Bone morphogenetic protein

Source: Wikipedia, the free encyclopedia.

Bone morphogenetic proteins (BMPs) are a group of

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. 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 esophageal adenocarcinoma.[4]

Recombinant human BMPs (rhBMPs) are used in

off-label
.

Medical uses

BMPs for clinical use are produced using recombinant DNA technology (recombinant human BMPs; rhBMPs). Recombinant BMP-2 and BMP-7 are currently approved for human use.[5]

rhBMPs are used in oral surgeries.[6][7][8] 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.

A 2022 study by researchers from the

lipid particles, loaded onto sponges, and surgically implanted into the bone defects. They remained localized around the site of application. Compared to receiving rhBMP-2 directly, bony tissues regenerated after mRNA treatment displayed superior strength and less formation of massive callus.[9]

Off-label use

Although rhBMP-2 and rhBMP-7 are used in the treatment of a variety of bone-related conditions including

off-label.[10] rhBMP-2 is used extensively in other lumbar spinal fusion techniques (e.g., using a posterior approach, anterior or posterior cervical fusions[10]
).

Alternative to autograft in long bone nonunions

In 2001, the

intramedullary nail fixation.[10] In these products, 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. The BMPs are eluted through a purified collagen matrix which is implanted in the site of the fracture.[5] rhBMP-2 helps grow bone better than any other rhBMP so it is much more widely used clinically.[5] There is "little debate or controversy" about the effectiveness of rhBMP-2 to grow bone to achieve spinal fusions,[5] and Medtronic generates $700 million in annual sales from their product.[11]

Contraindications

anterior cervical discectomy and fusion

Bone morphogenetic protein (rhBMP) should not be routinely used in any type of anterior cervical spine fusion, such as with

difficulty swallowing and pressure on the respiratory tract.[12]

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). Specifically BMP-4 and its inhibitors play a major role in neurulation and the development of the neural plate. BMP-4 signals ectoderm cells to develop into skin cells, but the secretion of inhibitors by the underlying mesoderm blocks the action of BMP-4 to allow the ectoderm to continue on its normal course of neural cell development. Additionally, secretion of BMPs by the roof plate in the developing spinal cord helps to specify dorsal sensory interneurons.[13]

As a member of the transforming growth factor-beta superfamily, BMP signaling regulates a variety of embryonic patterning during fetal and embryonic development. For example, BMP signaling controls the early formation of the Müllerian duct (MD) which is a tubular structure in early embryonic developmental stage and eventually becomes female reproductive tracts. Chemical inhibiting BMP signals in chicken embryo caused a disruption of MD invagination and blocked the epithelial thickening of the MD-forming region, indicating that the BMP signals play a role in early MD development.[14] Moreover, BMP signaling is involved in the formation of foregut and hindgut,[15] intestinal villus patterning, and endocardial differentiation. Villi contribute to increase the effective absorption of nutrients by extending the surface area in small intestine. Gain or lose function of BMP signaling altered the patterning of clusters and emergence of villi in mouse intestinal model.[16] BMP signal derived from myocardium is also involved in endocardial differentiation during heart development. Inhibited BMP signal in zebrafish embryonic model caused strong reduction of endocardial differentiation, but only had little effect in myocardial development.[17] In addition, Notch-Wnt-Bmp crosstalk is required for radial patterning during mouse cochlea development via antagonizing manner.[18]

Mutations in BMPs and their inhibitors 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).

BMPs are also involved in adipogenesis and functional regulation of adipose tissue.[19] BMP4 favors white adipogenesis, whereas BMP7 activates brown fat functionality; BMP inhibitors are also involved in this regulation [19]

Types

Originally, seven such proteins were discovered. Of these, six (BMP2 through BMP7) belong to the

metalloprotease. Since then, thirteen more BMPs, all of which are in the TGF-beta family, have been discovered, bringing the total to twenty.[5]
The current nomenclature only recognizes 13, as many others are put under the growth differentiation factor naming instead.

BMP Known functions Gene Locus
BMP1 *BMP1 does not belong to the TGF-β family of proteins. It is a
procollagen
I, II, and III. It is involved in cartilage development.
Chromosome: 8
; Location: 8p21
BMP2 Acts as a
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, epidermis formation, dorsal-ventral axis formation, and ovarian follical development.
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. Controls iron homeostasis via regulation of hepcidin.
Chromosome: 6
; Location: 6p12.1
BMP7 Plays a key role in
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
BMP11 Controls anterior-posterior patterning.
Chromosome: 12
; Location: 12p
BMP15 May play a role in oocyte and follicular development.
Chromosome: X
; Location: Xp11.2
Sequence relationships among mammalian bone morphogenetic proteins (mouse/human). Modified after Ducy & Karsenty 2000[20]

History

From the time of Hippocrates it has been known that bone has considerable potential for regeneration and repair. Nicholas 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.[21] Pierre Lacroix proposed that there might be a hypothetical substance, osteogenin, that might initiate bone growth.[22]

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 discovery was published in 1965 by Urist in Science.[23] Urist proposed the name "Bone Morphogenetic Protein" in the scientific literature in the Journal of Dental Research in 1971.[24]

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.[25] 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, Hari Reddi and Kuber Sampath used dissociative extractants, such as 4M guanidine HCL, 8M urea, or 1% SDS.[26] 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 by the Reddi laboratory,[27][28] but ultimately also enabled the cloning of BMPs by John Wozney and colleagues at Genetics Institute.[29]

Society

Costs

At between

orthopaedic
revision in multiple surgeries.

While there is little debate that rhBMPs are successful clinically,

adverse events associated with treatment. In the 13 original industry-sponsored publications related to safety, there were zero adverse events in 780 patients.[34] It has since been revealed that potential complications can arise from the use including implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation.[33][34]

Based on a study conducted by the Department of Family Medicine at the Oregon Health and Science University the use of BMP increased rapidly, from 5.5% of fusion cases in 2003 to 28.1% of fusion cases in 2008. BMP use was greater among patients with previous surgery and among those having complex fusion procedures (combined anterior and posterior approach, or greater than 2 disc levels). Major medical complications, wound complications, and 30-day rehospitalization rates were nearly identical with or without BMP. Reoperation rates were also very similar, even after stratifying by previous surgery or surgical complexity, and after adjusting for demographic and clinical features. On average, adjusted hospital charges for operations involving BMP were about $15,000 more than hospital charges for fusions without BMP, though reimbursement under Medicare's Diagnosis-Related Group system averaged only about $850 more. Significantly fewer patients receiving BMP were discharged to a skilled nursing facility.[35]

References

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  30. ^ Toi Williams (2012-12-20). "Medtronic Accused Of Editing Product Studies". DC Progressive. Retrieved 2013-05-12.
  31. ^ Rebecca Farbo (2013-01-16). "World-renowned Orthopedic Surgeon Sues Medical Device Company For Breach Of Contract". PR Newswire. Retrieved 2013-05-12.
  32. ^ Susan Perry (2012-10-26). "Report reveals disturbing details of Medtronic's role in shaping InFuse articles". MinnPost. Retrieved 2013-05-13.
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  35. ^ Spinal Fusion and Bone Morphogenetic Protein

Further reading

External links

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