:Bone morphogenetic protein

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.

rhBMPs are used in oral surgeries.{{cite web|title=Medtronic Receives Approval to Market Infuse Bone Graft for Certain Oral Maxillofacial And Dental Regenerative Applications| url=http://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=1173788328615&lang=en_US| access-date=January 19, 2011}}{{cite journal | vauthors = Wikesjö UM, Qahash M, Huang YH, Xiropaidis A, Polimeni G, Susin C | title = Bone morphogenetic proteins for periodontal and alveolar indications; biological observations - clinical implications | journal = Orthodontics & Craniofacial Research | volume = 12 | issue = 3 | pages = 263–270 | date = Aug 2009 | pmid = 19627529 | doi = 10.1111/j.1601-6343.2009.01461.x | url = http://www3.interscience.wiley.com/journal/122510612/abstract?CRETRY=1&SRETRY=0 | archive-url = https://archive.today/20130105071641/http://www3.interscience.wiley.com/journal/122510612/abstract?CRETRY=1&SRETRY=0 | url-status = dead | archive-date = 2013-01-05 }}{{cite journal | vauthors = Moghadam HG, Urist MR, Sandor GK, Clokie CM | title = Successful mandibular reconstruction using a BMP bioimplant | journal = The Journal of Craniofacial Surgery | volume = 12 | issue = 2 | pages = 119–127 | date = Mar 2001 | pmid = 11314620 | doi = 10.1097/00001665-200103000-00005 }} 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 Mayo Clinic, Maastricht University, and Ethris GmBH, a biotech company that focuses on RNA therapeutics, found that chemically modified mRNA encoding BMP-2 promoted dosage-dependent healing of femoral osteotomies in male rats. The mRNA molecules were complexed within nonviral 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.{{Cite journal |last1=De La Vega |first1=Rodolfo E. |last2=van Griensven |first2=Martijn |last3=Zhang |first3=Wen |last4=Coenen |first4=Michael J. |last5=Nagelli |first5=Christopher V. |last6=Panos |first6=Joseph A. |last7=Peniche Silva |first7=Carlos J. |last8=Geiger |first8=Johannes |last9=Plank |first9=Christian |last10=Evans |first10=Christopher H. |last11=Balmayor |first11=Elizabeth R. |date=2022-02-18 |title=Efficient healing of large osseous segmental defects using optimized chemically modified messenger RNA encoding BMP-2 |journal=Science Advances |volume=8 |issue=7 |pages=eabl6242 |doi=10.1126/sciadv.abl6242 |issn=2375-2548 |pmc=8849297 |pmid=35171668|bibcode=2022SciA....8.6242D }}

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.{{cite journal | vauthors = Ong KL, Villarraga ML, Lau E, Carreon LY, Kurtz SM, Glassman SD | title = Off-label use of bone morphogenetic proteins in the United States using administrative data | journal = Spine | volume = 35 | issue = 19 | pages = 1794–800 | date = Sep 2010 | pmid = 20700081 | doi = 10.1097/brs.0b013e3181ecf6e4 | s2cid = 11664755 }} 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. rhBMP-2 is used extensively in other lumbar spinal fusion techniques (e.g., using a posterior approach, anterior or posterior cervical fusions).

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. In 2004, the humanitarian device exemption was extended as an alternative to autograft for posterolateral fusion. In 2002, rhBMP-2 (Infuse; Medtronic) was approved for anterior lumbar interbody fusions (ALIFs) with a lumbar fusion device. In 2008 it was approved to repair posterolateral lumbar pseudarthrosis, open tibia shaft fractures with intramedullary nail fixation. 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. rhBMP-2 helps grow bone better than any other rhBMP so it is much more widely used clinically. There is "little debate or controversy" about the effectiveness of rhBMP-2 to grow bone to achieve spinal fusions, and Medtronic generates $700 million in annual sales from their product.{{cite news |url= http://www.jsonline.com/watchdog/watchdogreports/doctors-didnt-disclose-spine-product-cancer-risk-in-journal-132391068.html |title= Doctors didn't disclose spine product cancer risk in journal |author= John Fauber |newspaper= Milwaukee Journal Sentinel |date= 2011-10-22 |access-date= 2013-05-12}}

File:ACDF surgery english.png

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.{{Citation |author1 = North American Spine Society |author1-link = North American Spine Society |date = February 2013 |title = Five Things Physicians and Patients Should Question |publisher = North American Spine Society |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://www.choosingwisely.org/doctor-patient-lists/north-american-spine-society/ |access-date = 25 March 2013}}, which cites

• {{cite web |url= https://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ucm062000.htm |title=Public Health Notifications (Medical Devices) - FDA Public Health Notification: Life-threatening Complications Associated with Recombinant Human Bone Morphogenetic Protein in Cervical Spine Fusion |first=Daniel G. |last=Schultz |work=fda.gov |date=July 1, 2008 |access-date=25 March 2014}}
• {{cite journal | vauthors = Woo EJ | title = Recombinant human bone morphogenetic protein-2: adverse events reported to the Manufacturer and User Facility Device Experience database | journal = The Spine Journal | volume = 12 | issue = 10 | pages = 894–9 | date = Oct 2012 | pmid = 23098616 | doi = 10.1016/j.spinee.2012.09.052 | url = https://zenodo.org/record/1000710 }} 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.

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.{{cite journal |last1=Andrews |first1=Madeline |title=BMPs direct sensory interneuron identity in the developing spinal cord using signal- specific not morphogenic activities |journal=eLife |date=19 September 2017 |volume=6 |doi= 10.7554/eLife.30647 |pmid=28925352 |pmc=5605194 |doi-access=free }}

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.{{cite journal | vauthors = Yuji , Yoshiko | year = 2016 | title = Early formation of the Mullerian duct is regulated by sequential actions of BMP/Pax2 and FGF/Lim1 signaling | journal = Development | volume = 143 | issue = 19| pages = 3549–3559 | doi = 10.1242/dev.137067 | pmid = 27578782 | doi-access = free | hdl = 2433/252845 | hdl-access = free }} Moreover, BMP signaling is involved in the formation of foregut and hindgut,{{cite journal | vauthors = Mariana | display-authors = etal | year = 2017 | title = Genomic integration of Wnt/β-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs | journal = Development | volume = 144 | issue = 7| pages = 1283–1295 | doi = 10.1242/dev.145789 | pmid = 28219948 | pmc = 5399627 | doi-access = free }} 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.{{cite journal | vauthors = Katherine | display-authors = etal | year = 2016 | title = Villification in the mouse: Bmp signals control intestinal villus patterning | journal = Development | volume = 143 | issue = 3| pages = 427–436 | doi = 10.1242/dev.130112 | pmid = 26721501 | pmc = 4760312 | doi-access = free }} 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.{{cite journal | vauthors = Sharina | display-authors = etal | year = 2015 | title = Myocardium and BMP signaling are required for endocardial differentiation | journal = Development | volume = 142 | issue = 13| pages = 2304–2315 | doi = 10.1242/dev.118687 | pmid = 26092845 | pmc = 4510589 | doi-access = free }} In addition, Notch-Wnt-Bmp crosstalk is required for radial patterning during mouse cochlea development via antagonizing manner.{{cite journal | vauthors = Vidhya | display-authors = etal | year = 2016 | title = Notch-Wnt-Bmp crosstalk regulates radial patterning in the mouse cochlea in a spatiotemporal manner | journal = Development | volume = 143 | issue = 21| pages = 4003–4015 | doi = 10.1242/dev.139469 | pmid = 27633988 | pmc = 5117145 | doi-access = free }}

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).{{cite journal |title=Cartilage-derived morphogenetic proteins. New members of the transforming growth factor-beta superfamily predominantly expressed in long bones during human embryonic development. |journal=Journal of Biological Chemistry |pmid=7961761 |url=https://www.sciencedirect.com/science/article/pii/S0021925818469189}}

BMPs are also involved in adipogenesis and functional regulation of adipose tissue.{{Cite journal|last1=Blázquez-Medela|first1=Ana M.|last2=Jumabay|first2=Medet|last3=Boström|first3=Kristina I.|date=2019-01-04|title=Beyond the bone: Bone morphogenetic protein signaling in adipose tissue|journal=Obesity Reviews|volume=20|issue=5|pages=648–658|doi=10.1111/obr.12822|issn=1467-789X|pmid=30609449|pmc=6447448}} BMP4 favors white adipogenesis, whereas BMP7 activates brown fat functionality; BMP inhibitors are also involved in this regulation

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, all of which are in the TGF-beta family, have been discovered, bringing the total to twenty.{{cite journal | vauthors = Even J, Eskander M, Kang J | title = Bone morphogenetic protein in spine surgery: current and future uses | journal = The Journal of the American Academy of Orthopaedic Surgeons | volume = 20 | issue = 9 | pages = 547–52 | date = Sep 2012 | pmid = 22941797 | doi = 10.5435/JAAOS-20-09-547 | doi-access = free }} The current nomenclature only recognizes 13, as many others are put under the growth differentiation factor naming instead.

File:Mammalian bone morphogenetic proteins.png

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.{{cite journal |last=Senn |first=N. |year=1889 |title=On the healing of aseptic bone cavities by implantation of antiseptic decalcified bone |journal=American Journal of the Medical Sciences |volume=98 |issue= 3|pages=219–243 |doi=10.1097/00000441-188909000-00001 |name-list-style=vanc |url=https://zenodo.org/record/1431945 }} Pierre Lacroix proposed that there might be a hypothetical substance, osteogenin, that might initiate bone growth.{{cite journal |last=Lacroix |first=P. |year=1945 |title=Recent investigation on the growth of bone |journal=Nature |volume=156 |issue= 3967|pages=576 |doi=10.1038/156576a0 |bibcode=1945Natur.156..576L |s2cid=46630297 |name-list-style=vanc|doi-access=free }}

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.{{cite journal | vauthors = Urist MR | title = Bone: formation by autoinduction | journal = Science | volume = 150 | issue = 3698 | pages = 893–899 | date = Nov 1965 | pmid = 5319761 | doi = 10.1126/science.150.3698.893 | bibcode = 1965Sci...150..893U | s2cid = 83951938 | author-link = Marshall R. Urist }} Urist proposed the name "Bone Morphogenetic Protein" in the scientific literature in the Journal of Dental Research in 1971.{{cite journal |last=Urist |first=Marshall R. |author2=Strates, Basil S. |title=Bone Morphogenetic Protein |journal=Journal of Dental Research |year=1971 |volume=50 |issue=6 |pages=1392–1406 |doi=10.1177/00220345710500060601 |pmid=4943222 |s2cid=44381411 |name-list-style=vanc }}

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.{{cite journal | vauthors = Reddi AH, Huggins C | title = Biochemical sequences in the transformation of normal fibroblasts in adolescent rats | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 69 | issue = 6 | pages = 1601–5 | year = 1972 | pmid = 4504376 | pmc = 426757 | doi = 10.1073/pnas.69.6.1601 | bibcode = 1972PNAS...69.1601R | doi-access = free }} 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.{{cite journal | vauthors = Sampath TK, Reddi AH | title = Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 12 | pages = 7599–7603 | date = Dec 1981 | pmid = 6950401 | pmc = 349316 | doi = 10.1073/pnas.78.12.7599 | bibcode = 1981PNAS...78.7599S | doi-access = free }} 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,{{cite journal | vauthors = Sampath TK, Muthukumaran N, Reddi AH | title = Isolation of osteogenin, an extracellular matrix-associated, bone-inductive protein, by heparin affinity chromatography | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 20 | pages = 7109–7113 | date = Oct 1987 | pmid = 3478684 | pmc = 299239 | doi = 10.1073/pnas.84.20.7109 | bibcode = 1987PNAS...84.7109S | doi-access = free }}{{cite journal | vauthors = Luyten FP, Cunningham NS, Ma S, Muthukumaran N, Hammonds RG, Nevins WB, Woods WI, Reddi AH | title = Purification and partial amino acid sequence of osteogenin, a protein initiating bone differentiation | journal = The Journal of Biological Chemistry | volume = 264 | issue = 23 | pages = 13377–13380 | date = Aug 1989 | doi = 10.1016/S0021-9258(18)80003-5 | pmid = 2547759 | doi-access = free }} but ultimately also enabled the cloning of BMPs by John Wozney and colleagues at Genetics Institute.{{cite journal | vauthors = Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA | title = Novel regulators of bone formation: molecular clones and activities | journal = Science | volume = 242 | issue = 4885 | pages = 1528–1534 | date = Dec 1988 | pmid = 3201241 | doi = 10.1126/science.3201241 | bibcode = 1988Sci...242.1528W }}

{{Globalize|article|USA|2name=the United States|date=March 2019}}

At between US$6,000 and $10,000 for a typical treatment, BMPs can be costly compared with other techniques such as bone grafting.{{Citation needed|date=January 2020}} 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, 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,{{cite news |url= http://dcprogressive.org/2012/12/20/medtronic-accused-of-editing-product-studies-nyse-mdt/ |author= Toi Williams |title= Medtronic Accused Of Editing Product Studies |publisher= DC Progressive |date= 2012-12-20 |access-date= 2013-05-12}}{{cite news |url= http://www.prnewswire.com/news-releases/world-renowned-orthopedic-surgeon-sues-medical-device-company-for-breach-of-contract-187183211.html |author= Rebecca Farbo |title= World-renowned Orthopedic Surgeon Sues Medical Device Company For Breach Of Contract |publisher = PR Newswire |date= 2013-01-16 |access-date= 2013-05-12}} 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.{{cite web |url= http://www.minnpost.com/second-opinion/2012/10/report-reveals-disturbing-details-medtronic-s-role-shaping-infuse-articles |author= Susan Perry |title= Report reveals disturbing details of Medtronic's role in shaping InFuse articles |publisher= MinnPost |date= 2012-10-26 |access-date= 2013-05-13}} 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;{{cite news |url= https://www.wsj.com/articles/SB10001424052702303627104576413663395567784 |author= John Carreyrou |author2= Tom McGinty |name-list-style= amp |title= Medtronic Surgeons Held Back, Study Says |newspaper= The Wall Street Journal |date= 2011-06-29 |access-date= 2013-05-12}} he was paid over $4 million by Medtronic. In another study, the lead author did not disclose any financial ties to Medtronic; he was paid at least $11 million by the company. In a series of 12 publications, the median financial ties of the authors to Medtronic were $12–16 million. 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. 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.{{cite journal | vauthors = Carragee EJ, Hurwitz EL, Weiner BK | title = A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned | journal = The Spine Journal | volume = 11 | issue = 6 | pages = 471–91 | date = Jun 2011 | pmid = 21729796 | doi = 10.1016/j.spinee.2011.04.023 }} It has since been revealed that potential complications can arise from the use including implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation.

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.Spinal Fusion and Bone Morphogenetic Protein

{{Reflist|30em}}

{{refbegin}}

• {{cite journal | vauthors = Reddi AH | title = Bone morphogenetic proteins: an unconventional approach to isolation of first mammalian morphogens | journal = Cytokine Growth Factor Rev. | volume = 8 | issue = 1 | pages = 11–20 | year = 1997 | pmid = 9174660 | doi = 10.1016/S1359-6101(96)00049-4 | doi-access = free }}
• {{cite journal | vauthors = Bessa PC, Casal M, Reis RL | title = Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I (basic concepts) | journal = Journal of Tissue Engineering and Regenerative Medicine | volume = 2 | issue = 1 | pages = 1–13 | date = Jan 2008 | pmid = 18293427 | doi = 10.1002/term.63 | url = http://www3.interscience.wiley.com/journal/117916474/abstract?CRETRY=1&SRETRY=0 | archive-url = https://archive.today/20121018132518/http://www3.interscience.wiley.com/journal/117916474/abstract?CRETRY=1&SRETRY=0 | url-status = dead | archive-date = 2012-10-18 | hdl = 1822/13420 | s2cid = 13038950 | hdl-access = free }}

{{refend}}

{{Commons category|Bone morphogenetic proteins}}

• [http://www.spineuniverse.com/displayarticle.php/article1992.html BMP: The What and the Who]
• [http://bmpedia.wikidot.com/bmp-family BMPedia - the Bone Morphogenetic Protein Wiki]
• {{MeshName|Bone+Morphogenetic+Proteins}}
• {{cite journal | vauthors = Chen D, Zhao M, Mundy GR | title = Bone morphogenetic proteins | journal = Growth Factors (Chur, Switzerland) | volume = 22 | issue = 4 | pages = 233–241 | date = Dec 2004 | pmid = 15621726 | doi = 10.1080/08977190412331279890 | s2cid = 22932278 }}
• {{cite journal | vauthors = 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 | title = Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs) | journal = The Journal of Bone and Joint Surgery. American Volume | volume = 85-A | issue = 8 | pages = 1544–52 | date = Aug 2003 | pmid = 12925636 | doi = 10.2106/00004623-200308000-00017 }} [https://archive.today/20130415051000/http://www.jbjs.org/article.aspx?articleid=26039 link]

{{TGF beta signaling}}

{{Drugs for treatment of bone diseases}}

{{TGFβ receptor superfamily modulators}}

{{DEFAULTSORT:Bone Morphogenetic Protein}}

Category:Animal developmental biology

Category:Proteins