Bone morphogenetic protein
Encyclopedia
Bone morphogenetic proteins (BMPs) are a group of growth factors also known as cytokines and as metabologens
. 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 . 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 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 . Bias and conflict of interest of relevant research is under investigation. http://www.google.com/search?q=Infuse&ie=utf-8&oe=utf-8&aq=t&rls=org.mozilla:en-US:official&client=firefox-a#sclient=psy&hl=en&client=firefox-a&hs=ojv&rls=org.mozilla:en-US%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
of proteins.
BMP1 is a metalloprotease.
Since then, thirteen more BMPs have been discovered, bringing the total to twenty.
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 (Medtronic) and OP-1 BMP-7 (Stryker Biotech). The Medtronic Infuse product has been approved for certain dental applications as well.
(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).
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. Pierre Lacroix proposed that there might be a hypothetical substance, osteogenin, that might initiate bone growth.
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
. Marshall Urist proposed the name "Bone Morphogenetic Protein" in the scientific literature in the Journal of Dental Research in 1971. Marshall Urist died on February 4, 2001. A tribute to him and his research was written in the Journal of Bone and Joint Surgery.
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. 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. 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, but ultimately also enabled the cloning of BMPs by John Wozney and colleagues at Genetics Institute.
(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.
Metabologen
A metabologen is defined as a morphogen that can initiate, promote and maintain metabolism and homeostasis. Based on this definition Bone Morphogenetic Proteins are metabologens since they are involved in iron homeostasis, brown fat adipogenesis and energy metabolism. Professor A...
. Originally discovered by their ability to induce the formation of bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
and cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue architecture throughout the body . 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 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 . Bias and conflict of interest of relevant research is under investigation. http://www.google.com/search?q=Infuse&ie=utf-8&oe=utf-8&aq=t&rls=org.mozilla:en-US:official&client=firefox-a#sclient=psy&hl=en&client=firefox-a&hs=ojv&rls=org.mozilla:en-US%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
Types
Originally, seven such proteins were discovered. Of these, six (BMP2 through BMP7) belong to the Transforming growth factor beta superfamilyTransforming growth factor beta superfamily
The transforming growth factor beta superfamily is a large family of structurally related cell regulatory proteins that was named after its first member, TGF-β1, originally described in 1983....
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 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 (Medtronic) and OP-1 BMP-7 (Stryker Biotech). The Medtronic Infuse product has been approved for certain dental applications as well.
Function
BMPs interact with specific receptors on the cell surface, referred to as bone morphogenetic protein receptorsBone morphogenetic protein receptors
There are three bone morphogenetic protein receptors in humans:* Bone morphogenetic protein receptor, type 1:** BMPR1A** BMPR1B* Bone morphogenetic protein receptor, type 2-External links:...
(BMPRs).
Signal transduction through BMPRs results in mobilization of members of the SMAD
SMAD (protein)
SMADs are intracellular proteins that transduce extracellular signals from transforming growth factor beta ligands to the nucleus where they activate downstream TGF-β gene transcription....
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
Noggin (protein)
Noggin, also known as NOG, is a protein which in humans is encoded by the NOG gene.Noggin inhibits TGF-β signal transduction by binding to TGF-β family ligands and preventing them from binding to their corresponding receptors. Noggin plays a key role in neural induction by inhibiting BMP4, along...
and chordin
Chordin
Chordin is a polypeptide that dorsalizes the developing embryo by binding ventralizing TGFβ proteins such as bone morphogenetic proteins. It may also play a role in organogenesis. There are five named isoforms of this protein that are produced by alternative splicing.In humans, the chordin peptide...
help regulate polarity of the embryo (i.e. back to front patterning).
Mutations in BMPs and their inhibitors (such as sclerostin
Sclerostin
Sclerostin, the product of the SOST gene, located on chromosome 17, locus q11.2 in humans, was originally believed to be a non-classical Bone morphogenetic protein antagonist. More recently Sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signalling pathway...
) 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. or "Bone morphogenetic proteins in tissue engineering: the road from laboratory to the clinic" in Journal of Tissue Engineering and Regenerative Medicine.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. Pierre Lacroix proposed that there might be a hypothetical substance, osteogenin, that might initiate bone growth.
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
Science (journal)
Science is the academic journal of the American Association for the Advancement of Science and is one of the world's top scientific journals....
. Marshall Urist proposed the name "Bone Morphogenetic Protein" in the scientific literature in the Journal of Dental Research in 1971. Marshall Urist died on February 4, 2001. A tribute to him and his research was written in the Journal of Bone and Joint Surgery.
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. 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. 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, but ultimately also enabled the cloning of BMPs by John Wozney and colleagues at Genetics Institute.
List of Bone Morphogenetic Proteins
| BMP | Known functions | Gene Locus |
|---|---|---|
| BMP1 Bone morphogenetic protein 1 Bone morphogenetic protein 1, also known as BMP1, is a protein which in humans is encoded by the BMP1 gene. There are seven isoforms of the protein created by alternate splicing.-Function:... |
*BMP1 does not belong to the TGF-β family of proteins. It is a metalloprotease that acts on procollagen I, II, and III. It is involved in cartilage development. | Chromosome: 8 Chromosome 8 (human) Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 145 million base pairs and represents between 4.5 and 5.0% of the total DNA in cells.... ; Location: 8p21 |
| BMP2 Bone morphogenetic protein 2 Bone morphogenetic protein 2 or BMP-2 belongs to the TGF-β superfamily of proteins.-Function:BMP-2 like other bone morphogenetic proteins, plays an important role in the development of bone and cartilage. It is involved in the hedgehog pathway, TGF beta signaling pathway, and in cytokine-cytokine... |
Acts as a disulfide Disulfide In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. Disulfide usually refer to a chemical compound that contains a disulfide bond, such as diphenyl disulfide, C6H5S-SC6H5.... -linked homodimer and induces bone and cartilage formation. It is a candidate as a retinoid Retinoid The retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth.... mediator. Plays a key role in osteoblast Osteoblast Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen... differentiation. |
Chromosome: 20 Chromosome 20 (human) Chromosome 20 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 20 spans around 63 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells... ; Location: 20p12 |
| BMP3 Bone morphogenetic protein 3 Bone morphogenetic protein 3 is a protein that in humans is encoded by the BMP3 gene.The protein encoded by this gene is a member of the transforming growth factor beta superfamily. It, like other bone morphogenetic proteins is known for its ability to induce bone and cartilage development. It is... |
Induces bone formation. | Chromosome: 14 Chromosome 14 (human) rightChromosome14 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 14 spans about 109 million base pairs and represents between 3 and 3.5% of the total DNA in cells.... ; Location: 14p22 |
| BMP4 Bone morphogenetic protein 4 Bone morphogenetic protein 4 is a protein that in humans is encoded by` BMP4 gene.BMP4 is a member of the bone morphogenetic protein family which is part of the transforming growth factor-beta superfamily... |
Regulates the formation of teeth, limbs and bone from mesoderm Mesoderm In all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and... . It also plays a role in fracture repair. |
Chromosome: 14 Chromosome 14 (human) rightChromosome14 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 14 spans about 109 million base pairs and represents between 3 and 3.5% of the total DNA in cells.... ; Location: 14q22-q23 |
| BMP5 Bone morphogenetic protein 5 Bone morphogenetic protein 5 is a protein that in humans is encoded by the BMP5 gene.The protein encoded by this gene is member of the TGFβ superfamily. Bone morphogenetic proteins are known for their ability to induce bone and cartilage development. BMP5 may play a role in certain cancers. Like... |
Performs functions in cartilage development. | Chromosome: 6 Chromosome 6 (human) Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs and represents between 5.5 and 6% of the total DNA in cells... ; Location: 6p12.1 |
| BMP6 Bone morphogenetic protein 6 Bone morphogenetic protein 6 is a protein that in humans is encoded by the BMP6 gene.The protein encoded by this gene is a member of the TGFβ superfamily. Bone morphogenetic proteins are known for their ability to induce the growth of bone and cartilage... |
Plays a role in joint integrity in adults. | Chromosome: 6 Chromosome 6 (human) Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs and represents between 5.5 and 6% of the total DNA in cells... ; Location: 6p12.1 |
| BMP7 Bone morphogenetic protein 7 Bone morphogenetic protein 7 or BMP7 is a protein that in humans is encoded by the BMP7 gene.-Function:The protein encoded by this gene is a member of the TGF-β superfamily... |
Plays a key role in osteoblast Osteoblast Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen... differentiation. It also induces the production of SMAD1. Also key in renal development and repair. |
Chromosome: 20 Chromosome 20 (human) Chromosome 20 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 20 spans around 63 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells... ; Location: 20q13 |
| BMP8a Bone morphogenetic protein 8A Bone morphogenetic protein 8A is a protein that in humans is encoded by the BMP8A gene.BMP8A is a polypeptide member of the TGFβ superfamily of proteins. It, like other bone morphogenetic proteins , is involved in the development of bone and cartilage. BMP8A may be involved in epithelial... |
Involved in bone and cartilage development. | Chromosome: 1 Chromosome 1 (human) Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 247 million nucleotide base pairs, which are the basic units of information for DNA... ; Location: 1p35-p32 |
| BMP8b Bone morphogenetic protein 8b Bone morphogenetic protein 8B is a protein that in humans is encoded by the BMP8B gene.The protein encoded by this gene is a member of the TGF-β superfamily. It has close sequence homology to BMP7 and BMP5 and is believed to play a role in bone and cartilage development... |
Expressed in the hippocampus Hippocampus The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in... . |
Chromosome: 1 Chromosome 1 (human) Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 247 million nucleotide base pairs, which are the basic units of information for DNA... ; Location: 1p35-p32 |
| BMP10 Bone morphogenetic protein 10 Bone morphogenetic protein 10 is a protein that in humans is encoded by the BMP10 gene.BMP10 is a polypeptide belonging to the TGF-β superfamily of proteins. It is a novel protein that, unlike most other BMP's, is likely to be involved in the tabeculation of the heart. Bone morphogenetic proteins... |
May play a role in the trabeculation of the embryonic heart. | Chromosome: 2 Chromosome 2 (human) Chromosome 2 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second largest human chromosome, spanning more than 237 million base pairs and representing almost 8% of the total DNA in cells.Identifying genes on each... ; Location: 2p14 |
| BMP15 Bone morphogenetic protein 15 Bone morphogenetic protein 15 is a protein that in humans is encoded by the BMP15 gene.The protein encoded by this gene is a member of the TGF-β superfamily. It is a paracrine signaling molecule involved in oocyte and follicular development. Using Northern blot analysis, BMP15 has been shown to be... |
May play a role in oocyte Oocyte An oocyte, ovocyte, or rarely ocyte, is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in the ovary during female gametogenesis. The female germ cells produce a primordial germ cell which undergoes a mitotic... and follicular Ovarian follicle Ovarian follicles are the basic units of female reproductive biology, each of which is composed of roughly spherical aggregations of cells found in the ovary. They contain a single oocyte . These structures are periodically initiated to grow and develop, culminating in ovulation of usually a single... development. |
Chromosome: X; Location: Xp11.2 |
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 AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(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
Bone grafting
Bone grafting is a surgical procedure that replaces missing bone in order to repair bone fractures that are extremely complex, pose a significant health risk to the patient, or fail to heal properly....
. 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.