RAP-011 augments callus formation in closed fractures in rats
ABSTRACT ACE‐011 is a bone anabolic agent generated by fusing the extracellular domain of the Activin Type 2A receptor (ActRIIA) to an IgG‐Fc. The orthopedic utility of ACE‐011 was investigated using a murine analogue, RAP‐011. Initially, a rat closed fracture model was tested using bi‐weekly (biw)...
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| Veröffentlicht in: | Journal of orthopaedic research 2016-02, Vol.34 (2), p.320-330 |
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| container_title | Journal of orthopaedic research |
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| creator | Morse, Alyson Cheng, Tegan L. Peacock, Lauren Mikulec, Kathy Little, David G. Schindeler, Aaron |
| description | ABSTRACT
ACE‐011 is a bone anabolic agent generated by fusing the extracellular domain of the Activin Type 2A receptor (ActRIIA) to an IgG‐Fc. The orthopedic utility of ACE‐011 was investigated using a murine analogue, RAP‐011. Initially, a rat closed fracture model was tested using bi‐weekly (biw) 10 mg/kg RAP‐011. RAP‐011 significantly increased callus length and callus bone volume (BV, +43% at 6w, p |
| doi_str_mv | 10.1002/jor.22985 |
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ACE‐011 is a bone anabolic agent generated by fusing the extracellular domain of the Activin Type 2A receptor (ActRIIA) to an IgG‐Fc. The orthopedic utility of ACE‐011 was investigated using a murine analogue, RAP‐011. Initially, a rat closed fracture model was tested using bi‐weekly (biw) 10 mg/kg RAP‐011. RAP‐011 significantly increased callus length and callus bone volume (BV, +43% at 6w, p < 0.01). The polar moment of inertia was calculated to be substantively increased (+80%, p < 0.01), however mechanical bending tests showed a more modest increase in maximum load to failure (+24%, p < 0.05). Histology indicated enhanced appositional bone growth, but it was hypothesized that reduced remodeling, evidenced by decreased serum CTX (−16% at 6w, p < 0.01), could be compromising bone quality in the callus. A second closed fracture study was performed to examine lower “pulse” [RAP‐011(p)] and “sustained” [RAP‐011(s)] regimens of biw 0.6mg/kg × 2, 0.35mg/kg × 3 and 0.18mg/kg × 2, 0.1mg/kg × 7 respectively, compared with PTH(1–34) (25 μg/kg/d) and vehicle controls. RAP‐011 treatments gave modest increases in callus length and callus BV at 6w (p < 0.01), but did not achieve an increase in maximum load over vehicle. In summary, RAP‐011 is effective in promoting bone formation during repair, but optimizing callus bone quality will require further investigation. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:320–330, 2016.</description><identifier>ISSN: 0736-0266</identifier><identifier>EISSN: 1554-527X</identifier><identifier>DOI: 10.1002/jor.22985</identifier><identifier>PMID: 26185108</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>activin ; Animals ; Biomechanical Phenomena ; bone ; bone formation ; Bony Callus - drug effects ; Drug Evaluation, Preclinical ; fracture ; Fractures, Bone - drug therapy ; Male ; orthopedics ; Rats, Wistar ; Recombinant Fusion Proteins - pharmacology ; Recombinant Fusion Proteins - therapeutic use</subject><ispartof>Journal of orthopaedic research, 2016-02, Vol.34 (2), p.320-330</ispartof><rights>2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4685-ef4177dcb0f3114986e9baf244eb04cf2088a477e38df95f3d0f47268e1831603</citedby><cites>FETCH-LOGICAL-c4685-ef4177dcb0f3114986e9baf244eb04cf2088a477e38df95f3d0f47268e1831603</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjor.22985$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjor.22985$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,778,782,1414,1430,27907,27908,45557,45558,46392,46816</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26185108$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morse, Alyson</creatorcontrib><creatorcontrib>Cheng, Tegan L.</creatorcontrib><creatorcontrib>Peacock, Lauren</creatorcontrib><creatorcontrib>Mikulec, Kathy</creatorcontrib><creatorcontrib>Little, David G.</creatorcontrib><creatorcontrib>Schindeler, Aaron</creatorcontrib><title>RAP-011 augments callus formation in closed fractures in rats</title><title>Journal of orthopaedic research</title><addtitle>J. Orthop. Res</addtitle><description>ABSTRACT
ACE‐011 is a bone anabolic agent generated by fusing the extracellular domain of the Activin Type 2A receptor (ActRIIA) to an IgG‐Fc. The orthopedic utility of ACE‐011 was investigated using a murine analogue, RAP‐011. Initially, a rat closed fracture model was tested using bi‐weekly (biw) 10 mg/kg RAP‐011. RAP‐011 significantly increased callus length and callus bone volume (BV, +43% at 6w, p < 0.01). The polar moment of inertia was calculated to be substantively increased (+80%, p < 0.01), however mechanical bending tests showed a more modest increase in maximum load to failure (+24%, p < 0.05). Histology indicated enhanced appositional bone growth, but it was hypothesized that reduced remodeling, evidenced by decreased serum CTX (−16% at 6w, p < 0.01), could be compromising bone quality in the callus. A second closed fracture study was performed to examine lower “pulse” [RAP‐011(p)] and “sustained” [RAP‐011(s)] regimens of biw 0.6mg/kg × 2, 0.35mg/kg × 3 and 0.18mg/kg × 2, 0.1mg/kg × 7 respectively, compared with PTH(1–34) (25 μg/kg/d) and vehicle controls. RAP‐011 treatments gave modest increases in callus length and callus BV at 6w (p < 0.01), but did not achieve an increase in maximum load over vehicle. In summary, RAP‐011 is effective in promoting bone formation during repair, but optimizing callus bone quality will require further investigation. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:320–330, 2016.</description><subject>activin</subject><subject>Animals</subject><subject>Biomechanical Phenomena</subject><subject>bone</subject><subject>bone formation</subject><subject>Bony Callus - drug effects</subject><subject>Drug Evaluation, Preclinical</subject><subject>fracture</subject><subject>Fractures, Bone - drug therapy</subject><subject>Male</subject><subject>orthopedics</subject><subject>Rats, Wistar</subject><subject>Recombinant Fusion Proteins - pharmacology</subject><subject>Recombinant Fusion Proteins - therapeutic use</subject><issn>0736-0266</issn><issn>1554-527X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kDtPwzAURi0EglIY-AMoIwxpr9_OwEArKC8BqniJxXISGwWSptiJgH9PSwob05WuzneGg9AehgEGIMPX2g8ISRRfQz3MOYs5kU_rqAeSihiIEFtoO4RXAJCYqE20RQRWHIPqoaPp8W0MGEemfansrAlRZsqyDZGrfWWaop5FxSzKyjrYPHLeZE3rbVj-vGnCDtpwpgx2d3X76P705G58Fl_dTM7Hx1dxxoTisXUMS5lnKTiKMUuUsElqHGHMpsAyR0Apw6S0VOUu4Y7m4JgkQlmsKBZA--ig8859_d7a0OiqCJktSzOzdRs0lgISSrgUC_SwQzNfh-Ct03NfVMZ_aQx6WUsvaumfWgt2f6Vt08rmf-RvngUw7ICPorRf_5v0xc30Vxl3iyI09vNvYfybFpJKrh-vJ_p5dPn4AKOpZvQbqiiBKw</recordid><startdate>201602</startdate><enddate>201602</enddate><creator>Morse, Alyson</creator><creator>Cheng, Tegan L.</creator><creator>Peacock, Lauren</creator><creator>Mikulec, Kathy</creator><creator>Little, David G.</creator><creator>Schindeler, Aaron</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><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>7X8</scope></search><sort><creationdate>201602</creationdate><title>RAP-011 augments callus formation in closed fractures in rats</title><author>Morse, Alyson ; Cheng, Tegan L. ; Peacock, Lauren ; Mikulec, Kathy ; Little, David G. ; Schindeler, Aaron</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4685-ef4177dcb0f3114986e9baf244eb04cf2088a477e38df95f3d0f47268e1831603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>activin</topic><topic>Animals</topic><topic>Biomechanical Phenomena</topic><topic>bone</topic><topic>bone formation</topic><topic>Bony Callus - drug effects</topic><topic>Drug Evaluation, Preclinical</topic><topic>fracture</topic><topic>Fractures, Bone - drug therapy</topic><topic>Male</topic><topic>orthopedics</topic><topic>Rats, Wistar</topic><topic>Recombinant Fusion Proteins - pharmacology</topic><topic>Recombinant Fusion Proteins - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Morse, Alyson</creatorcontrib><creatorcontrib>Cheng, Tegan L.</creatorcontrib><creatorcontrib>Peacock, Lauren</creatorcontrib><creatorcontrib>Mikulec, Kathy</creatorcontrib><creatorcontrib>Little, David G.</creatorcontrib><creatorcontrib>Schindeler, Aaron</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of orthopaedic research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morse, Alyson</au><au>Cheng, Tegan L.</au><au>Peacock, Lauren</au><au>Mikulec, Kathy</au><au>Little, David G.</au><au>Schindeler, Aaron</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RAP-011 augments callus formation in closed fractures in rats</atitle><jtitle>Journal of orthopaedic research</jtitle><addtitle>J. Orthop. Res</addtitle><date>2016-02</date><risdate>2016</risdate><volume>34</volume><issue>2</issue><spage>320</spage><epage>330</epage><pages>320-330</pages><issn>0736-0266</issn><eissn>1554-527X</eissn><abstract>ABSTRACT
ACE‐011 is a bone anabolic agent generated by fusing the extracellular domain of the Activin Type 2A receptor (ActRIIA) to an IgG‐Fc. The orthopedic utility of ACE‐011 was investigated using a murine analogue, RAP‐011. Initially, a rat closed fracture model was tested using bi‐weekly (biw) 10 mg/kg RAP‐011. RAP‐011 significantly increased callus length and callus bone volume (BV, +43% at 6w, p < 0.01). The polar moment of inertia was calculated to be substantively increased (+80%, p < 0.01), however mechanical bending tests showed a more modest increase in maximum load to failure (+24%, p < 0.05). Histology indicated enhanced appositional bone growth, but it was hypothesized that reduced remodeling, evidenced by decreased serum CTX (−16% at 6w, p < 0.01), could be compromising bone quality in the callus. A second closed fracture study was performed to examine lower “pulse” [RAP‐011(p)] and “sustained” [RAP‐011(s)] regimens of biw 0.6mg/kg × 2, 0.35mg/kg × 3 and 0.18mg/kg × 2, 0.1mg/kg × 7 respectively, compared with PTH(1–34) (25 μg/kg/d) and vehicle controls. RAP‐011 treatments gave modest increases in callus length and callus BV at 6w (p < 0.01), but did not achieve an increase in maximum load over vehicle. In summary, RAP‐011 is effective in promoting bone formation during repair, but optimizing callus bone quality will require further investigation. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:320–330, 2016.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>26185108</pmid><doi>10.1002/jor.22985</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | activin Animals Biomechanical Phenomena bone bone formation Bony Callus - drug effects Drug Evaluation, Preclinical fracture Fractures, Bone - drug therapy Male orthopedics Rats, Wistar Recombinant Fusion Proteins - pharmacology Recombinant Fusion Proteins - therapeutic use |
| title | RAP-011 augments callus formation in closed fractures in rats |
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