pnas.69.6.1601 (http://dx.doi.org/10.1073%2Fpnas.69.6.1601) . http://www.pnas.org/content/69/6/1601.abstract. ^ Sampath, T. K.; Reddi, A. H. (1981). "Dissociative Extraction and Reconstitution of Bone Matrix Components Involved in Local Bone Differentiation" (http://www.pnas.org/content/78/12/7599.abstract) . PNAS 78 (12): 75997603. doi:10.1073/pnas.78.12.7599 (http://dx.doi.org/10.1073%2Fpnas.78.12.7599) . PMC 349316 (http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=349316) . PMID 6950401 (http://www.ncbi.nlm.nih.gov/pubmed/6950401) . http://www.pnas.org/content/78/12/7599.abstract. ^ Sampath, T. K.; Muthukumaran, N.; Reddi, A. H. (1987). "Isolation of Osteogenin, an Extracellular Matrix-Associated Bone-Inductive Protein, by Heparin Affinity Chromatography" (http://www.pnas.org/content/84/20/7109.abstract) . PNAS 84 (20): 71097113. doi:10.1073/pnas.84.20.7109 (http://dx.doi.org/10.1073%2Fpnas.84.20.7109) . PMC 299239 (http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=299239) . PMID 3478684 (http://www.ncbi.nlm.nih.gov/pubmed/3478684) . http://www.pnas.org/content/84/20/7109.abstract. ^ Luyten, F. P.; et al. (15 August 1989). "Purification and Partial Amino Acid Sequence of Osteogenin, a Protein Initiating Bone Differentiation" (http://www.jbc.org/cgi/content/abstract/264/23/13377) . Journal of Biological Chemistry 264 (23): 1337713380. PMID 2547759 (http://www.ncbi.nlm.nih.gov/pubmed/2547759) . http://www.jbc.org/cgi/content/abstract/264/23/13377. ^ Wozney, J. M.; Rosen, V.; Celeste, A. J.; et al. (1988). "Novel regulators of bone formation: Molecular clones and activities". Science 242 (4885): 15281534. doi:10.1126/science.3201241 (http://dx.doi.org/10.1126%2Fscience.3201241) . PMID 3201241 (http://www.ncbi.nlm.nih.gov/pubmed/3201241) .

External links
BMP: The What and the Who (http://www.spineuniverse.com/displayarticle.php/article1992.html) BMPedia - the Bone Morphogenetic Protein Wiki (http://bmpedia.wikidot.com/bmp-family) MeSH Bone+Morphogenetic+Proteins (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Bone+Morphogenetic+Proteins) Chen, Di, Zhao, Ming, and Mundy, Gregory R. (2004). "Bone Morphogenetic Proteins". Growth Factors 22 (4): 233241. doi:10.1080/08977190412331279890 (http://dx.doi.org/10.1080%2F08977190412331279890) . PMID 15621726 (http://www.ncbi.nlm.nih.gov/pubmed/15621726) . Cheng H, Jiang W, Phillips F, Haydon R, Peng Y, Zhou L, Luu H, An N, Breyer B, Vanichakarn P, Szatkowski J, Park J, He T (2003). "Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs)". J Bone Joint Surg Am 85-A (8): 154452. PMID 12925636 (http://www.ncbi.nlm.nih.gov/pubmed/12925636) . link (http://www.ejbjs.org/cgi/content/abstract/85/8/1544) Retrieved from "http://en.wikipedia.org/wiki/Bone_morphogenetic_protein" Categories: Growth factors | Developmental biology | Proteins | Bone morphogenetic protein This page was last modified on 8 August 2011 at 10:55. Text is available under the Creative Commons Attribution-ShareAlike License; additional terms may apply. See Terms of use for details. Wikipedia is a registered trademark of the Wikimedia Foundation, Inc., a non-profit organization.