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Sclerostin Antibody Augments the Anabolic Bone Formation Response in a Mouse Model of Mechanical Tibial Loading
ABSTRACT Decreased activity or expression of sclerostin, an endogenous inhibitor of Wnt/β‐catenin signaling, results in increased bone formation and mass. Antibodies targeting and neutralizing sclerostin (Scl‐Ab) have been shown to increase bone mass and reduce fracture risk. Sclerostin is also impo...
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Published in: | Journal of bone and mineral research 2018-03, Vol.33 (3), p.486-498 |
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description | ABSTRACT
Decreased activity or expression of sclerostin, an endogenous inhibitor of Wnt/β‐catenin signaling, results in increased bone formation and mass. Antibodies targeting and neutralizing sclerostin (Scl‐Ab) have been shown to increase bone mass and reduce fracture risk. Sclerostin is also important in modulating the response of bone to changes in its biomechanical environment. However, the effects of Scl‐Ab on mechanotransduction are unclear, and it was speculated that the loading response may be altered for individuals receiving Scl‐Ab therapy. To address this, we carried out a 2‐week study of tibial cyclic compressive loading on C57Bl/6 mice treated with vehicle or 100 mg/kg/wk Scl‐Ab. Increases in bone volume, density, and dynamic bone formation were found with loading, and the anabolic response was further increased by the combination of load and Scl‐Ab. To investigate the underlying mechanism, gene profiling by RNA sequencing (RNAseq) was performed on tibias isolated from mice from all four experimental groups. Major alterations in Wnt/β‐catenin gene expression were found with tibial loading, however not with Scl‐Ab treatment alone. Notably, the combination of load and Scl‐Ab elicited a synergistic response from a number of specific Wnt‐related and mechanotransduction factors. An unexpected finding was significant upregulation of factors in the Rho GTPase signaling pathway with combination treatment. In summary, combination therapy had a more profound anabolic response than either Scl‐Ab or loading treatment alone. The Wnt/β‐catenin and Rho GTPase pathways were implicated within bone mechanotransduction and support the concept that bone mechanotransduction is likely to encompass a number of interconnected signaling pathways. © 2017 American Society for Bone and Mineral Research. |
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Decreased activity or expression of sclerostin, an endogenous inhibitor of Wnt/β‐catenin signaling, results in increased bone formation and mass. Antibodies targeting and neutralizing sclerostin (Scl‐Ab) have been shown to increase bone mass and reduce fracture risk. Sclerostin is also important in modulating the response of bone to changes in its biomechanical environment. However, the effects of Scl‐Ab on mechanotransduction are unclear, and it was speculated that the loading response may be altered for individuals receiving Scl‐Ab therapy. To address this, we carried out a 2‐week study of tibial cyclic compressive loading on C57Bl/6 mice treated with vehicle or 100 mg/kg/wk Scl‐Ab. Increases in bone volume, density, and dynamic bone formation were found with loading, and the anabolic response was further increased by the combination of load and Scl‐Ab. To investigate the underlying mechanism, gene profiling by RNA sequencing (RNAseq) was performed on tibias isolated from mice from all four experimental groups. Major alterations in Wnt/β‐catenin gene expression were found with tibial loading, however not with Scl‐Ab treatment alone. Notably, the combination of load and Scl‐Ab elicited a synergistic response from a number of specific Wnt‐related and mechanotransduction factors. An unexpected finding was significant upregulation of factors in the Rho GTPase signaling pathway with combination treatment. In summary, combination therapy had a more profound anabolic response than either Scl‐Ab or loading treatment alone. The Wnt/β‐catenin and Rho GTPase pathways were implicated within bone mechanotransduction and support the concept that bone mechanotransduction is likely to encompass a number of interconnected signaling pathways. © 2017 American Society for Bone and Mineral Research.</description><identifier>ISSN: 0884-0431</identifier><identifier>EISSN: 1523-4681</identifier><identifier>DOI: 10.1002/jbmr.3330</identifier><identifier>PMID: 29090474</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>ANABOLICS ; Bone density ; Bone growth ; Bone mass ; BONE QCT/µCT ; Catenin ; Gene expression ; Guanosine triphosphatases ; Mechanical loading ; Mechanotransduction ; Osteogenesis ; PRECLINICAL STUDIES ; Ribonucleic acid ; RNA ; Signal transduction ; SOST protein ; THERAPEUTICS ; Wnt protein ; WNT/β‐CATENIN/LRPS</subject><ispartof>Journal of bone and mineral research, 2018-03, Vol.33 (3), p.486-498</ispartof><rights>2017 American Society for Bone and Mineral Research</rights><rights>2017 American Society for Bone and Mineral Research.</rights><rights>2018 American Society for Bone and Mineral Research</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3880-7ee36c7db59c55f6d22f82cff3f8eb525985e2a50439ded731e8e29669fc46c03</citedby><cites>FETCH-LOGICAL-c3880-7ee36c7db59c55f6d22f82cff3f8eb525985e2a50439ded731e8e29669fc46c03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29090474$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morse, Alyson</creatorcontrib><creatorcontrib>Schindeler, Aaron</creatorcontrib><creatorcontrib>McDonald, Michelle M</creatorcontrib><creatorcontrib>Kneissel, Michaela</creatorcontrib><creatorcontrib>Kramer, Ina</creatorcontrib><creatorcontrib>Little, David G</creatorcontrib><title>Sclerostin Antibody Augments the Anabolic Bone Formation Response in a Mouse Model of Mechanical Tibial Loading</title><title>Journal of bone and mineral research</title><addtitle>J Bone Miner Res</addtitle><description>ABSTRACT
Decreased activity or expression of sclerostin, an endogenous inhibitor of Wnt/β‐catenin signaling, results in increased bone formation and mass. Antibodies targeting and neutralizing sclerostin (Scl‐Ab) have been shown to increase bone mass and reduce fracture risk. Sclerostin is also important in modulating the response of bone to changes in its biomechanical environment. However, the effects of Scl‐Ab on mechanotransduction are unclear, and it was speculated that the loading response may be altered for individuals receiving Scl‐Ab therapy. To address this, we carried out a 2‐week study of tibial cyclic compressive loading on C57Bl/6 mice treated with vehicle or 100 mg/kg/wk Scl‐Ab. Increases in bone volume, density, and dynamic bone formation were found with loading, and the anabolic response was further increased by the combination of load and Scl‐Ab. To investigate the underlying mechanism, gene profiling by RNA sequencing (RNAseq) was performed on tibias isolated from mice from all four experimental groups. Major alterations in Wnt/β‐catenin gene expression were found with tibial loading, however not with Scl‐Ab treatment alone. Notably, the combination of load and Scl‐Ab elicited a synergistic response from a number of specific Wnt‐related and mechanotransduction factors. An unexpected finding was significant upregulation of factors in the Rho GTPase signaling pathway with combination treatment. In summary, combination therapy had a more profound anabolic response than either Scl‐Ab or loading treatment alone. The Wnt/β‐catenin and Rho GTPase pathways were implicated within bone mechanotransduction and support the concept that bone mechanotransduction is likely to encompass a number of interconnected signaling pathways. © 2017 American Society for Bone and Mineral Research.</description><subject>ANABOLICS</subject><subject>Bone density</subject><subject>Bone growth</subject><subject>Bone mass</subject><subject>BONE QCT/µCT</subject><subject>Catenin</subject><subject>Gene expression</subject><subject>Guanosine triphosphatases</subject><subject>Mechanical loading</subject><subject>Mechanotransduction</subject><subject>Osteogenesis</subject><subject>PRECLINICAL STUDIES</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Signal transduction</subject><subject>SOST protein</subject><subject>THERAPEUTICS</subject><subject>Wnt protein</subject><subject>WNT/β‐CATENIN/LRPS</subject><issn>0884-0431</issn><issn>1523-4681</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kU9PGzEQxS3UqqShB75AZamX9rDBf9aO95hE0IISVaL0bHm9Y3C0a6frXVX59jgEOCBxmtHoN08z7yF0TsmMEsIutnXXzzjn5ARNqGC8KKWiH9CEKFUWpOT0FH1OaUsIkULKT-iUVaQi5bycoPjHttDHNPiAF2HwdWz2eDHedxCGhIcHyFNTx9ZbvIwB8FXsOzP4GPAtpF0MCXDeNHgTx9xuYgMtjg5vwD6Y4K1p8Z2vfS7raBof7s_QR2faBF-e6xT9vbq8W_0q1r9_Xq8W68JypUgxB-DSzptaVFYIJxvGnGLWOe4U1IKJSglgRuTnqgaaOaeggFVSVs6W0hI-Rd-Purs-_hshDbrzyULbmgD5VE0roUQpBC0z-u0Nuo1jH_J1mhFKVLZMqkz9OFI2u5V6cHrX-870e02JPqSgDynoQwqZ_fqsONYdNK_ki-0ZuDgC_30L-_eV9M1yc_sk-QjrXZEb</recordid><startdate>201803</startdate><enddate>201803</enddate><creator>Morse, Alyson</creator><creator>Schindeler, Aaron</creator><creator>McDonald, Michelle M</creator><creator>Kneissel, Michaela</creator><creator>Kramer, Ina</creator><creator>Little, David G</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TS</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201803</creationdate><title>Sclerostin Antibody Augments the Anabolic Bone Formation Response in a Mouse Model of Mechanical Tibial Loading</title><author>Morse, Alyson ; Schindeler, Aaron ; McDonald, Michelle M ; Kneissel, Michaela ; Kramer, Ina ; Little, David G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3880-7ee36c7db59c55f6d22f82cff3f8eb525985e2a50439ded731e8e29669fc46c03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>ANABOLICS</topic><topic>Bone density</topic><topic>Bone growth</topic><topic>Bone mass</topic><topic>BONE QCT/µCT</topic><topic>Catenin</topic><topic>Gene expression</topic><topic>Guanosine triphosphatases</topic><topic>Mechanical loading</topic><topic>Mechanotransduction</topic><topic>Osteogenesis</topic><topic>PRECLINICAL STUDIES</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Signal transduction</topic><topic>SOST protein</topic><topic>THERAPEUTICS</topic><topic>Wnt protein</topic><topic>WNT/β‐CATENIN/LRPS</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Morse, Alyson</creatorcontrib><creatorcontrib>Schindeler, Aaron</creatorcontrib><creatorcontrib>McDonald, Michelle M</creatorcontrib><creatorcontrib>Kneissel, Michaela</creatorcontrib><creatorcontrib>Kramer, Ina</creatorcontrib><creatorcontrib>Little, David G</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Physical Education Index</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of bone and mineral research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morse, Alyson</au><au>Schindeler, Aaron</au><au>McDonald, Michelle M</au><au>Kneissel, Michaela</au><au>Kramer, Ina</au><au>Little, David G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sclerostin Antibody Augments the Anabolic Bone Formation Response in a Mouse Model of Mechanical Tibial Loading</atitle><jtitle>Journal of bone and mineral research</jtitle><addtitle>J Bone Miner Res</addtitle><date>2018-03</date><risdate>2018</risdate><volume>33</volume><issue>3</issue><spage>486</spage><epage>498</epage><pages>486-498</pages><issn>0884-0431</issn><eissn>1523-4681</eissn><abstract>ABSTRACT
Decreased activity or expression of sclerostin, an endogenous inhibitor of Wnt/β‐catenin signaling, results in increased bone formation and mass. Antibodies targeting and neutralizing sclerostin (Scl‐Ab) have been shown to increase bone mass and reduce fracture risk. Sclerostin is also important in modulating the response of bone to changes in its biomechanical environment. However, the effects of Scl‐Ab on mechanotransduction are unclear, and it was speculated that the loading response may be altered for individuals receiving Scl‐Ab therapy. To address this, we carried out a 2‐week study of tibial cyclic compressive loading on C57Bl/6 mice treated with vehicle or 100 mg/kg/wk Scl‐Ab. Increases in bone volume, density, and dynamic bone formation were found with loading, and the anabolic response was further increased by the combination of load and Scl‐Ab. To investigate the underlying mechanism, gene profiling by RNA sequencing (RNAseq) was performed on tibias isolated from mice from all four experimental groups. Major alterations in Wnt/β‐catenin gene expression were found with tibial loading, however not with Scl‐Ab treatment alone. Notably, the combination of load and Scl‐Ab elicited a synergistic response from a number of specific Wnt‐related and mechanotransduction factors. An unexpected finding was significant upregulation of factors in the Rho GTPase signaling pathway with combination treatment. In summary, combination therapy had a more profound anabolic response than either Scl‐Ab or loading treatment alone. The Wnt/β‐catenin and Rho GTPase pathways were implicated within bone mechanotransduction and support the concept that bone mechanotransduction is likely to encompass a number of interconnected signaling pathways. © 2017 American Society for Bone and Mineral Research.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>29090474</pmid><doi>10.1002/jbmr.3330</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | ANABOLICS Bone density Bone growth Bone mass BONE QCT/µCT Catenin Gene expression Guanosine triphosphatases Mechanical loading Mechanotransduction Osteogenesis PRECLINICAL STUDIES Ribonucleic acid RNA Signal transduction SOST protein THERAPEUTICS Wnt protein WNT/β‐CATENIN/LRPS |
title | Sclerostin Antibody Augments the Anabolic Bone Formation Response in a Mouse Model of Mechanical Tibial Loading |
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