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]
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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.
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 (Medtronic) and OP-1 BMP-7 (Stryker Biotech). The Medtronic Infuse product has been approved for certain dental applications as well. [7]
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).
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]
| BMP | Known functions | Gene Locus |
|---|---|---|
| BMP1 | *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; Location: 8p21 |
| BMP2 | Acts as a disulfide-linked homodimer and induces bone and cartilage formation. It is a candidate as a retinoid mediator. Plays a key role in osteoblast differentiation. | Chromosome: 20; Location: 20p12 |
| BMP3 | Induces bone formation. | Chromosome: 14; Location: 14p22 |
| BMP4 | Regulates the formation of teeth, limbs and bone from mesoderm. It also plays a role in fracture repair. | Chromosome: 14; Location: 14q22-q23 |
| BMP5 | Performs functions in cartilage development. | Chromosome: 6; Location: 6p12.1 |
| BMP6 | Plays a role in joint integrity in adults. | Chromosome: 6; Location: 6p12.1 |
| BMP7 | Plays a key role in osteoblast differentiation. It also induces the production of SMAD1. Also key in renal development and repair. | Chromosome: 20; Location: 20q13 |
| BMP8a | Involved in bone and cartilage development. | Chromosome: 1; Location: 1p35-p32 |
| BMP8b | Expressed in the hippocampus. | Chromosome: 1; Location: 1p35-p32 |
| BMP10 | May play a role in the trabeculation of the embryonic heart. | Chromosome: 2; Location: 2p14 |
| BMP15 | May play a role in oocyte and follicular development. | Chromosome: X; Location: Xp11.2 |
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.
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