BMP type I receptor inhibition reduces heterotopic ossification
Ectopic ossification often involves the transformation of soft tissue into bone. In this new study, Paul Yu et al. show that inflammation is a key step in disease progression and that a small molecule inhibitor of the disease gene’s protein product is therapeutic, thus offering a potential treatment...
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| Veröffentlicht in: | Nature medicine 2008-12, Vol.14 (12), p.1363-1369 |
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| creator | Yu, Paul B Deng, Donna Y Lai, Carol S Hong, Charles C Cuny, Gregory D Bouxsein, Mary L Hong, Deborah W McManus, Patrick M Katagiri, Takenobu Sachidanandan, Chetana Kamiya, Nobuhiro Fukuda, Tomokazu Mishina, Yuji Peterson, Randall T Bloch, Kenneth D |
| description | Ectopic ossification often involves the transformation of soft tissue into bone. In this new study, Paul Yu
et al.
show that inflammation is a key step in disease progression and that a small molecule inhibitor of the disease gene’s protein product is therapeutic, thus offering a potential treatment for this devastating condition.
Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues
1
,
2
,
3
,
4
and is without known effective treatments. Affected individuals harbor conserved mutations in the
ACVR1
gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2)
5
. Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref.
6
), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling. |
| doi_str_mv | 10.1038/nm.1888 |
| format | Article |
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et al.
show that inflammation is a key step in disease progression and that a small molecule inhibitor of the disease gene’s protein product is therapeutic, thus offering a potential treatment for this devastating condition.
Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues
1
,
2
,
3
,
4
and is without known effective treatments. Affected individuals harbor conserved mutations in the
ACVR1
gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2)
5
. Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref.
6
), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/nm.1888</identifier><identifier>PMID: 19029982</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Adenovirus ; Amino acids ; Animals ; Biomedical and Life Sciences ; Biomedicine ; Bone Morphogenetic Protein Receptors, Type I - antagonists & inhibitors ; Bone Morphogenetic Protein Receptors, Type I - metabolism ; Bone morphogenetic proteins ; Cancer Research ; Care and treatment ; Cell Line ; Cell receptors ; Cellular biology ; Congenital diseases ; Disease Models, Animal ; Gene expression ; Genetic aspects ; Health aspects ; Infectious Diseases ; letter ; Metabolic Diseases ; Mice ; Mice, Inbred C57BL ; Molecular Medicine ; Molecular Structure ; Mutation ; Myositis Ossificans - genetics ; Myositis Ossificans - metabolism ; Myositis Ossificans - pathology ; Neurosciences ; Ossification ; Ossification, Heterotopic - drug therapy ; Ossification, Heterotopic - genetics ; Ossification, Heterotopic - metabolism ; Ossification, Heterotopic - pathology ; Physiological aspects ; Pyrazoles - chemistry ; Pyrazoles - therapeutic use ; Pyrimidines - chemistry ; Pyrimidines - therapeutic use ; Rodents ; Signal transduction ; Signal Transduction - drug effects ; Tissues ; Tomography, X-Ray Computed</subject><ispartof>Nature medicine, 2008-12, Vol.14 (12), p.1363-1369</ispartof><rights>Springer Nature America, Inc. 2008</rights><rights>COPYRIGHT 2008 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Dec 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c732t-270fa1139e09a632f1e777e661f50f2654a10e810f20556bcc01453a77beb65b3</citedby><cites>FETCH-LOGICAL-c732t-270fa1139e09a632f1e777e661f50f2654a10e810f20556bcc01453a77beb65b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,27933,27934</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19029982$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, Paul B</creatorcontrib><creatorcontrib>Deng, Donna Y</creatorcontrib><creatorcontrib>Lai, Carol S</creatorcontrib><creatorcontrib>Hong, Charles C</creatorcontrib><creatorcontrib>Cuny, Gregory D</creatorcontrib><creatorcontrib>Bouxsein, Mary L</creatorcontrib><creatorcontrib>Hong, Deborah W</creatorcontrib><creatorcontrib>McManus, Patrick M</creatorcontrib><creatorcontrib>Katagiri, Takenobu</creatorcontrib><creatorcontrib>Sachidanandan, Chetana</creatorcontrib><creatorcontrib>Kamiya, Nobuhiro</creatorcontrib><creatorcontrib>Fukuda, Tomokazu</creatorcontrib><creatorcontrib>Mishina, Yuji</creatorcontrib><creatorcontrib>Peterson, Randall T</creatorcontrib><creatorcontrib>Bloch, Kenneth D</creatorcontrib><title>BMP type I receptor inhibition reduces heterotopic ossification</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><description>Ectopic ossification often involves the transformation of soft tissue into bone. In this new study, Paul Yu
et al.
show that inflammation is a key step in disease progression and that a small molecule inhibitor of the disease gene’s protein product is therapeutic, thus offering a potential treatment for this devastating condition.
Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues
1
,
2
,
3
,
4
and is without known effective treatments. Affected individuals harbor conserved mutations in the
ACVR1
gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2)
5
. Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref.
6
), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.</description><subject>Adenovirus</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Bone Morphogenetic Protein Receptors, Type I - antagonists & inhibitors</subject><subject>Bone Morphogenetic Protein Receptors, Type I - metabolism</subject><subject>Bone morphogenetic proteins</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Cell Line</subject><subject>Cell receptors</subject><subject>Cellular biology</subject><subject>Congenital diseases</subject><subject>Disease Models, Animal</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Infectious Diseases</subject><subject>letter</subject><subject>Metabolic Diseases</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Molecular Medicine</subject><subject>Molecular Structure</subject><subject>Mutation</subject><subject>Myositis Ossificans - genetics</subject><subject>Myositis Ossificans - metabolism</subject><subject>Myositis Ossificans - pathology</subject><subject>Neurosciences</subject><subject>Ossification</subject><subject>Ossification, Heterotopic - drug therapy</subject><subject>Ossification, Heterotopic - genetics</subject><subject>Ossification, Heterotopic - metabolism</subject><subject>Ossification, Heterotopic - pathology</subject><subject>Physiological aspects</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - therapeutic use</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - therapeutic use</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Tissues</subject><subject>Tomography, X-Ray Computed</subject><issn>1078-8956</issn><issn>1546-170X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkltrFDEUxwdRbK3iN5DBh6oPs-Yyub1UavGyUKl4w7eQSc_spswka5IR--3NsovtlqKSh4Rzfucfzjn_qnqM0QwjKl_6cYallHeqfcxa3mCBvt8tbyRkIxXje9WDlC4QQhQxdb_awwoRpSTZr169_vCxzpcrqOd1BAurHGLt_NJ1LrvgS-x8spDqJWSIIYeVs3VIyfXOmjXwsLrXmyHBo-19UH19--bLyfvm9Ozd_OT4tLGCktwQgXqDMVWAlOGU9BiEEMA57hnqCWetwQgkLm_EGO-sRbhl1AjRQcdZRw-qo43uaupGOLfgczSDXkU3mnipg3F6N-PdUi_CT01ky1smi8CzrUAMPyZIWY8uWRgG4yFMSUtGWyHL54U8_CvJlRStUvyfIEGEI0rbAj69AV6EKfoyL00ILWNhWBSo2UALM4B2vg-lD7sAD6Wd4KF3JXyMVatQK8ladHYLX845jM7eWvBip6AwGX7lhZlS0vPPn_6fPfu2yx5eY5dghrxMYZjW9ki74HYFNhYLRej_rA8jvbax9qNe27iQT65v-4rb-rYAzzdAKim_gHg10ZtavwFF1fYg</recordid><startdate>20081201</startdate><enddate>20081201</enddate><creator>Yu, Paul B</creator><creator>Deng, Donna Y</creator><creator>Lai, Carol S</creator><creator>Hong, Charles C</creator><creator>Cuny, Gregory D</creator><creator>Bouxsein, Mary L</creator><creator>Hong, Deborah W</creator><creator>McManus, Patrick M</creator><creator>Katagiri, Takenobu</creator><creator>Sachidanandan, Chetana</creator><creator>Kamiya, Nobuhiro</creator><creator>Fukuda, Tomokazu</creator><creator>Mishina, Yuji</creator><creator>Peterson, Randall T</creator><creator>Bloch, Kenneth D</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20081201</creationdate><title>BMP type I receptor inhibition reduces heterotopic ossification</title><author>Yu, Paul B ; Deng, Donna Y ; Lai, Carol S ; Hong, Charles C ; Cuny, Gregory D ; Bouxsein, Mary L ; Hong, Deborah W ; McManus, Patrick M ; Katagiri, Takenobu ; Sachidanandan, Chetana ; Kamiya, Nobuhiro ; Fukuda, Tomokazu ; Mishina, Yuji ; Peterson, Randall T ; Bloch, Kenneth D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c732t-270fa1139e09a632f1e777e661f50f2654a10e810f20556bcc01453a77beb65b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adenovirus</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Bone Morphogenetic Protein Receptors, Type I - antagonists & inhibitors</topic><topic>Bone Morphogenetic Protein Receptors, Type I - metabolism</topic><topic>Bone morphogenetic proteins</topic><topic>Cancer Research</topic><topic>Care and treatment</topic><topic>Cell Line</topic><topic>Cell receptors</topic><topic>Cellular biology</topic><topic>Congenital diseases</topic><topic>Disease Models, Animal</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Infectious Diseases</topic><topic>letter</topic><topic>Metabolic Diseases</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Molecular Medicine</topic><topic>Molecular Structure</topic><topic>Mutation</topic><topic>Myositis Ossificans - genetics</topic><topic>Myositis Ossificans - metabolism</topic><topic>Myositis Ossificans - pathology</topic><topic>Neurosciences</topic><topic>Ossification</topic><topic>Ossification, Heterotopic - drug therapy</topic><topic>Ossification, Heterotopic - genetics</topic><topic>Ossification, Heterotopic - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, Paul B</au><au>Deng, Donna Y</au><au>Lai, Carol S</au><au>Hong, Charles C</au><au>Cuny, Gregory D</au><au>Bouxsein, Mary L</au><au>Hong, Deborah W</au><au>McManus, Patrick M</au><au>Katagiri, Takenobu</au><au>Sachidanandan, Chetana</au><au>Kamiya, Nobuhiro</au><au>Fukuda, Tomokazu</au><au>Mishina, Yuji</au><au>Peterson, Randall T</au><au>Bloch, Kenneth D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BMP type I receptor inhibition reduces heterotopic ossification</atitle><jtitle>Nature medicine</jtitle><stitle>Nat Med</stitle><addtitle>Nat Med</addtitle><date>2008-12-01</date><risdate>2008</risdate><volume>14</volume><issue>12</issue><spage>1363</spage><epage>1369</epage><pages>1363-1369</pages><issn>1078-8956</issn><eissn>1546-170X</eissn><abstract>Ectopic ossification often involves the transformation of soft tissue into bone. In this new study, Paul Yu
et al.
show that inflammation is a key step in disease progression and that a small molecule inhibitor of the disease gene’s protein product is therapeutic, thus offering a potential treatment for this devastating condition.
Fibrodysplasia ossificans progressiva (FOP) is a congenital disorder of progressive and widespread postnatal ossification of soft tissues
1
,
2
,
3
,
4
and is without known effective treatments. Affected individuals harbor conserved mutations in the
ACVR1
gene that are thought to cause constitutive activation of the bone morphogenetic protein (BMP) type I receptor, activin receptor-like kinase-2 (ALK2)
5
. Here we show that intramuscular expression in the mouse of an inducible transgene encoding constitutively active ALK2 (caALK2), resulting from a glutamine to aspartic acid change at amino acid position 207, leads to ectopic endochondral bone formation, joint fusion and functional impairment, thus phenocopying key aspects of human FOP. A selective inhibitor of BMP type I receptor kinases, LDN-193189 (ref.
6
), inhibits activation of the BMP signaling effectors SMAD1, SMAD5 and SMAD8 in tissues expressing caALK2 induced by adenovirus specifying Cre (Ad.Cre). This treatment resulted in a reduction in ectopic ossification and functional impairment. In contrast to localized induction of caALK2 by Ad.Cre (which entails inflammation), global postnatal expression of caALK2 (induced without the use of Ad.Cre and thus without inflammation) does not lead to ectopic ossification. However, if in this context an inflammatory stimulus was provided with a control adenovirus, ectopic bone formation was induced. Like LDN-193189, corticosteroid inhibits ossification in Ad.Cre-injected mutant mice, suggesting caALK2 expression and an inflammatory milieu are both required for the development of ectopic ossification in this model. These results support the role of dysregulated ALK2 kinase activity in the pathogenesis of FOP and suggest that small molecule inhibition of BMP type I receptor activity may be useful in treating FOP and heterotopic ossification syndromes associated with excessive BMP signaling.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>19029982</pmid><doi>10.1038/nm.1888</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Nature medicine, 2008-12, Vol.14 (12), p.1363-1369 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2846458 |
| source | MEDLINE; Nature Journals Online; Alma/SFX Local Collection |
| subjects | Adenovirus Amino acids Animals Biomedical and Life Sciences Biomedicine Bone Morphogenetic Protein Receptors, Type I - antagonists & inhibitors Bone Morphogenetic Protein Receptors, Type I - metabolism Bone morphogenetic proteins Cancer Research Care and treatment Cell Line Cell receptors Cellular biology Congenital diseases Disease Models, Animal Gene expression Genetic aspects Health aspects Infectious Diseases letter Metabolic Diseases Mice Mice, Inbred C57BL Molecular Medicine Molecular Structure Mutation Myositis Ossificans - genetics Myositis Ossificans - metabolism Myositis Ossificans - pathology Neurosciences Ossification Ossification, Heterotopic - drug therapy Ossification, Heterotopic - genetics Ossification, Heterotopic - metabolism Ossification, Heterotopic - pathology Physiological aspects Pyrazoles - chemistry Pyrazoles - therapeutic use Pyrimidines - chemistry Pyrimidines - therapeutic use Rodents Signal transduction Signal Transduction - drug effects Tissues Tomography, X-Ray Computed |
| title | BMP type I receptor inhibition reduces heterotopic ossification |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-02T20%3A46%3A02IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=BMP%20type%20I%20receptor%20inhibition%20reduces%20heterotopic%20ossification&rft.jtitle=Nature%20medicine&rft.au=Yu,%20Paul%20B&rft.date=2008-12-01&rft.volume=14&rft.issue=12&rft.spage=1363&rft.epage=1369&rft.pages=1363-1369&rft.issn=1078-8956&rft.eissn=1546-170X&rft_id=info:doi/10.1038/nm.1888&rft_dat=%3Cgale_pubme%3EA194904824%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=223113517&rft_id=info:pmid/19029982&rft_galeid=A194904824&rfr_iscdi=true |