Bone

morphogenetic
protein

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. 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]
Recombinant human BMPs (rhBMPs) are
used in orthopedic applications such as
spinal fusions, nonunions and oral
surgery. rhBMP-2 and rhBMP-7 are Food
and Drug Administration (FDA)-approved
for some uses. rhBMP-2 causes more
overgrown bone than any other BMPs
and is widely used off-label.

Medical uses
BMPs for clinical use are produced using
recombinant DNA technology
(recombinant human BMPs; rhBMPs).

rhBMPs are used in oral surgeries.[5][6][7]

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.

Off-label use

Although rhBMP-2 and rhBMP-7 are used

in the treatment of a variety of bone-
related conditions including spinal
fusions and nonunions, the risks of this
off-label treatment are not understood.[8]
While rhBMPs are approved for specific
applications (spinal lumbar fusions with
an anterior approach and tibia
nonunions), up to 85% of all BMP usage
is off-label.[8] rhBMP-2 is used
extensively in other lumbar spinal fusion
techniques (e.g., using a posterior
approach, anterior or posterior cervical
fusions[8]).

Alternative to autograft in
long bone nonunions

In 2001, the Food and Drug

Administration (FDA) approved rhBMP-7
(a.k.a. OP-1; Stryker Biotech) for a
humanitarian device exemption as an
alternative to autograft in long bone
nonunions.[8] In 2004, the humanitarian
device exemption was extended as an
alternative to autograft for posterolateral
fusion.[8] In 2002, rhBMP-2 (Infuse;
Medtronic) was approved for anterior
lumbar interbody fusions (ALIFs) with a
lumbar fusion device.[8] In 2008 it was
approved to repair posterolateral lumbar
pseudarthrosis, open tibia shaft fractures
with intramedullary nail fixation.[8] 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.[9]
rhBMP-2 helps grow bone better than any
other rhBMP so it is much more widely
used clinically.[9] There is "little debate or
controversy" about the effectiveness of
rhBMP-2 to grow bone to achieve spinal
fusions,[9] and Medtronic generates $700
million in annual sales from their
product.[10]

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 anterior cervical discectomy and
fusion.[11] There are reports of this
therapy causing swelling of soft tissue
which in turn can cause life-threatening
complications due to difficulty
swallowing and pressure on the
respiratory tract.[11]

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.

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 Mullerian 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.[12]
Moreover, BMP signaling is involved in
the formation of foregut and hindgut,[13]
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.[14] 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.[15] In addition,
Notch-Wnt-Bmp crosstalk is required for
radial patterning during mouse cochlea
development via antagonizing manner.[16]

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).

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.[9]
 BMP Known functions Gene Locus

*BMP1 does not belong to the TGF-β family of proteins. It is a Chromosome:

BMP1 metalloprotease that acts on procollagen I, II, and III. It is involved in 8; Location:
cartilage development. 8p21

Acts as a disulfide-linked homodimer and induces bone and Chromosome:

BMP2 cartilage formation. It is a candidate as a retinoid mediator. Plays a 20; Location:
key role in osteoblast differentiation. 20p12

Chromosome:
BMP3 Induces bone formation. 14; Location:
14p22

Regulates the formation of teeth, limbs and bone from mesoderm. It Chromosome:
BMP4 also plays a role in fracture repair, epidermis formation, dorsal- 14; Location:
ventral axis formation, and ovarian follical development. 14q22-q23

Chromosome:
BMP5 Performs functions in cartilage development. 6; Location:
6p12.1

Chromosome:
Plays a role in joint integrity in adults. Controls iron homeostasis via
BMP6 6; Location:
regulation of hepcidin.
6p12.1

Chromosome:
Plays a key role in osteoblast differentiation. It also induces the
BMP7 20; Location:
production of SMAD1. Also key in renal development and repair.
20q13

Chromosome:
BMP8a Involved in bone and cartilage development. 1; Location:
1p35–p32

Chromosome:
BMP8b Expressed in the hippocampus. 1; Location:
1p35–p32

Chromosome:
BMP10 May play a role in the trabeculation of the embryonic heart. 2; Location:
2p14

Chromosome:
BMP11 Controls anterior-posterior patterning. 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[17]

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.[18] Pierre Lacroix proposed
that there might be a hypothetical
substance, osteogenin, that might initiate
bone growth.[19]

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.[20] Urist
proposed the name "Bone
Morphogenetic Protein" in the scientific
literature in the Journal of Dental
Research in 1971.[21]

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.[22] 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.[23]
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,[24][25] but ultimately also
enabled the cloning of BMPs by John
Wozney and colleagues at Genetics
Institute.[26]

Society
Costs

At between US$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.

While there is little debate that rhBMPs

are successful clinically,[9] there is
controversy about their use. It is
common for orthopedic surgeons to be
paid for their contribution to the
development of a new product,[27][28] but
some of the surgeons responsible for the
original Medtronic-supported studies on
the efficacy of rhBMP-2 have been
accused of bias and conflict of
interest.[29] For example, one surgeon, a
lead author on four of these research
papers, did not disclose any financial ties
while with the company on three of the
papers;[30] he was paid over $4 million by
Medtronic.[30] In another study, the lead
author did not disclose any financial ties
to Medtronic; he was paid at least $11
million by the company.[30] In a series of
12 publications, the median financial ties
of the authors to Medtronic were $12–16
million.[31] In those studies that had more
than 20 and 100 patients, one or more
authors had financial ties of $1 million
and $10 million, respectively.[31] Early
clinical trials using rhBMP-2
underreported adverse events associated
with treatment. In the 13 original
industry-sponsored publications related
to safety, there were zero adverse events
in 780 patients.[31] It has since been
revealed that potential complications can
arise from the use including implant
displacement, subsidence, infection,
urogenital events, and retrograde
ejaculation.[30][31]
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.[32]

References
1. Reddi AH, Reddi A (2009). "Bone
morphogenetic proteins (BMPs): from
morphogens to metabologens". Cytokine
& Growth Factor Reviews. 20 (5–6): 341–
2. doi:10.1016/j.cytogfr.2009.10.015 .
PMID 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 (Sep 2007). "Bone
morphogenetic protein signaling
suppresses tumorigenesis at gastric
epithelial transition zones in mice".
Cancer Research. 67 (17): 8149–55.
doi:10.1158/0008-5472.CAN-06-4659 .
PMID 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 (May 2008). "The bone
morphogenetic protein pathway is
inactivated in the majority of sporadic
colorectal cancers". Gastroenterology.
134 (5): 1332–41.
doi:10.1053/j.gastro.2008.02.059 .
PMID 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 (Jun
2007). "Bone morphogenetic protein 4
expressed in esophagitis induces a
columnar phenotype in esophageal
squamous cells" . Gastroenterology. 132
(7): 2412–21.
doi:10.1053/j.gastro.2007.03.026 .
PMID 17570215 .
5. "Medtronic Receives Approval to
Market Infuse Bone Graft for Certain Oral
Maxillofacial And Dental Regenerative
Applications" . Retrieved January 19,
2011.
6. Wikesjö UM, Qahash M, Huang YH,
Xiropaidis A, Polimeni G, Susin C (Aug
2009). "Bone morphogenetic proteins for
periodontal and alveolar indications;
biological observations - clinical
implications" . Orthodontics &
Craniofacial Research. 12 (3): 263–270.
doi:10.1111/j.1601-6343.2009.01461.x .
PMID 19627529 .
7. Moghadam HG, Urist MR, Sandor GK,
Clokie CM (Mar 2001). "Successful
mandibular reconstruction using a BMP
bioimplant". The Journal of Craniofacial
Surgery. 12 (2): 119–127.
doi:10.1097/00001665-200103000-
00005 . PMID 11314620 .
8. Ong KL, Villarraga ML, Lau E, Carreon
LY, Kurtz SM, Glassman SD (Sep 2010).
"Off-label use of bone morphogenetic
proteins in the United States using
administrative data". Spine. 35 (19):
1794–800.
doi:10.1097/brs.0b013e3181ecf6e4 .
PMID 20700081 .
9. Even J, Eskander M, Kang J (Sep 2012).
"Bone morphogenetic protein in spine
surgery: current and future uses". The
Journal of the American Academy of
Orthopaedic Surgeons. 20 (9): 547–52.
doi:10.5435/JAAOS-20-09-547 .
PMID 22941797 .
10. John Fauber (2011-10-22). "Doctors
didn't disclose spine product cancer risk
in journal" . Milwaukee Journal Sentinel.
Retrieved 2013-05-12.
11. North American Spine Society
(February 2013), "Five Things Physicians
and Patients Should Question" , Choosing
Wisely: an initiative of the ABIM
Foundation, North American Spine
Society, retrieved 25 March 2013, which
cites
Schultz, Daniel G. (July 1, 2008).
"Public Health Notifications (Medical
Devices) - FDA Public Health
Notification: Life-threatening
Complications Associated with
Recombinant Human Bone
Morphogenetic Protein in Cervical
Spine Fusion" . fda.gov. Retrieved
25 March 2014.
Woo EJ (Oct 2012). "Recombinant
human bone morphogenetic protein-
2: adverse events reported to the
Manufacturer and User Facility
 Device Experience database". The
Spine Journal. 12 (10): 894–9.
doi:10.1016/j.spinee.2012.09.052 .
PMID 23098616 .
12. Yuji and Yoshiko (2016). “Early
formation of the Mullerian duct is
regulated by sequential actions of
BMP/Pax2 and FGF/Lim1 signaling”. The
Company of Biologists Ltd/ Development.
143, 3549-3559 doi:10.1242/dev.137067.
13. Mariana et al,. (2017). “Genomic
integration of Wnt/β-catenin and
BMP/Smad1 signaling coordinates
foregut and hindgut transcriptional
programs”. The Company of Biologists
Ltd/ Development. 144, 1283-1295
doi:10.1242/dev.145789.
14. Katherine et al,. (2016). “Villification in
the mouse: Bmp signals control intestinal
villus patterning”. The Company of
Biologists Ltd/ Development. 143, 427-
436 doi:10.1242/dev.130112.
15. Sharina et al,. (2015). “Myocardium
and BMP signaling are required for
endocardial differentiation”. The Company
of Biologists Ltd/ Development. 142,
2304-2315 doi:10.1242/dev.118687.
16. Vidhya et al,. (2016). “Notch-Wnt-Bmp
crosstalk regulates radial patterning in the
mouse cochlea in a spatiotemporal
manner”. The Company of Biologists Ltd/
Development. 143, 4003-4015
doi:10.1242/dev.139469.
17. Ducy P, Karsenty G (2000). "The family
of bone morphogenetic proteins". Kidney
Int. 57 (6): 2207–14. doi:10.1046/j.1523-
1755.2000.00081.x . PMID 10844590 .
18. Senn N (1889). "On the healing of
aseptic bone cavities by implantation of
antiseptic decalcified bone". American
Journal of the Medical Sciences. 98 (3):
219–243. doi:10.1097/00000441-
188909000-00001 .
19. Lacroix P (1945). "Recent
investigation on the growth of bone".
Nature. 156 (3967): 576.
doi:10.1038/156576a0 .
20. Urist MR (Nov 1965). "Bone: formation
by autoinduction". Science. 150 (3698):
893–899.
doi:10.1126/science.150.3698.893 .
PMID 5319761 .
21. Urist MR, Strates, Basil S. (1971).
"Bone Morphogenetic Protein" . Journal of
Dental Research. 50 (6): 1392–1406.
doi:10.1177/00220345710500060601 .
22. Reddi AH, Huggins C (1972).
"Biochemical sequences in the
transformation of normal fibroblasts in
adolescent rats" . Proc. Natl. Acad. Sci.
U.S.A. 69 (6): 1601–5.
doi:10.1073/pnas.69.6.1601 .
PMC 426757 . PMID 4504376 .
23. Sampath TK, Reddi AH (Dec 1981).
"Dissociative extraction and reconstitution
of extracellular matrix components
involved in local bone differentiation" .
Proceedings of the National Academy of
Sciences of the United States of America.
78 (12): 7599–7603.
doi:10.1073/pnas.78.12.7599 .
PMC 349316 . PMID 6950401 .
24. Sampath TK, Muthukumaran N, Reddi
AH (Oct 1987). "Isolation of osteogenin,
an extracellular matrix-associated, bone-
inductive protein, by heparin affinity
chromatography" . Proceedings of the
National Academy of Sciences of the
United States of America. 84 (20): 7109–
7113. doi:10.1073/pnas.84.20.7109 .
PMC 299239 . PMID 3478684 .
25. Luyten FP, Cunningham NS, Ma S,
Muthukumaran N, Hammonds RG, Nevins
WB, Woods WI, Reddi AH (Aug 1989).
"Purification and partial amino acid
sequence of osteogenin, a protein
initiating bone differentiation" . The
Journal of Biological Chemistry. 264 (23):
13377–13380. PMID 2547759 .
26. Wozney JM, Rosen V, Celeste AJ,
Mitsock LM, Whitters MJ, Kriz RW, Hewick
RM, Wang EA (Dec 1988). "Novel
regulators of bone formation: molecular
clones and activities". Science. 242
(4885): 1528–1534.
doi:10.1126/science.3201241 .
PMID 3201241 .
27. Toi Williams (2012-12-20). "Medtronic
Accused Of Editing Product Studies" . DC
Progressive. Retrieved 2013-05-12.
28. Rebecca Farbo (2013-01-16). "World-
renowned Orthopedic Surgeon Sues
Medical Device Company For Breach Of
Contract" . PR Newswire. Retrieved
2013-05-12.
29. Susan Perry (2012-10-26). "Report
reveals disturbing details of Medtronic's
role in shaping InFuse articles" .
MinnPost. Retrieved 2013-05-13.
30. John Carreyrou & Tom McGinty (2011-
06-29). "Medtronic Surgeons Held Back,
Study Says" . The Wall Street Journal.
Retrieved 2013-05-12.
31. Carragee EJ, Hurwitz EL, Weiner BK
(Jun 2011). "A critical review of
recombinant human bone morphogenetic
protein-2 trials in spinal surgery: emerging
safety concerns and lessons learned".
The Spine Journal. 11 (6): 471–91.
doi:10.1016/j.spinee.2011.04.023 .
PMID 21729796 .
32. Spinal Fusion and Bone
Morphogenetic Protein

Further reading
Reddi AH (1997). "Bone morphogenetic
proteins: an unconventional approach to
isolation of first mammalian morphogens".
 Cytokine Growth Factor Rev. 8 (1): 11–20.
doi:10.1016/S1359-6101(96)00049-4 .
PMID 9174660 .
Bessa PC, Casal M, Reis RL (Jan 2008).
"Bone morphogenetic proteins in tissue
engineering: the road from the laboratory to
the clinic, part I (basic concepts)" . Journal
of Tissue Engineering and Regenerative
Medicine. 2 (1): 1–13.
doi:10.1002/term.63 . PMID 18293427 .

External links
Wikimedia Commons has media related
to Bone morphogenetic proteins.

BMP: The What and the Who

BMPedia - the Bone Morphogenetic
Protein Wiki
Bone+Morphogenetic+Proteins at the
US National Library of Medicine
Medical Subject Headings (MeSH)
Chen D, Zhao M, Mundy GR (Dec
2004). "Bone morphogenetic proteins".
Growth Factors (Chur, Switzerland). 22
(4): 233–241.
doi:10.1080/08977190412331279890
. PMID 15621726 .
Cheng H, Jiang W, Phillips FM, Haydon
RC, Peng Y, Zhou L, Luu HH, An N,
Breyer B, Vanichakarn P, Szatkowski JP,
Park JY, He TC (Aug 2003).
"Osteogenic activity of the fourteen
 types of human bone morphogenetic
proteins (BMPs)". The Journal of Bone
and Joint Surgery. American Volume.
85-A (8): 1544–52. PMID 12925636 .
link

Retrieved from
"https://en.wikipedia.org/w/index.php?
title=Bone_morphogenetic_protein&oldid=868059
219"

Last edited 2 months ago by Intern…

Content is available under CC BY-SA 3.0 unless

otherwise noted.