Bone morphogenetic protein

Bone Morphogenetic Proteins (BMPs) are a group of growth factors and cytokines known for their ability to induce the formation of bone and cartilage.

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. These formulations have found applications^{[citation needed]} in many disciplines of medicine and dentistry. Orthopaedic surgery and oral surgery^[1] have benefited^{[citation needed]} greatly from commercially available BMP formualtions in the last few years.

BMPs are also available in an oral form under the commercial name Ostinol(TM). It is being marketed as a supplement for bone and joint health^{[citation needed]} by alternative health care practitioners. However, the product would never work properly in the body and has clear dangers. BMPs are known to induce ectopic bone formation (i.e. outside of the bones) if injected, thus they carry the risk of triggering calcification in different parts of the body, when ingested orally. In addition, the half-life of BMPs is very reduced, requiring a sustained release directly to the bone, to prevent both the risk of ectopic bone formation and the protein degradation (since BMPs are very unstable in solution).

In regenerative medicine, BMPs are delivered to the site of the fracture, by being incorporated into the bone implant, which should released the BMP slowly and gradually, to allow bone formation (the stimilus 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).

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 referred 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.^[2] or "Bone morphogenetic proteins in tissue engineering: the road from laboratory to the clinic" in Journal of Tissue Engineering and Regenerative Medicine. ^[3]

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.^[4] Pierre Lacroix proposed, that in bone, there might be a hypothetical substance, osteogenin, that might initiate bone growth.^[5]

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.^[6] Marshall Urist proposed the name "Bone Morphogenetic Protein" in the scientific literature in the Journal of Dental Research in 1971.^[7] Marshall Urist died on February 4, 2001. A tribute to him and his research was written in the Journal of Bone and Joint Surgery.^[8]

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.^[9] 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.^[10] 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,^[11][12] but ultimately also enabled the cloning of BMPs by John Wozney and colleagues at Genetics Institute.^[13]

List of Bone Morphogenetic Proteins

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

External links

• BMP: The What and the Who
• BMPedia - the Bone Morphogenetic Protein Wiki
• MeSH Bone+Morphogenetic+Proteins
• Chen, Di, Zhao, Ming, and Mundy, Gregory R. (2004). "Bone Morphogenetic Proteins". Growth Factors 22 (4): 233–241. doi:10.1080/08977190412331279890. PMID 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): 1544–52. PMID 12925636.  link