Bone morphogenetic protein 7: Difference between revisions

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{{Protbox
{{Infobox gene}}
  |Name=Bone Morphogentic Protein 7
'''Bone morphogenetic protein 7''' or '''BMP7''' (also known as '''osteogenic protein-1''' or '''OP-1''') is a [[protein]] that in humans is encoded by the ''BMP7'' [[gene]].<ref name="pmid1427904">{{cite journal | vauthors = Hahn GV, Cohen RB, Wozney JM, Levitz CL, Shore EM, Zasloff MA, Kaplan FS | title = A bone morphogenetic protein subfamily: chromosomal localization of human genes for BMP5, BMP6, and BMP7 | journal = Genomics | volume = 14 | issue = 3 | pages = 759–62 |date=November 1992 | pmid = 1427904 | doi = 10.1016/S0888-7543(05)80181-8  | url =  }}</ref>
  |Photo=Noggin.png
  |Caption=Photo of Bone Morphogenetic Protein-7 (Bmp-7) In Complex With The Secreted Antagonist [[Noggin (protein)|Noggin]]
  |Gene = [[HUGO]] code: [http://www.gene.ucl.ac.uk/nomenclature/data/get_data.php?hgnc_id=HGNC:1074 BMP7]      |Structure =
  |Review =
  |Type=
  |Functions= [[cell signaling]], bone development
  |Domains= [[TGFβ]]
  |Diseases=
  |Taxa = many metazoan phyla
  | Cells = [[mesenchymal]]
  | Location =
  |Mods=
  |Names= '''Osteogenic protein 1 (OP1)'''
  |Interactions= [[SOSTDC1]], [[Noggin (protein)|noggin]], [[Endoglin]]  
  |Pages=
  |Codes=
  | HGNCid = 1074
  | Symbol = BMP7
  | AltSymbols = OP-1
  | EntrezGene = 655
  | OMIM = 112267
  | RefSeq = NM_001719
  | UniProt = P18075
  | PDB =  
  | ECnumber =  
  | Chromosome = 20
   | Arm = q
  | Band = 13
}}
__NOTOC__
{{SI}}
{{CMG}}


==Function==
The protein encoded by this gene is a member of the [[Transforming growth factor|TGF-β]] superfamily. Like other members of the [[bone morphogenetic protein]] family of proteins, it plays a key role in the transformation of [[mesenchymal]] cells into bone and cartilage. It is inhibited by [[Noggin (protein)|noggin]] and a similar protein, chordin, which are expressed in the Spemann-Mangold Organizer. BMP7 may be involved in bone [[homeostasis]]. It is expressed in the [[brain]], [[kidneys]] and [[urinary bladder|bladder]].<ref name="pmid15621726">{{cite journal | vauthors = Chen D, Zhao M, Mundy GR | title = Bone morphogenetic proteins | journal = Growth Factors | volume = 22 | issue = 4 | pages = 233–41 |date=December 2004 | pmid = 15621726 | doi = 10.1080/08977190412331279890  }}</ref>


==Overview==
BMP7 induces the phosphorylation of [[SMAD1]] and [[SMAD5]], which in turn induce transcription of numerous osteogenic genes.<ref name="pmid11483516">{{cite journal | vauthors = Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S | title = Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads | journal = EMBO J. | volume = 20 | issue = 15 | pages = 4132–42 |date=August 2001 | pmid = 11483516 | pmc = 149146 | doi = 10.1093/emboj/20.15.4132  }}</ref> It has been demonstrated that BMP7 treatment is sufficient to induce all of the genetic markers of [[osteoblast]] [[Cellular differentiation|differentiation]] in many cell types.<ref name="pmid15621726"/>
'''Bone morphogenetic protein 7''' or '''BMP7''' (also known as '''Osteogenic Protein-1''' or '''OP-1''') is a member of the [[Transforming growth factor|TGF-β]] superfamily of proteins. Like other members of the [[bone morphogenetic protein]] family of proteins, it plays a key role in the transformation of [[mesenchymal]] cells into bone and cartilage. It is inhibited by [[Noggin (protein)|noggin]] and a similar protein, chordin, which are expressed in the Spemann-Mangold Organizer. BMP7 may be involved in bone [[homeostasis]]. It is expressed in the [[brain]], [[kidneys]] and [[urinary bladder|bladder]].


BMP7 induces the phosphorylation of [[SMAD1]] and [[SMAD5]], which in turn induce transcription of numerous osteogenic genes. It has been demonstrated that BMP7 treatment is sufficient to induce all of the genetic markers of [[osteoblast]] [[Cellular differentiation|differentiation]] in many cell types.
== Role in vertebrate development ==


The role of BMP7 in mammalian kidney development is through induction of MET of the metanephrogenic blastema.<ref name="Zeisberg_2003">{{cite journal | vauthors = Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Müller GA, Kalluri R | title = Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models | journal = Am. J. Physiol. Renal Physiol. | volume = 285 | issue = 6 | pages = F1060–7 | year = 2003 | pmid = 12915382 | doi = 10.1152/ajprenal.00191.2002 }}</ref> The epithelial tissue emerging from this MET process eventually forms the tubules and glomeruli of the nephron.<ref name="Zeisberg_2003"/> BMP-7 is also important in homeostasis of the adult kidney by inhibiting ephithelial-mesenchymal transition (EMT). BMP-7 expression is attenuated when the nephron is placed under inflammatory or ischemic stress, leading to EMT, which can result in fibrosis of the kidney.<ref name="Kalluri_2009">{{cite journal | vauthors = Kalluri R, Weinberg RA | title = The basics of epithelial-mesenchymal transition | journal = J. Clin. Invest. | volume = 119 | issue = 6 | pages = 1420–8 | year = 2009 | pmid = 19487818 | pmc = 2689101 | doi = 10.1172/JCI39104 }}</ref> This type of fibrosis often leads to renal failure, and is predictive of end stage renal disease.<ref name="Wang_2001">{{cite journal | vauthors = Wang SN, Lapage J, Hirschberg R | title = Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy | journal = J. Am. Soc. Nephrol. | volume = 12 | issue = 11 | pages = 2392–9 | year = 2001 | pmid = 11675415 | doi = }}</ref>


==Role of BMP7 in vertebrate development==
BMP7 has been discovered to be crucial in the determination of ventral-dorsal organization in zebrafish. BMP7 causes the expression of ventral phenotypes while its complete inhibition creates a dorsal phenotype. Moreover, BMP7 is eventually partially "turned off" in embryonic development in order to create the dorsal parts of the organism.<ref name="pmid11846479">{{cite journal | vauthors = Myers DC, Sepich DS, Solnica-Krezel L | title = Bmp activity gradient regulates convergent extension during zebrafish gastrulation | journal = Dev. Biol. | volume = 243 | issue = 1 | pages = 81–98 |date=March 2002 | pmid = 11846479 | doi = 10.1006/dbio.2001.0523  }}</ref>
BMP7 has been discovered to be crucial in the determination of ventral-dorsal organization in zebrafish. BMP7 causes the expression of ventral phenotypes while its complete inhibition creates a dorsal phenotype. Moreover, BMP7 is eventually partially "turned off" in embryonic development in order to create the dorsal parts of the organism.  


In many early developmental experiments using zebrafish, scientists used caBMPR (constitutively active) and tBMP (truncated receptor) to determine the affect of BMP7 in embryogensis. They found that the constitutively active, which causes BMP to be expressed everywhere creates a ventralized phenotype, whereas truncated, dorsalized.
In many early developmental experiments using zebrafish, scientists used caBMPR (constitutively active) and tBMP (truncated receptor) to determine the effect of BMP7 in embryogensis. They found that the constitutively active, which causes BMP to be expressed everywhere creates a ventralized phenotype, whereas truncated, dorsalized.


==Recombinant human BMP-7 protein as a drug==
== Therapeutic application ==
BMP7 has Surgical uses and is marketed under the name brand name OP1 Sold by Stryker. It can be used to aid in the fusion of vertebral bodies to prevent neurologic trauma. Also in the treatment of [[tibia]]l non-union, frequently in cases where an [[bone graft]] has failed.
{{See also|Bone morphogenetic protein#Clinical uses}}
Human recombinant BMP7 has surgical uses and is marketed under the brand name OP1 (sold by Olympus, who bought it from Stryker). It can be used to aid in the fusion of vertebral bodies to prevent neurologic trauma.<ref name="pmid17588821">{{cite journal | vauthors = Vaccaro AR, Whang PG, Patel T, Phillips FM, Anderson DG, Albert TJ, Hilibrand AS, Brower RS, Kurd MF, Appannagari A, Patel M, Fischgrund JS | title = The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study | journal = Spine J | volume = 8 | issue = 3 | pages = 457–65 | year = 2008 | pmid = 17588821 | doi = 10.1016/j.spinee.2007.03.012  }}</ref> Also in the treatment of [[tibia]]l non-union, frequently in cases where a [[bone graft]] has failed.<ref name="pmid17989951">{{cite journal | vauthors = Zimmermann G, Müller U, Löffler C, Wentzensen A, Moghaddam A | title = [Therapeutic outcome in tibial pseudarthrosis: bone morphogenetic protein 7 (BMP-7) versus autologous bone grafting for tibial fractures] | language = German | journal = Unfallchirurg | volume = 110 | issue = 11 | pages = 931–8 |date=November 2007 | pmid = 17989951 | doi = 10.1007/s00113-007-1347-y  }}</ref> rhBMP-2 is much more widely used clinically because it helps grow bone better than rhBMP-7 and other BMPs.<ref name="Even">{{cite journal |vauthors= Even J, Eskander M, Kang J |title= Bone morphogenetic protein in spine surgery: current and future uses |journal= J Am Acad Orthop Surg |year = 2012 |issue= 9 |pages= 547–52 |PMID =22941797 |doi=10.5435/JAAOS-20-09-547 |volume=20}}</ref>


BMP7 also has the potential for treatment of chronic kidney disease. Curis, Inc., reported in 2002 on the role BMP7 plays in the kidneys. <ref>http://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=253558&highlight=</ref><ref>http://phx.corporate-ir.net/phoenix.zhtml?c=123198&p=irol-newsArticle&ID=280064&highlight=</ref> In 2007 Johnson & Johnson returned its exclusive license for theurapeutic use of BMP-7 to Curis, with Curis being disappointed in the lack of development by J&J in ensuing time.<ref>http://seekingalpha.com/article/47830-curis-the-wall-street-analyst-forum-presentation-transcript</ref>
BMP7 also has the potential for treatment of chronic kidney disease.<ref name="Gould_2002">{{cite journal | vauthors = Gould SE, Day M, Jones SS, Dorai H | title = BMP-7 regulates chemokine, cytokine, and hemodynamic gene expression in proximal tubule cells | journal = Kidney Int. | volume = 61 | issue = 1 | pages = 51–60 | year = 2002 | pmid = 11786084 | doi = 10.1046/j.1523-1755.2002.00103.x  }}</ref><ref name="pmid11918739">{{cite journal | vauthors = González EA, Lund RJ, Martin KJ, McCartney JE, Tondravi MM, Sampath TK, Hruska KA | title = Treatment of a murine model of high-turnover renal osteodystrophy by exogenous BMP-7 | journal = Kidney Int. | volume = 61 | issue = 4 | pages = 1322–31 |date=April 2002 | pmid = 11918739 | doi = 10.1046/j.1523-1755.2002.00258.x  }}</ref> Kidney disease is characterized by derangement of the tubular architecture by both myofibroblast buildup and monocyte infiltration <ref name="Morrissey_2002">{{cite journal | vauthors = Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S | title = Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function | journal = J. Am. Soc. Nephrol. | volume = 13 Suppl 1 | issue = | pages = S14–21 | year = 2002 | pmid = 11792757 | doi = }}</ref> Because endogenous BMP-7 is an inhibitor of the TGF-β signaling cascade that induces fibrosis, the use of exogenous recombinant BMP-7 (rhBMP-7) could be a viable treatment of chronic kidney disease.<ref name="Zeisberg_2003"/> It is also thought that BMP-7 reverses fibrosis and EMT through reduction in monocyte infiltration into inflamed tissue.<ref name="Gould_2002"/> On a molecular level, BMP-7 represses inflammation by knocking down the expression of several pro-inflammatory cytokines produced by monocytes.<ref name="Gould_2002"/> Reducing this inflammatory stress, in turn, reduces the chance of fibrosis.<ref name="Kalluri_2009"/>


==References==
Regardless of the mechanism of fibrosis or the origin of myofibroblasts, exogenous BMP-7 has been shown to reverse the EMT process and trigger MET.<ref name="Zeisberg_2003"/> Eventually this restores the healthy epithelial cell population, and normal function of the kidneys in mice.<ref name="Zeisberg_2003"/> This is pertinent in humans as well, because many diseases stemming from organ fibrosis occur via the EMT process.<ref name="Kalluri_2009"/> The epithelial-menenchymal transition is also problematic in cancer metastasis, so the diminution of EMT with recombinant DNA could have great implications in future cancer treatment options.<ref name="Kalluri_2009"/>
{{reflist|2}}


BMP7 administration has been proposed as a possible treatment for human infertility due to poor response to [[Follicle-stimulating hormone|FSH]] treatment.<ref name="pmid19108831">{{cite journal | vauthors = Shi J, Yoshino O, Osuga Y, Nishii O, Yano T, Taketani Y | title = Bone morphogenetic protein 7 (BMP-7) increases the expression of follicle-stimulating hormone (FSH) receptor in human granulosa cells | journal = Fertil. Steril. | volume = 93 | issue = 4 | pages = 1273–9 |date=March 2010 | pmid = 19108831 | doi = 10.1016/j.fertnstert.2008.11.014 | url = | issn = }}</ref>
== Promotion of brown fat  ==
It was discovered that mice injected with BMP7 increased their production of "good" brown fat cells, while keeping their levels of the normal white fat cells constant. A BMP7 therapy for obesity in humans may be developed as a result.<ref name="urlObesity: Scientists identify protein that promotes fat-burning | Science | ">{{cite web | url = https://www.theguardian.com/science/2008/aug/21/brown.fat.obesity | title = Obesity: Scientists identify protein that promotes fat-burning  | author = Jha A | date = 2008-08-21 | format = | work = Science  | publisher = guardian.co.uk | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-09-03}}</ref><ref name="pmid18719589">{{cite journal | vauthors = Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR | title = New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure | journal = Nature | volume = 454 | issue = 7207 | pages = 1000–4 |date=August 2008 | pmid = 18719589 | doi = 10.1038/nature07221 | url = | pmc = 2745972  }}</ref>
== References ==
{{Reflist|colwidth=30em}}
==Further reading==
{{refbegin|colwidth=30em}}
*{{cite journal  |vauthors=Xiao HQ, Shi W, Zhang Y, Liang YZ |title=[Effect of bone morphogenic protein 7 on nephrin expression and distribution in diabetic rat kidneys] |journal=Nan Fang Yi Ke Da Xue Xue Bao |volume=29 |issue= 4 |pages= 671–5 |year= 2009 |pmid= 19403392 |doi=  }}
*{{cite journal  |vauthors=Murray LA, Hackett TL, Warner SM |title=BMP-7 does not protect against bleomycin-induced lung or skin fibrosis. |journal=PLoS ONE |volume=3 |issue= 12 |pages= e4039 |year= 2008 |pmid= 19112509 |doi= 10.1371/journal.pone.0004039  |pmc=2603595  |editor1-last=Eickelberg  |editor1-first=Oliver |display-authors=etal}}
*{{cite journal  |vauthors=Freedman BI, Bowden DW, Ziegler JT |title=Bone morphogenetic protein 7 (BMP7) gene polymorphisms are associated with inverse relationships between vascular calcification and BMD: the Diabetes Heart Study |journal=J. Bone Miner. Res. |volume=24 |issue= 10 |pages= 1719–27 |year= 2009 |pmid= 19453255 |doi= 10.1359/jbmr.090501  |pmc=2743282  |display-authors=etal}}
*{{cite journal  |vauthors=Garriock HA, Kraft JB, Shyn SI |title=A genomewide association study of citalopram response in major depressive disorder |journal=Biol. Psychiatry |volume=67 |issue= 2 |pages= 133–8 |year= 2010 |pmid= 19846067 |doi= 10.1016/j.biopsych.2009.08.029  |pmc=2794921 |display-authors=etal}}
*{{cite journal  |author=Reddi AH |title=Bone morphogenetic proteins and skeletal development: the kidney-bone connection |journal=Pediatr. Nephrol. |volume=14 |issue= 7 |pages= 598–601 |year= 2000 |pmid= 10912525 |doi=10.1007/s004670000364  }}
*{{cite journal  |vauthors=Gautschi OP, Cadosch D, Zellweger R |title=Apoptosis induction and reduced proliferation in human osteoblasts by rhBMP-2, -4 and -7 |journal=J Musculoskelet Neuronal Interact |volume=9 |issue= 1 |pages= 53–60 |year=  2009|pmid= 19240369 |doi=  |display-authors=etal}}
*{{cite journal  |vauthors=Alarmo EL, Pärssinen J, Ketolainen JM |title=BMP7 influences proliferation, migration, and invasion of breast cancer cells |journal=Cancer Lett. |volume=275 |issue= 1 |pages= 35–43 |year= 2009 |pmid= 18980801 |doi= 10.1016/j.canlet.2008.09.028 |display-authors=etal}}
*{{cite journal  |vauthors=Elshaier AM, Hakimiyan AA, Rappoport L |title=Effect of interleukin-1beta on osteogenic protein 1-induced signaling in adult human articular chondrocytes |journal=Arthritis Rheum. |volume=60 |issue= 1 |pages= 143–54 |year= 2009 |pmid= 19116903 |doi= 10.1002/art.24151  |pmc=2626196 |display-authors=etal}}
*{{cite journal  |vauthors=Yerges LM, Klei L, Cauley JA |title=High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men |journal=J. Bone Miner. Res. |volume=24 |issue= 12 |pages= 2039–49 |year= 2009 |pmid= 19453261 |doi= 10.1359/jbmr.090524  |pmc=2791518  |display-authors=etal}}
*{{cite journal  |vauthors=Dudas PL, Argentieri RL, Farrell FX |title=BMP-7 fails to attenuate TGF-beta1-induced epithelial-to-mesenchymal transition in human proximal tubule epithelial cells |journal=Nephrol. Dial. Transplant. |volume=24 |issue= 5 |pages= 1406–16 |year= 2009 |pmid= 19056781 |doi= 10.1093/ndt/gfn662 }}
*{{cite journal  |vauthors=Honsawek S, Chayanupatkul M, Tanavalee A |title=Relationship of plasma and synovial fluid BMP-7 with disease severity in knee osteoarthritis patients: a pilot study |journal=Int Orthop |volume=33 |issue= 4 |pages= 1171–5 |year= 2009 |pmid= 19301001  |pmc=2898966 |doi= 10.1007/s00264-009-0751-z |display-authors=etal}}
*{{cite journal  |vauthors=Sengle G, Ono RN, Lyons KM |title=A new model for growth factor activation: type II receptors compete with the prodomain for BMP-7 |journal=J. Mol. Biol. |volume=381 |issue= 4 |pages= 1025–39 |year= 2008 |pmid= 18621057 |doi= 10.1016/j.jmb.2008.06.074  |pmc=2705212 |display-authors=etal}}
*{{cite journal  |vauthors=Mitu G, Hirschberg R |title=Bone morphogenetic protein-7 (BMP7) in chronic kidney disease |journal=Front. Biosci. |volume=13 |issue=  |pages= 4726–39 |year= 2008 |pmid= 18508541 |doi=  10.2741/3035}}
*{{cite journal  |vauthors=Brown A, Stock G, Patel AA |title=Osteogenic protein-1 : a review of its utility in spinal applications |journal=BioDrugs |volume=20 |issue= 4 |pages= 243–51 |year= 2006 |pmid= 16831023 |doi=  10.2165/00063030-200620040-00005|display-authors=etal}}
*{{cite journal  |vauthors=Fajardo M, Liu CJ, Egol K |title=Levels of expression for BMP-7 and several BMP antagonists may play an integral role in a fracture nonunion: a pilot study |journal=Clin. Orthop. Relat. Res. |volume=467 |issue= 12 |pages= 3071–8 |year= 2009 |pmid= 19597895 |doi= 10.1007/s11999-009-0981-9  |pmc=2772945 }}
*{{cite journal  |vauthors=Giannoudis PV, Kanakaris NK, Dimitriou R |title=The synergistic effect of autograft and BMP-7 in the treatment of atrophic nonunions |journal=Clin. Orthop. Relat. Res. |volume=467 |issue= 12 |pages= 3239–48 |year= 2009 |pmid= 19396502 |doi= 10.1007/s11999-009-0846-2  |pmc=2772926 |display-authors=etal}}
*{{cite journal  |vauthors=Kalluri R, Neilson EG |title=Epithelial-mesenchymal transition and its implications for fibrosis |journal=J. Clin. Invest. |volume=112 |issue= 12 |pages= 1776–84 |year= 2003 |pmid= 14679171 |doi= 10.1172/JCI20530  |pmc=297008 }}
*{{cite journal  |vauthors=Zhu L, Chuanchang D, Wei L |title=Enhanced healing of goat femur-defect using BMP7 gene-modified BMSCs and load-bearing tissue-engineered bone |journal=J. Orthop. Res. |volume=28 |issue= 3 |pages= 412–8 |year= 2010 |pmid= 19725097 |doi= 10.1002/jor.20973 |display-authors=etal}}
*{{cite journal  |vauthors=Vieira AR, McHenry TG, Daack-Hirsch S |title=Candidate gene/loci studies in cleft lip/palate and dental anomalies finds novel susceptibility genes for clefts |journal=Genet. Med. |volume=10 |issue= 9 |pages= 668–74 |year= 2008 |pmid= 18978678 |doi= 10.1097/GIM.0b013e3181833793  |pmc=2734954 |display-authors=etal}}
*{{cite journal  |vauthors=Kron K, Pethe V, Briollais L |title=Discovery of novel hypermethylated genes in prostate cancer using genomic CpG island microarrays |journal=PLoS ONE |volume=4 |issue= 3 |pages= e4830 |year= 2009 |pmid= 19283074 |doi= 10.1371/journal.pone.0004830  |pmc=2653233  |editor1-last=Blagosklonny  |editor1-first=Mikhail V. |display-authors=etal}}
{{refend}}
==External links==
* {{MeshName|bone+morphogenetic+protein+7|3=bone morphogenetic protein 7}}
* [https://web.archive.org/web/20160304120408/http://www.biotechniques.com/news/2011-Molecule-of-the-Year/biotechniques-332657.html#.Uvo8TGJdUrU BMP7 as Molecule of the Year 2011]
* {{UCSC gene info|BMP7}}
{{PDB Gallery|geneid=655}}
{{TGF beta signaling}}
{{TGF beta signaling}}
{{TGFβ receptor superfamily modulators}}


[[Category:Bone morphogenetic protein]]
[[Category:Bone morphogenetic protein]]
[[Category:Developmental biology]]
[[Category:Developmental genes and proteins]]
[[Category:TGFβ domain]]
[[Category:TGFβ domain]]

Revision as of 18:44, 9 November 2018

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Bone morphogenetic protein 7 or BMP7 (also known as osteogenic protein-1 or OP-1) is a protein that in humans is encoded by the BMP7 gene.[1]

Function

The protein encoded by this gene is a member of the TGF-β superfamily. Like other members of the bone morphogenetic protein family of proteins, it plays a key role in the transformation of mesenchymal cells into bone and cartilage. It is inhibited by noggin and a similar protein, chordin, which are expressed in the Spemann-Mangold Organizer. BMP7 may be involved in bone homeostasis. It is expressed in the brain, kidneys and bladder.[2]

BMP7 induces the phosphorylation of SMAD1 and SMAD5, which in turn induce transcription of numerous osteogenic genes.[3] It has been demonstrated that BMP7 treatment is sufficient to induce all of the genetic markers of osteoblast differentiation in many cell types.[2]

Role in vertebrate development

The role of BMP7 in mammalian kidney development is through induction of MET of the metanephrogenic blastema.[4] The epithelial tissue emerging from this MET process eventually forms the tubules and glomeruli of the nephron.[4] BMP-7 is also important in homeostasis of the adult kidney by inhibiting ephithelial-mesenchymal transition (EMT). BMP-7 expression is attenuated when the nephron is placed under inflammatory or ischemic stress, leading to EMT, which can result in fibrosis of the kidney.[5] This type of fibrosis often leads to renal failure, and is predictive of end stage renal disease.[6]

BMP7 has been discovered to be crucial in the determination of ventral-dorsal organization in zebrafish. BMP7 causes the expression of ventral phenotypes while its complete inhibition creates a dorsal phenotype. Moreover, BMP7 is eventually partially "turned off" in embryonic development in order to create the dorsal parts of the organism.[7]

In many early developmental experiments using zebrafish, scientists used caBMPR (constitutively active) and tBMP (truncated receptor) to determine the effect of BMP7 in embryogensis. They found that the constitutively active, which causes BMP to be expressed everywhere creates a ventralized phenotype, whereas truncated, dorsalized.

Therapeutic application

See also: Bone morphogenetic protein § Clinical uses

Human recombinant BMP7 has surgical uses and is marketed under the brand name OP1 (sold by Olympus, who bought it from Stryker). It can be used to aid in the fusion of vertebral bodies to prevent neurologic trauma.[8] Also in the treatment of tibial non-union, frequently in cases where a bone graft has failed.[9] rhBMP-2 is much more widely used clinically because it helps grow bone better than rhBMP-7 and other BMPs.[10]

BMP7 also has the potential for treatment of chronic kidney disease.[11][12] Kidney disease is characterized by derangement of the tubular architecture by both myofibroblast buildup and monocyte infiltration [13] Because endogenous BMP-7 is an inhibitor of the TGF-β signaling cascade that induces fibrosis, the use of exogenous recombinant BMP-7 (rhBMP-7) could be a viable treatment of chronic kidney disease.[4] It is also thought that BMP-7 reverses fibrosis and EMT through reduction in monocyte infiltration into inflamed tissue.[11] On a molecular level, BMP-7 represses inflammation by knocking down the expression of several pro-inflammatory cytokines produced by monocytes.[11] Reducing this inflammatory stress, in turn, reduces the chance of fibrosis.[5]

Regardless of the mechanism of fibrosis or the origin of myofibroblasts, exogenous BMP-7 has been shown to reverse the EMT process and trigger MET.[4] Eventually this restores the healthy epithelial cell population, and normal function of the kidneys in mice.[4] This is pertinent in humans as well, because many diseases stemming from organ fibrosis occur via the EMT process.[5] The epithelial-menenchymal transition is also problematic in cancer metastasis, so the diminution of EMT with recombinant DNA could have great implications in future cancer treatment options.[5]

BMP7 administration has been proposed as a possible treatment for human infertility due to poor response to FSH treatment.[14]

Promotion of brown fat

It was discovered that mice injected with BMP7 increased their production of "good" brown fat cells, while keeping their levels of the normal white fat cells constant. A BMP7 therapy for obesity in humans may be developed as a result.[15][16]

References

  1. ↑ Hahn GV, Cohen RB, Wozney JM, Levitz CL, Shore EM, Zasloff MA, Kaplan FS (November 1992). "A bone morphogenetic protein subfamily: chromosomal localization of human genes for BMP5, BMP6, and BMP7". Genomics. 14 (3): 759–62. doi:10.1016/S0888-7543(05)80181-8. PMID 1427904.
  2. ↑ 2.0 2.1 Chen D, Zhao M, Mundy GR (December 2004). "Bone morphogenetic proteins". Growth Factors. 22 (4): 233–41. doi:10.1080/08977190412331279890. PMID 15621726.
  3. ↑ Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S (August 2001). "Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads". EMBO J. 20 (15): 4132–42. doi:10.1093/emboj/20.15.4132. PMC 149146. PMID 11483516.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Müller GA, Kalluri R (2003). "Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models". Am. J. Physiol. Renal Physiol. 285 (6): F1060–7. doi:10.1152/ajprenal.00191.2002. PMID 12915382.
  5. ↑ 5.0 5.1 5.2 5.3 Kalluri R, Weinberg RA (2009). "The basics of epithelial-mesenchymal transition". J. Clin. Invest. 119 (6): 1420–8. doi:10.1172/JCI39104. PMC 2689101. PMID 19487818.
  6. ↑ Wang SN, Lapage J, Hirschberg R (2001). "Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy". J. Am. Soc. Nephrol. 12 (11): 2392–9. PMID 11675415.
  7. ↑ Myers DC, Sepich DS, Solnica-Krezel L (March 2002). "Bmp activity gradient regulates convergent extension during zebrafish gastrulation". Dev. Biol. 243 (1): 81–98. doi:10.1006/dbio.2001.0523. PMID 11846479.
  8. ↑ Vaccaro AR, Whang PG, Patel T, Phillips FM, Anderson DG, Albert TJ, Hilibrand AS, Brower RS, Kurd MF, Appannagari A, Patel M, Fischgrund JS (2008). "The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study". Spine J. 8 (3): 457–65. doi:10.1016/j.spinee.2007.03.012. PMID 17588821.
  9. ↑ Zimmermann G, Müller U, Löffler C, Wentzensen A, Moghaddam A (November 2007). "[Therapeutic outcome in tibial pseudarthrosis: bone morphogenetic protein 7 (BMP-7) versus autologous bone grafting for tibial fractures]". Unfallchirurg (in German). 110 (11): 931–8. doi:10.1007/s00113-007-1347-y. PMID 17989951.
  10. ↑ Even J, Eskander M, Kang J (2012). "Bone morphogenetic protein in spine surgery: current and future uses". J Am Acad Orthop Surg. 20 (9): 547–52. doi:10.5435/JAAOS-20-09-547. PMID 22941797.
  11. ↑ 11.0 11.1 11.2 Gould SE, Day M, Jones SS, Dorai H (2002). "BMP-7 regulates chemokine, cytokine, and hemodynamic gene expression in proximal tubule cells". Kidney Int. 61 (1): 51–60. doi:10.1046/j.1523-1755.2002.00103.x. PMID 11786084.
  12. ↑ González EA, Lund RJ, Martin KJ, McCartney JE, Tondravi MM, Sampath TK, Hruska KA (April 2002). "Treatment of a murine model of high-turnover renal osteodystrophy by exogenous BMP-7". Kidney Int. 61 (4): 1322–31. doi:10.1046/j.1523-1755.2002.00258.x. PMID 11918739.
  13. ↑ Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S (2002). "Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function". J. Am. Soc. Nephrol. 13 Suppl 1: S14–21. PMID 11792757.
  14. ↑ Shi J, Yoshino O, Osuga Y, Nishii O, Yano T, Taketani Y (March 2010). "Bone morphogenetic protein 7 (BMP-7) increases the expression of follicle-stimulating hormone (FSH) receptor in human granulosa cells". Fertil. Steril. 93 (4): 1273–9. doi:10.1016/j.fertnstert.2008.11.014. PMID 19108831.
  15. ↑ Jha A (2008-08-21). "Obesity: Scientists identify protein that promotes fat-burning". Science. guardian.co.uk. Retrieved 2008-09-03.
  16. ↑ Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR (August 2008). "New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure". Nature. 454 (7207): 1000–4. doi:10.1038/nature07221. PMC 2745972. PMID 18719589.

Further reading

External links

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